|Year : 2018 | Volume
| Issue : 3 | Page : 373-385
Cerebral ischemia and neuroregeneration
Reggie H. C. Lee1, Michelle H. H. Lee2, Celeste Y. C. Wu1, Alexandre Couto e Silva3, Harlee E Possoit1, Tsung-Han Hsieh1, Alireza Minagar4, Hung Wen Lin5
1 Department of Neurology, Louisiana State University Health Science Center; Center for Brain Health, Louisiana State University Health Science Center, Shreveport, LA, USA
2 Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan, China
3 Department of Cellular Biology and Anatomy, Louisiana State University Health Science Center, Shreveport, LA, USA
4 Department of Neurology, Louisiana State University Health Science Center, Shreveport, LA, USA
5 Department of Neurology, Louisiana State University Health Science Center; Center for Brain Health, Louisiana State University Health Science Center; Department of Cellular Biology and Anatomy, Louisiana State University Health Science Center, Shreveport, LA, USA; Cardiovascular and Metabolomics Research Center, Hualien Tzu Chi Hospital, Hualien, Taiwan, China
|Date of Acceptance||01-Feb-2018|
|Date of Web Publication||4-Apr-2018|
Hung Wen Lin
Department of Neurology, Louisiana State University Health Science Center; Center for Brain Health, Louisiana State University Health Science Center; Department of Cellular Biology and Anatomy, Louisiana State University Health Science Center, Shreveport, LA; Cardiovascular and Metabolomics Research Center, Hualien Tzu Chi Hospital, Hualien, Taiwan, China
Source of Support: This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke grant 1R01NS096225-01A1, the American Heart Association grants AHA-13SDG1395001413, AHA-17GRNT33660336, AHA-17POST33660174, the Louisiana State University Grant in Aid research council, and The Malcolm Feist Cardiovascular Research Fellowship, Conflict of Interest: None
Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke (a form of cerebral ischemia)-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics (i.e., tissue plasminogen activator) and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies against stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism(s) underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies (i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells) as it relates to cerebral ischemia.
Keywords: cerebral ischemia; melatonin; resveratrol; protein kinase C; pifithrin-α; fatty acids; sympathetic nervous system; neuromodulation therapy; traditional Chinese therapies; stem cell
|How to cite this article:|
Lee RH, Lee MH, Wu CY, Couto e Silva A, Possoit HE, Hsieh TH, Minagar A, Lin HW. Cerebral ischemia and neuroregeneration. Neural Regen Res 2018;13:373-85
|How to cite this URL:|
Lee RH, Lee MH, Wu CY, Couto e Silva A, Possoit HE, Hsieh TH, Minagar A, Lin HW. Cerebral ischemia and neuroregeneration. Neural Regen Res [serial online] 2018 [cited 2020 Oct 23];13:373-85. Available from: http://www.nrronline.org/text.asp?2018/13/3/373/228711
Reggie H. C. Lee, Michelle H. H. Lee. These authors contributed
equally to this work.
| Introduction|| |
Stroke (a form of cerebral ischemia) remains the fifth leading cause of death and disability in the United States. A first or recurrent stroke occurs every 40 seconds, which affects approximately 800,000 people per year (Go et al., 2014). Stroke occurs when blood vessel(s) are interrupted by a blood clot/thrombus or when blood vessel(s) rupture (i.e., hemorrhage) due to arteriovenous malformations or aneurysms. Since the brain is one of the most high-energy consuming organs, the lack of oxygen and nutrient supply elicited by stroke can cause severe brain damage resulting in neurological disorders.
Stroke can be classified into two categories: ischemic (87% of the population) and hemorrhagic stroke (23% of the population) (Ovbiagele and Nguyen-Huynh, 2011). Ischemic stroke is characterized by vascular thrombus formation, interruption of blood supply to the brain, which causes neuronal cell death and neurological deficits, such as learning/memory and locomotor deficiencies (Janardhan and Qureshi, 2004; Li et al., 2013). The middle cerebral artery, the largest branch of the internal carotid artery, is a prevalent site for ischemic stroke, which provides oxygen and nutrient supply to the primary motor, sensory, and speech areas of the brain including the frontal and the lateral surface of the temporal and parietal lobes. Thus, patients with middle cerebral artery occlusions suffer from hemiparesis or monoparesis, hemisensory and visual deficits, dysarthria, and ataxia (Gautier and Pullicino, 1985; No authors listed, 1990).
Another common type of ischemic stroke is transient ischemic attack (TIA or mini-stroke). TIA is characterized by a temporary blockage of cerebral blood flow (CBF), caused by the formation of blood clots and/or atherosclerotic plaques, damaging inner walls of brain vasculature (Eliasziw et al., 2004; Ovbiagele et al., 2008; Coutts, 2017). This form of ischemic stroke does not cause permanent brain damage due to the acute (minutes to hours) nature of the ischemia. However, One-third of TIA patients are expected to have an ischemic stroke within a year indicating that post-TIA care/treatment is paramount to favorable outcomes (Amarenco et al., 2016).
Hemorrhagic stroke is characterized by an aneurysm, arteriovenous malformation, or weakening of blood vessel walls causing rupture in the brain. Untreated hypertension and aging blood vessels are the major risk factors for hemorrhagic stroke. In fact, if hypertension is not properly controlled, patients are 10 times more likely to develop hemorrhagic stroke as compared to normotensive patients (Semple, 1995). An added consequence of hemorrhagic stroke is the elevation of intracranial pressure causing severe brain damage leading to high morbidity and mortality (van Asch et al., 2010; Keep et al., 2012). Hemorrhagic strokes can be further classified into two subtypes: intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) (Grysiewicz et al., 2008; Caceres and Goldstein, 2012). ICH occurs in the brain parenchyma, while SAH is predominately found between the pial and arachnoid space caused by the rupture of cerebral vessels.
Other non-stroke ischemia-related conditions include global ischemia (i.e., cardiac arrest) and small vessel diseases (SVD). Life-threatening medical conditions, such as cardiac arrest, shock, severe hypotension, and asphyxia, result in insufficient blood supply throughout the entire brain (namely global ischemia) to cause neuronal cell death in the vulnerable CA1 region of the hippocampus and cortex (Kirino, 1982; White et al., 1996; Schaller and Graf, 2004; Nour et al., 2013). Since the neurons in the CA1 region of the hippocampus and cortex play an important role in learning/memory formation, patients with global ischemia suffer severe learning/memory deficits. SVD has been frequently diagnosed in the elderly via neuroimaging (i.e., computed tomography and magnetic resonance imaging scans). The pathological progression of SVD includes small cortical infarctions or hemorrhages, microbleeds, white matter attenuation (leukoaraiosis), Virchow-Robin spaces (enlarged perivascular spaces), and brain atrophy (brain volume loss) (Nitkunan et al., 2011; Wardlaw et al., 2013a, b), which are highly related to vascular dementia, cognitive or motor impairments, and depression (Mok et al., 2004; Pantoni and Gorelick, 2014).
Therapeutic strategies against cerebral ischemia are limited. For example, treatments against hemorrhagic stroke are dependent on surgery (i.e., aneurysm clipping, coil embolization, and arteriovenous malformation repair) to reduce bleeding and intracranial pressure. In terms of ischemic stroke, intravenous thrombolysis with tissue plasminogen activator (tPA) (National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995; Kanazawa et al., 2017) is the only FDA approved therapy for the treatment of acute ischemic stroke (Hacke et al., 2008; Zivin, 2009; Farbu et al., 2011; Cheng and Kim, 2015). However, tPA’s narrow therapeutic time window (within 4.5 hours after the onset of stroke) significantly reduces its’ therapeutic efficacy in the treatment against ischemic stroke. As for treatments against TIA and cardiac arrest, all therapies except hypothermia have failed to reduce neuronal injury. Thus, the goal of the treatments mainly focus on preventing risk factors for TIA and cardiac arrest (i.e., high blood pressure, hyperlipidemia, smoking, and heart disease) indicating that developing novel therapies against cerebral ischemia is greatly needed. We will discuss the mechanisms underlying stroke/cerebral ischemia-induced brain injury as well as current and future novel therapies as it relates to cerebral ischemia.
| Mechanisms Underlying Ischemic Brain Injury|| |
Excitotoxicity and apoptosis/necrosis
Glutamate, the most abundant excitatory neurotransmitter in the brain, is a major contributor to cerebral ischemia-induced excitotoxicity (excitatory amino acids-induced neurotoxicity) and subsequent apoptosis/necrosis (Xu et al., 2001; Lai et al., 2014). Adenine triphosphate (ATP) deficiency (energy failure) and glutamate transporter dysfunction following cerebral ischemia can cause an increase in neuronal excitability and subsequent glutamate release and accumulation in the synaptic cleft (Bosley et al., 1983; Benveniste et al., 1984; Drejer et al., 1985; Hagberg et al., 1985; Silverstein et al., 1986; Dawson et al., 2000). This results in excessive activation of N-methyl-D-aspartate receptors (an ionotropic receptor) to cause massive calcium influx and dyshomeostasis in neurons (Berdichevsky et al., 1983; Jancso et al., 1984). Neuronal calcium overload can further activate calpains (calcium-dependent proteases) to cleave apoptotic regulatory proteins (i.e., caspase family), as a result of lysosome-associated apoptosis and necrosis (Bisset, 1978; Schielke et al., 1998; Yamashima, 2004; Li and Yuan, 2008; Mrschtik and Ryan, 2015).
In addition to glutamate-induced cellular excitotoxicity, cerebral ischemia alone can induce overexpression of the death receptor ligands (i.e., tumor necrosis factor (TNF)-α and FasL), as a result of serine/threonine-protein kinase 1-mediated neuronal necroptosis (Holler et al., 2000; Degterev et al., 2005, 2008). Furthermore, enhanced expression of c-Jun N-terminal kinase (JNK, a stress-activated protein kinase) after cerebral ischemia (Irving and Bamford, 2002; Borsello et al., 2003) can activate Fas- and Bim-mediated pro-apoptotic signals (Herdegen et al., 1998; Putcha et al., 2003; Okuno et al., 2004) leading to neuronal cell death.
Reperfusion injury and neuroinflammation
Reperfusion injury occurs when a tissue/organ encounters deprivation of blood supply followed by a restoration of blood flow to the ischemic area (Nour et al., 2013). Following reperfusion, reoxygenation, however, causes secondary injury (Chen and Nunez, 2010; Eltzschig and Eckle, 2011) due to excessive formation of reactive radical oxide species (ROS) and/or peroxynitrite (Peters et al., 1998; Bolanos and Almeida, 1999; Shen et al., 2003; Vitturi and Patel, 2011; Kietadisorn et al., 2012; Li et al., 2012; Olmez and Ozyurt, 2012; Rodriguez et al., 2013) and activation of the immune system (Eltzschig and Eckle, 2011).
In terms of ischemia induced-neuroinflammation, infiltrating immune cells release inflammatory mediators to recruit multiple immune and glia cells. These immunoreactive cells further limit the extent of the injury and restore tissue integrity (Kumar and Loane, 2012; Xanthos and Sandkuhler, 2014). However, excessive activation of microglia can occur following cerebral ischemia resulting in the release of pro-inflammatory cytokines, such as TNF-α, interleukin (IL)-1β, IL-6, IL-12, and interferon (IFN)γ (Schmidt et al., 2005; Hernandez-Ontiveros et al., 2013), as a result of blood brain barrier leakage (Chodobski et al., 2011). Moreover, pro-inflammatory cytokines increases neurotoxic molecules and free radicals (i.e., ROS), reactive nitrogen species, cyclooxygenase-2, and inducible nitric oxide synthase] to cause secondary neuronal cell death (Qin et al., 2007; Erickson and Banks, 2011; Tremblay et al., 2011; Park et al., 2012; Biesmans et al., 2013; Hernandez-Ontiveros et al., 2013; Kabadi and Faden, 2014).
It is interesting to note that the ischemia-induced neuroinflammation mainly occurs in the non-microbial environment. Thus, the host receptor (i.e., toll-like receptors) can be can be activated via non-microbial ligands, namely damage-associated molecular patterns (Chen and Nunez, 2010; Eltzschig and Eckle, 2011). These damage-associated molecular patterns, such as high-mobility group box1 protein and ATP are released from the cytoplasm upon tissue injury and/or cell death to initiate series of innate immune responses, as a result of excessive production of proinflammatory cytokines/chemokines (Iyer et al., 2009; Chen and Nunez, 2010; McDonald et al., 2010), which causes peroxynitrite- and ROS-mediated lipid peroxidation, DNA damage, and cell dysfunction/death (Garry et al., 2015).
Impaired axonal regeneration
Besides excitotoxicity, apoptosis/necrosis, reperfusion, and neuroinflammation, impaired axonal regeneration is another major contributor to neuronal cell death following cerebral ischemia. One of the major hallmarks of cerebral ischemia is the inherent glial scar formation. Glial scar (a tissue barrier) is formed by reactive astrocytes, microglia, and infiltrating immune cells to protect survival neurons from the harmful environment (i.e., nitric oxide toxicity and glutamate-induced cellular excitotoxicity) (Reier and Houle, 1988; Fitch and Silver, 1997; Rolls et al., 2009; Huang et al., 2014b). These immunoreactive cells are responsible for trophic and metabolic support (i.e., insulin-like growth factors, nerve growth factors, brain-derived neurotrophic factor, and neurotrophin-3), as well as scavenging excessive accumulation of glutamate, potassium, and other ions after cerebral ischemia (Schwartz and Nishiyama, 1994; Wu et al., 1998; do Carmo Cunha et al., 2007; White et al., 2008; Rolls et al., 2009). However, the immunoreactive cells, in particular astrocytes, become hypertrophic and release chondroitin sulfate proteoglycans (an inhibitory extracellular molecule) in response to cerebral ischemia (McKeon et al., 1991), which restricts axonal regeneration and neuronal survival via RhoA/ROCK-mediated pathways (Silver and Miller, 2004; Yiu and He, 2006). In addition to glial scar, myelin (the laminated membrane structure that surrounds the axon) is also responsible for the failure of axonal regeneration. Although myelin has been reported to regulate the axonal cytoskeleton, axon caliber, neurofilament spacing (Yin et al., 1998), and microtubule formation (Hsieh et al., 1994; Nguyen et al., 2009), numerous studies have shown that myelin-associated glycoproteins, such as oligodendrocyte-myelin glycoprotein and nogoA are actually detrimental to axonal regeneration and sprouting after cerebral ischemia (Caroni and Schwab, 1988; McKerracher et al., 1994; Mukhopadhyay et al., 1994).
| Novel Neuroregenerative Agents|| |
A stroke lesion can be classified into the ischemic core and the surrounding penumbra (Yuan, 2009), while the irreversible cell death mainly occurs in the ischemic core area. Thus, most of the studies are targeted to prevent neuronal cell death in the hypoperfused penumbra region. We will discuss current and future novel neuroregenerative agents as it relates to cerebral ischemia in subsequent paragraphs. The clinical evidence for each neuroregenerative agent is summarized in the [Table 1].
Fibroblast growth factors (FGFs)
FGFs are a group of structurally similar polypeptide mitogens, which promote tissue repair, angiogenesis, neurogenesis, axonal growth, embryonic development, and various endocrine signaling pathways. 23 members of FGFs have been isolated (Zechel et al., 2010), while the expression of FGF-2 is significantly increased after various brain injuries including seizures (Riva et al., 1992), transient forebrain ischemia (Takami et al., 1993; Speliotes et al., 1996), and traumatic ischemic brain injury (Christian Alzheimer, 2000-2013). In addition, the FGF-2-deficient mice presented with larger infarct volume (75% more) following experimental brain ischemia, via middle cerebral artery occlusion (MCAO) suggesting that FGF-2 had neuroprotective effects against ischemic brain injury (Kiprianova et al., 2004).
The use of FGF-2 has been implicated in several pre-clinical trials of cerebral ischemia. Administration of FGF-2 in rats has been shown to increase the number of neurons and markers for neurogenesis in the hippocampus and dentate gyrus after MCAO (Bethel et al., 1997; Wagner et al., 1999; Cheng et al., 2002; Wang et al., 2008). Subsequent studies by Leker et al, 2007 and Yoshimura et al, 2001 further indicate that up-regulation of FGF-2 via adeno-associated viral vectors in the infarct area can increase the number of proliferating cells and motor behavior after MCAO (Yoshimura et al., 2001; Leker et al., 2007). Overall, FGF-2 can enhance neural proliferation/differentiation following cerebral ischemia, which may provide future therapeutic opportunities.
Nicotinamide adenine dinucleotide (NAD)
NAD is a coenzyme of vitamin B3 critical for many biochemical reactions including energy production, ion homeostasis, and biosynthesis of glucose and fatty acids (Ying, 2006; Belenky et al., 2007). Numerous studies indicate that NAD+ (oxidized form) depletion and subsequent ATP loss during/after cerebral ischemia result in energy failure and cell death (Jagtap and Szabo, 2005), which suggests that repletion of NAD+ is beneficial in the treatment against cerebral ischemia.
Zhao et al. (2015) found that overexpression of nicotinamide phosphoribosyltransferase (Nampt, the rate-limiting enzyme for NAD+ biosynthesis) enhanced neurogenesis after MCAO in mice. Additionally, post-treatment of nicotinamide mononucleotide (an intermediate of NAD+ biosynthesis) enhanced neuronal survival and neurogenesis after MCAO (Zhao et al., 2015), while intraperitoneal (IP) injection of nicotinamide (a NAD+ precursor) after MCAO enhanced intracellular NAD+ concentration in the brain. NAD+ derivatives reduced infarct volume via sirtuin-1 and sirtuin-2-mediated pathways (Liu et al., 2009; Siegel and McCullough, 2013; Zhao et al., 2015). Overall, the development of novel therapies targeting the Nampt-NAD+ cascade may be valuable against ischemic brain injury.
Melatonin (N-acetyl-5-methoxy tryptamine)
Melatonin, a hormone synthesized and released from the pineal gland, plays a crucial role in the regulation of sleep and wake cycles (Reiter, 1991). Thus, melatonin has been widely used for the treatment of sleep disorders including insomnia, delayed sleep phase syndrome, and rapid eye movement sleep behavior disorder (Laudon and Frydman-Marom, 2014; Tordjman et al., 2017; Xie et al., 2017). Interestingly, recent studies suggest that melatonin provides other non-sleep/wake cycle related pharmacological effects, such as anti-nitric oxide (NO) production, anti-oxyradicals, and anti-peroxynitrite effects (Poeggeler et al., 1994; Pozo et al., 1994; Gilad et al., 1997; Cuzzocrea et al., 2000). Oxyradicals, NO, and peroxynitrite play a crucial role in the pathological progression of neuronal cell death following cerebral ischemia (Beckman et al., 1990; Crow and Beckman, 1995), which suggests that melatonin may provide neuroprotection against cerebral ischemia.
IP injection and/or oral treatment of melatonin has been shown to reduce infarct volume and neuronal cell death (Pei et al., 2003; Kilic et al., 2004; Koh, 2008) after MCAO. Administration of melatonin (via IP) 30 minutes before bilateral common carotid arteries occlusion-induced transient cerebral ischemia alleviates neuronal cell death in the CA1 and CA2 regions of the hippocampus (Kim and Lee, 2014). Mechanisms underlying melatonin-induced neuroprotection after cerebral ischemia are highly complicated and remains to be elucidated. Kilic et al., (2004) reported that melatonin prevents cerebral ischemia-induced brain injury via inhibition of endothelin converting enzyme-1, while others’ suggest that melatonin reduces ischemic brain injury via inhibition of matrix metalloproteinase-9 (Kim and Lee, 2014) or enhanced MEK/ERK/p90RSK/Bad signaling cascade (Koh, 2008). In summary, melatonin may be used to combat cerebral ischemia by inhibition of oxyradicals/peroxynitrite production, endothelin biosynthesis, and promote MEK/ERK-mediated cell proliferation and differentiation.
Resveratrol, 3, 5, 4′-trihydroxy-trans-stilbene, is a poly-phenol found in red wine, grapes, chocolate, and many plants, such as knotweeds and pine trees. Numerous studies have shown that resveratrol has multifactorial effects including anti-inflammation and anti-oxidation, which suggests that the use of resveratrol may provide benefits in the treatment against cerebral ischemia. Many studies conducted in experimental brain ischemia further suggest that administration of resveratrol (0.1 μg/kg to 40 mg/kg) reduced infarct volume following MCAO- and bilateral common carotid artery occlusion-induced cerebral ischemia (Tsai et al., 2007; Dong et al., 2008; Fang et al., 2015; Kizmazoglu et al., 2015; Narayanan et al., 2015; He et al., 2017).
Mechanisms underlying resveratrol-induced neuroprotection against cerebral ischemia are multifactorial. Tsai et al. (2007) reported that resveratrol reduced MCAO-induced infarction by inhibition of inducible nitric oxide synthase (iNOS) production, while upregulation of endothelial nitric oxide synthase (eNOS) expression. Other studies suggest that resveratrol attenuates ischemic brain injury via inhibition of myeloperoxidase levels, pyrin domain-containing 3 inflammasome formation, cerebral TNF-α production, and markers for apoptosis (i.e., Bcl-2, Bax, p53, and annexin V) (Fang et al., 2015; Kizmazoglu et al., 2015; He et al., 2017). Furthermore, resveratrol activates nuclear erythroid 2-related factor 2- and sirtuin-1-mediated pathways to enhance neuronal survival in response to cerebral ischemia (Koronowski et al., 2015; Narayanan et al., 2015) indicating that resveratrol is a potential candidate in the treatment of cerebral ischemia.
Protein kinase C (PKC) isozymes, δPKC and εPKC
Enhanced expression of δPKC after cerebral ischemia (Shimohata et al., 2007b; Dave et al., 2011) can initiate phosphorylation of mitochondrial phospolipid scramblase 3 (PLSCR3) (He et al., 2007), dephosphorylation of Bad, and formation of Bax/Bak pores, as a result of cytochrome c release and mitochondria-mediated apoptosis (Gonzalvez et al., 2005; He et al., 2007; Ghibelli and Diederich, 2010). Subsequent studies by Lin et al. (2012) further suggest that inhibition of δPKC via δPKC specific inhibitor, δV1-1, can alleviate neuronal cell death and CBF derangements, which suggest the neuroprotective effects of δPKC inhibition after cerebral ischemia. Unlike the detrimental role of δPKC in ischemic brain injury, εPKC (another PKC isozyme) expression is actually enhanced during therapeutic hypothermia and ischemic preconditioning, which suggest εPKC’s possible neuroprotective role in ischemic brain injury (Raval et al., 2003; Shimohata et al., 2007a).
The Perez-Pinzon research group further investigated the activation of εPKC following oxygen and glucose deprivation (an in vitro ischemia injury model) can reduce GABAA receptor-mediated excitotoxicity in the hippocampal neurons (DeFazio et al., 2009). Furthermore, pretreatment of specific εPKC activator, ψεRACK, can attenuate CBF derangements and neuronal cell death elicited by asphyxial cardiac arrest (ACA)- and bilateral carotid artery occlusion-induced cerebral ischemia, which suggests that development of novel therapies to inhibit δPKC but activate εPKC may provide potential benefits in the treatment against cerebral ischemia.
Recent studies suggest that the tumor suppressor protein p53-induced apoptosis plays a crucial role in neuronal cell death after cerebral ischemia (Broughton et al., 2009; Hong et al., 2010). Culmsee et al. (2001) thus developed a synthetic p53 inhibitor, PFT-α, to evaluate the therapeutic potentials of p53 inhibition on ischemic brain injury. They found that IP injection of PFT-α 30 minutes before MCAO can reduce neuronal cell death in the CA1 region of the hippocampus, which suggests that the use of PFT-α may have therapeutic potential against cerebral ischemia in the near future. Mechanisms underlying PFT-α-induced neuroprotection after cerebral ischemia remains to be elucidated. Zhang et al. (2016) reported that PFT-α can stimulate angiogenesis and neurogenesis after MCAO, while other studies suggest PFT-α reduces infarct volume and neurological and locomotor deficits via vascular endothelial growth factor-mediated pathways.
| Other Neuroregenerative Factors/Agents|| |
The normal body core temperature is near 37°C in humans, while hypothermia is defined as body core temperature below 35°C. Hypothermia can be a medical emergency if the body temperature falls below 32°C or less, which results in multiple organ failure and even death. However, Busto et al. (1987) first discovered that moderate decrease of brain temperature provides neuroprotection against experimental brain ischemia. In Busto et al’s studies, the rat brain temperature was maintained at 36, 33, or 30°C following four-vessel or bilateral carotid artery occlusion-induced cerebral ischemia. They found that hypothermia treatment (at 33 and 30°C) significantly reduced neuronal metabolic demand and glutamate release, ultimately attenuating neuronal cell death in the CA1 region of the hippocampus after cerebral ischemia (Busto et al., 1987; Dietrich et al., 1993). Busto et al’s landmark findings were further established by a different experimental brain ischemia including MCAO and traumatic brain injury (Morikawa et al., 1992; Dietrich et al., 1994; Kollmar et al., 2007; Li and Wang, 2011) suggesting that hypothermia is actually beneficial in the treatment of general cerebral ischemia.
In addition to experimental brain ischemia, moderate hypothermia has been shown to significantly reduce intracranial pressure, cerebral edema, and neurological deficits in patients with severe middle cerebral artery infarction (Schwab et al., 1998; Els et al., 2006; Hong et al., 2014). Multiple factors are involved in hypothermia-mediated neuroprotection after cerebral ischemia. Hypothermia inhibits glutamate-induced excitotoxicity (Busto et al., 1987; Zhao et al., 2007; Yenari and Han, 2012), while reducing the production of superoxide, peroxynitrite, hydrogen peroxide, and hydroxyl radicals to relieve oxidative stress after cerebral ischemia (Globus et al., 1995; Hall, 1997; Yenari and Han, 2012). Furthermore, hypothermia has also been reported to reduce apoptosis, autophagy, and inflammation (Prakasa Babu et al., 2000; Lee et al., 2016; Jiang et al., 2017), as well as blood-brain barrier leakage and brain metabolism after cerebral ischemia (Busto et al., 1987; Dietrich et al., 1990; Dietrich et al., 1991), which suggests that the use of hypothermia during/after cerebral ischemia provides high therapeutic potential in the treatment of patients with stroke or other central nervous system disorders.
Saturated fatty acids were traditionally considered as a “detrimental” class of fatty acids, which can increase the risk of cardiovascular diseases. Lin et al. (2008, 2014) however, found palmitic acid methyl ester (PAME) released from the sympathetic nervous system is a novel vasodilator and CBF mediator. Since hypoperfusion (decrease in CBF) following cerebral ischemia plays a crucial role in the pathological progression of neuronal cell death and neurological deficits, the vasodilatory properties of PAME suggest its therapeutic potential in the treatment against cerebral ischemia. Subsequent investigations by Lin’s research group further indicate that pre-treatment of PAME increased CBF and neuronal viability after MCAO and ACA (Lin et al., 2014), which suggests that PAME is a novel neuroprotective agent against cerebral ischemia.
Attenuation of sympathetic nervous system
Autonomic dysregulation after cardiac arrest can be detrimental to the brain. Lee et al, 2017 first reported that excessive activation of perivascular sympathetic nervous system in the brain is one of the major causes of hypoperfusion, neuronal cell death, and neurological deficits after ACA-induced cerebral ischemia (Lee et al., 2017). Thus, surgical interruption of perivascular sympathetic nerves via decentralization of superior cervical ganglion (a sympathetic ganglion that innervates cerebral arteries) can alleviate ACA-induced hypoperfusion and brain injury (Lee et al., 2017). Interestingly, interruption of cervical sympathetic chain via bolus injection of bupivacaine and clonidine (ganglionic and α2 blocker, respectively) in the superior cervical ganglion has been shown to reduce neurological deficits after aneurysmal subarachnoid hemorrhage in humans (Treggiari et al., 2003), which suggests that developing novel therapies target on the perivascular sympathetic nervous system may be beneficial.
Neuromodulation therapy is a novel technique that utilizes implantable neuromodulatory device/stimulator to deliver electrical or magnetic stimuli directly upon injured neurons. There are growing evidences suggest that neuromodulation therapies can promote functional recovery, in particular locomotor function after stroke. For example, the use of repetitive transcranial magnetic stimulation (TMS) (at ~1 and ~10 Hz) to stimulate motor cortex has been shown to enhance motor function after experimental ischemia (Adkins-Muir and Jones, 2003; Kleim et al., 2003; Plautz et al., 2003; Teskey et al., 2003; Naeser et al., 2005; Kirton, 2017). In addition to experimental ischemia, recent clinical studies suggest that non-invasive brain stimulation via transcranial direct current stimulation (tDCS) or theta burst stimulation (TBS, a neuromodulatory device that provides continuous theta frequency low-intensity stimuli into target brain regions) can facilitate motor and language recovery after chronic stroke (Lindenberg et al., 2010; Cazzoli et al., 2012; Bonni et al., 2014; Yamada et al., 2014; Lee and Lee, 2015; Triccas et al., 2015; Allman et al., 2016; Rocha et al., 2016; Kirton, 2017). Since over 70% of stroke survivors suffer from gait abnormalities, one of the major therapeutic challenges for stroke survivors is gait rehabilitation indicating that neuromodulation therapy’s potential in the treatment of cerebral ischemia.
Traditional Chinese therapies
Traditional Chinese therapies (i.e., plant-based medicines and acupuncture) are considered novel therapies against stroke/cerebral ischemia due to their multifactorial effects (i.e., anti-inflammation and anti-oxidation). For example, Buyang Huanwu decoction (BHD) is derived from extracts from various Chinese herbs, including Radix Astragali (the root of Astragalus membranaceus), Radix Angelicae Sinensis (the root of Angelica sinensis), Radix Paeoniae Rubra (chishao, the root of Paeonia lactiflora Pall), Chuanxiong Rhizoma (the root and rhizome of Ligusticum chuanxiong Hort), Semen Persicae (taoren, the seeds of Amygdalu spersica), Flos Carthami (the flower of Carthamus tinctorius L, and Pheretima [the body of Pheretima aspergillum (earth worm)] (Mu et al., 2014). Numerous studies have shown that BHD can reduce cerebral ischemia-induced neuronal damage by inhibiting excitotoxicity, inflammation, and apoptosis (Chen et al., 2008; Wang and Jiang, 2009), while promoting angiogenesis (Shen et al., 2014), proliferation, differentiation, and migration of neuroprogenitor cells (NPCs) to the infarct area (Cai et al., 2007).
In addition to BHD, Dragon’s blood dropping pills (the red resin from Dracaena cochinchinensis) and Bilobalide (EGb 761, a ginkgo biloba extract) have also been shown to alleviate cerebral water content, oxidative stress, and glutamate release in the infarct area following MCAO, thus reducing excitotoxicity, infarct volume, and neurological deficits (Lang et al., 2011; Xin et al., 2013b). Furthermore, clinical studies suggest that flower extracts, including Dengzhan Xixin (erigeron breviscapus, a Chinese daisy) and Dengzhanhua can enhance acute stroke patients’ CBF, plasma viscosity, and platelet adhesion to improve neurological function (Huang et al., 2014c; Li et al., 2017; Wang et al., 2017).
In additional to the aforementioned traditional Chinese medicines, acupuncture has also been considered as a complementary and alternative therapies for stroke patients in Asian countries. Acupuncture can be divided into traditional acupuncture and electro-acupuncture. The traditional acupuncture utilizes thin metal needles to stimulate acupuncture points over the body, while electro-acupuncture combines traditional acupuncture with modern electrotherapy to enhance stimulations to acupuncture points. Acupuncture has been shown to ameliorate neuronal cell death, neurological deficits, and brain edema following MCAO (Lu et al., 2016). In addition to experimental stroke models, recent clinical studies suggest that acupuncture can reduce disability rates, while enhance stroke patients’ activities of daily living evaluated by Barthel Index, National Institutes of Health Stroke Scale, and Revised Scandinavian Stroke Scale (Tan et al., 2013; Liu et al., 2015; Yang et al., 2017). Furthermore, a multicenter randomized controlled trial from 862 stroke patients suggests that patients received acupuncture therapies 5 times per week for 3 to 4 weeks have higher survival rate than patients without acupuncture treatments (Zhang et al., 2015), which suggest acupuncture’s potential in the treatment against stoke/cerebral ischemia.
Multiple pathways are involved in acupuncture-mediated neuroprotective effects following cerebral ischemia. Huang et al. (2017) reported that acupuncture enhances IκB-α expression to reduce NF-κB-mediated inflammation. Kim et al. (2013b) and Wang et al. (2002), however, suggest that acupuncture can inhibit apoptotic signaling cascade via enhancing Akt, Bcl-2, Bcl-xL, and cIAP1/2, while reducing apoptotic mediators (i.e., death receptor 5 and caspases-3, -8, and -9). In addition to acupuncture’s anti-inflammatory and anti-apoptotic effects, Kim et al. (2014) reported that acupuncture promotes astrocytes and neuronal progenitor cells proliferation via Wnt/β-catenin- and ERK1/2-mediated pathways (Xie et al., 2013; Huang et al., 2014a; Chen et al., 2015), as a result of brain-derived neurotrophic factor/vascular endothelial growth factor (VEGF)-mediated neurogenesis (Kim et al., 2014). Furthermore, acupuncture enhances post-ischemia CBF by promoting VEGF and angiogenin-1-mediated angiogenesis (Ma and Luo, 2008), as well as enhanced release of vasoactive mediators (i.e., acetylcholine and nitric oxide) (Kim et al., 2013a) after cerebral ischemia. Overall, traditional Chinese therapies (i.e., plant-based medicines and acupuncture) can inhibit cerebral ischemia-induced excitotoxicity, inflammation, and apoptosis, while promoting angiogenesis and cerebral blood flow after cerebral ischemia. The use of traditional Chinese traditional may provide therapeutic opportunities against cerebral ischemia.
Stem cell therapy
In addition to the above mentioned neuroregenerative agents, stem cell therapy is also a promising option for patients with stroke/cerebral ischemia due to stem cells’ self-regenerative, differentiating, and multifunctional properties (Trounson and McDonald, 2015). Stem cell therapies can be divided into endogenous and exogenous therapies. The endogenous therapies utilize neurotrophic and growth factors, such as epidermal growth factor, glial cell-derived neurotrophic factor, FGF-2, insulin-like growth factor-1, and brain-derived neurotrophic factor (Dempsey et al., 2003; Kobayashi et al., 2006; Leker et al., 2007; Jin-qiao et al., 2009) to enhance vascular regeneration and brain synaptic plasticity, while it stimulates the reparative abilities of the endogenous neural stem cells (NSCs) in the injured dentate gyrus and subventricular zone (SVZ) (Picard-Riera et al., 2004), thus reducing lesion size and locomotor deficits. On the contrary, exogenous therapies use tissue extraction, in vitro cultivation, and subsequent stem cell transplantation into damaged brain regions caused by stroke/cerebral ischemia (Azad et al., 2016).
Mechanisms underlying endogenous stem cell therapies against cerebral ischemia are highly complicated and remains to be elucidated (Arvidsson et al., 2002). Endogenous activation of neural stem cells (NSCs) in the subgranular zone (SGZ) and SVZ after cerebral ischemia have been shown to produce neurotrophic factors (i.e., brain-derived neurotrophic factor), which reduce inflammation, while promoting angiogenesis via activation of pro-angiogenic complexes, such as netrin-4, laminins, and integrins (Goldman and Nottebohm, 1983; Anderson, 2001; Doetsch et al., 2002; Staquicini et al., 2009), thus reducing brain injury elicited by hypoxia/ischemia. Additionally, the activated NSCs after cerebral ischemia can produce and secrete thrombospondins to promote synaptic regeneration and axonal sprouting (Liauw et al., 2008).
In terms of exogenous stem cell therapies, NPCs, bone-marrow derived stromal cells (BMSCs), and immortalized cell lines have been widely used in the treatment of cerebral ischemia (Bliss et al., 2010). Transplantation of NPCs following ischemic stroke results in the migration of mature and immature neurons towards the injured brain regions, as a result of long-term cell survival, electrical balance, synaptic plasticity recovery (Daadi et al., 2009; Clarkson et al., 2010; Darsalia et al., 2011; Bacigaluppi et al., 2016), and functional outcome improvement (i.e., sensorimotor and memory) (Jin et al., 2010). The major advantage of the NPCs therapy is NPCs’ self-differentiate abilities into astrocytes, neurons, and oligodendrocytes (Gage, 2000; Chojnacki and Weiss, 2008). However, NPCs are commonly associated with teratoma formation due to their endless self-renewing ability (Rong et al., 2012), which reduces NPCs’ therapeutic efficacy in the treatment of cerebral ischemia indicating that further studies are necessary to evaluate safety and efficacy of NPCs in the treatment against cerebral ischemia.
BMSCs are another type of multipotent stem cells with high-differentiation and migration (Polymeri et al., 2016). BMSCs’ anti-inflammatory, immune suppressive, and low tissue rejection properties (Ryan et al., 2005; Zhao et al., 2012; Ankrum et al., 2014) provide therapeutic potential in the treatment against cerebral ischemia. In vivo studies have shown that implantation of BMSCs in rats after cerebral ischemia results in an increase in axonal sprouting (Li et al., 2000), neurogenesis, and angiogenesis (Chen et al., 2001, 2003; Yoo et al., 2008; Xin et al., 2013a), thus reducing brain injury, neuronal cell death, and neurological deficits (Chen et al., 2003; Zheng et al., 2010; Xin et al., 2013a). Mechanisms underlying BMSCs-induced neuroprotection remains unclear. Previous studies, however, suggest that trophic factors (i.e., brain-derived neurotrophic factor) released from BMSCs after cerebral ischemia are the major contributors to BMSCs-induced angiogenesis and regrowth/repair of nerve tissue (Bao et al., 2011). Additionally, BMSCs have also been reported to reduce the expression of axonal-growth inhibitory proteins (i.e., Rho-associated and coiled-coil-containing protein kinase 2) (Song et al., 2013), thus enhancing axon growth and formation following cerebral ischemia.
In addition to NPCs and BMSCs, recent studies also focus on investigating the therapeutic potential of immortalized cell lines as another option for cerebral ischemia treatment due to immortalized cell lines’ ability to proliferate indefinitely (Kondziolka et al., 2000, 2005; Stroemer et al., 2009). Furthermore, immortalized cell lines can differentiate into oligodendroglial and endothelial cells to promote/restore endogenous neurogenesis in the SVZ after cerebral ischemia (Stroemer et al., 2009). Thus, treatment with immortalized cell lines (i.e., CTX0E03) can enhance functional sensorimotor recovery (evaluated via bilateral asymmetry and rotameter test) after cerebral ischemia elicited by MCAO. Since immortalized cell lines are mainly derived from tumor cells and contain oncogenes, the major drawback of immortalized cell lines is their propensity to form tumors. Although results from several Phase I and II clinical trials suggest that implantation of Ntera2/D1 neuron-like cells, another immortalized cell line derived from teratocarcinoma, has no adverse effects in stroke patients (Kondziolka et al., 2000, 2005), more studies are needed to evaluate the safety and efficacy of the immortalized cell lines in the treatment against cerebral ischemia.
| Conclusions|| |
Despite improved education (i.e., dietary), psychological care, and better therapeutic treatments [i.e., less door-to-needle time for plasminogen activator], cerebral ischemia is still one of the leading causes of morbidity and mortality worldwide (Lopez et al., 2006; Feigin et al., 2009). The stroke-related costs are expected to reach 240.67 billion by 2030 according to the American Heart Association (Ovbiagele et al., 2013) indicating that developing novel therapies that can effectively alleviate post-stroke long-term disability is greatly needed. Although more studies are needed to evaluate the safety and efficacy of the novel neuroregenerative agents as we have already discussed, agents that have been investigated in clinical studies, such as hypothermia, bolus injection of bupivacaine and clonidine in the superior cervical ganglion, neuromodulation therapy, stem cell and traditional Chinese therapies should be considered for treatment against stroke and general ischemia.
Author contributions: RHCL, MHHL: drafted manuscript, revised manuscript critically for important intellectual content, and final approval. CYCW, ACS, HEP, THH: drafted manuscript and final approval. AM, and HWL: revised manuscript critically for important intellectual content and final approval.
Conflicts of interest: None declared.
Financial support: This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke grant 1R01NS096225-01A1, the American Heart Association grants AHA-13SDG1395001413, AHA-17GRNT33660336, AHA-17POST33660174, the Louisiana State University Grant in Aid research council, and The Malcolm Feist Cardiovascular Research Fellowship.
Plagiarism check: Checked twice by iThenticate.
Peer review: Externally peer reviewed.
Open peer reviewer: Shasha Li, Harvard Medical School, USA.
Funding: This work was supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke grant 1R01NS096225-01A1, the American Heart Association grants AHA-13SDG1395001413, AHA-17GRNT33660336, AHA-17POST33660174, the Louisiana State University Grant in Aid research council, and The Malcolm Feist Cardiovascular Research Fellowship.
| References|| |
Adkins-Muir DL, Jones TA (2003) Cortical electrical stimulation combined with rehabilitative training: enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats. Neurol Res 25:780-788.
Allman C, Amadi U, Winkler AM, Wilkins L, Filippini N, Kischka U, Stagg CJ, Johansen-Berg H (2016) Ipsilesional anodal tDCS enhances the functional benefits of rehabilitation in patients after stroke. Sci Transl Med 8:330re331.
Amarenco P, Lavallee PC, Labreuche J, Albers GW, Bornstein NM, Canhao P, Caplan LR, Donnan GA, Ferro JM, Hennerici MG, Molina C, Rothwell PM, Sissani L, Skoloudik D, Steg PG, Touboul PJ, Uchiyama S, Vicaut E, Wong LK, Investigators TIo (2016) One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med 374:1533-1542.
Anderson DJ (2001) Stem cells and pattern formation in the nervous system: the possible versus the actual. Neuron 30:19-35.
Ankrum JA, Ong JF, Karp JM (2014) Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol 32:252-260.
Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8:963-970.
Azad TD, Veeravagu A, Steinberg GK (2016) Neurorestoration after stroke. Neurosurg Focus 40:E2.
Bacigaluppi M et al. (2016) Neural stem cell transplantation induces stroke recovery by upregulating glutamate transporter GLT-1 in astrocytes. J Neurosci 36:10529-10544.
Bao X, Wei J, Feng M, Lu S, Li G, Dou W, Ma W, Ma S, An Y, Qin C, Zhao RC, Wang R (2011) Transplantation of human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and endogenous neurogenesis after cerebral ischemia in rats. Brain Res 1367:103-113.
Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 87:1620-1624.
Belenky P, Bogan KL, Brenner C (2007) NAD+ metabolism in health and disease. Trends Biochem Sci 32:12-19.
Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369-1374.
Berdichevsky E, Riveros N, Sanchez-Armass S, Orrego F (1983) Kainate, N-methylaspartate and other excitatory amino acids increase calcium influx into rat brain cortex cells in vitro. Neurosci Lett 36:75-80.
Bethel A, Kirsch JR, Koehler RC, Finklestein SP, Traystman RJ (1997) Intravenous basic fibroblast growth factor decreases brain injury resulting from focal ischemia in cats. Stroke 28:609-615; discussion 615-616.
Biesmans S, Meert TF, Bouwknecht JA, Acton PD, Davoodi N, De Haes P, Kuijlaars J, Langlois X, Matthews LJ, Ver Donck L, Hellings N, Nuydens R (2013) Systemic immune activation leads to neuroinflammation and sickness behavior in mice. Mediators Inflamm 2013:271359.
Bisset KA (1978) Demonstration of the initial cell in Streptomyces griseus by a new microscopic technique. J Gen Microbiol 104:157-159.
Bliss TM, Andres RH, Steinberg GK (2010) Optimizing the success of cell transplantation therapy for stroke. Neurobiol Dis 37:275-283.
Bolanos JP, Almeida A (1999) Roles of nitric oxide in brain hypoxia-ischemia. Biochim Biophys Acta 1411:415-436.
Bonni S, Ponzo V, Caltagirone C, Koch G (2014) Cerebellar theta burst stimulation in stroke patients with ataxia. Funct Neurol 29:41-45.
Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, Bonny C (2003) A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 9:1180-1186.
Bosley TM, Woodhams PL, Gordon RD, Balazs R (1983) Effects of anoxia on the stimulated release of amino acid neurotransmitters in the cerebellum in vitro. J Neurochem 40:189-201.
Broughton BR, Reutens DC, Sobey CG (2009) Apoptotic mechanisms after cerebral ischemia. Stroke 40:e331-339.
Busto R, Dietrich WD, Globus MY, Valdes I, Scheinberg P, Ginsberg MD (1987) Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 7:729-738.
Caceres JA, Goldstein JN (2012) Intracranial hemorrhage. Emerg Med Clin North Am 30:771-794.
Cai G, Liu B, Liu W, Tan X, Rong J, Chen X, Tong L, Shen J (2007) Buyang Huanwu Decoction can improve recovery of neurological function, reduce infarction volume, stimulate neural proliferation and modulate VEGF and Flk1 expressions in transient focal cerebral ischaemic rat brains. J Ethnopharmacol 113:292-299.
Caroni P, Schwab ME (1988) Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1:85-96.
Cazzoli D, Muri RM, Schumacher R, von Arx S, Chaves S, Gutbrod K, Bohlhalter S, Bauer D, Vanbellingen T, Bertschi M, Kipfer S, Rosenthal CR, Kennard C, Bassetti CL, Nyffeler T (2012) Theta burst stimulation reduces disability during the activities of daily living in spatial neglect. Brain 135:3426-3439.
Chen A, Wang H, Zhang J, Wu X, Liao J, Li H, Cai W, Luo X, Ju G (2008) BYHWD rescues axotomized neurons and promotes functional recovery after spinal cord injury in rats. J Ethnopharmacol 117:451-456.
Chen B, Tao J, Lin Y, Lin R, Liu W, Chen L (2015) Electro-acupuncture exerts beneficial effects against cerebral ischemia and promotes the proliferation of neural progenitor cells in the cortical peri-infarct area through the Wnt/beta-catenin signaling pathway. Int J Mol Med 36:1215-1222.
Chen GY, Nunez G (2010) Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10:826-837.
Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M (2001) Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 189:49-57.
Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, Lu M, Gautam SC, Chopp M (2003) Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73:778-786.
Cheng NT, Kim AS (2015) Intravenous thrombolysis for acute ischemic stroke within 3 hours versus between 3 and 4.5 hours of symptom onset. Neurohospitalist 5:101-109.
Cheng Y, Black IB, DiCicco-Bloom E (2002) Hippocampal granule neuron production and population size are regulated by levels of bFGF. Eur J Neurosci 15:3-12.
Chodobski A, Zink BJ, Szmydynger-Chodobska J (2011) Blood-brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res 2:492-516.
Chojnacki A, Weiss S (2008) Production of neurons, astrocytes and oligodendrocytes from mammalian CNS stem cells. Nat Protoc 3:935-940.
Christian Alzheimer SW (2000-2013) Fibroblast Growth Factors. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience.
Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael ST (2010) Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468:305-309.
Coutts SB (2017) Diagnosis and management of transient ischemic attack. Continuum 23:82-92.
Crow JP, Beckman JS (1995) The role of peroxynitrite in nitric oxide-mediated toxicity. Curr Top Microbiol Immunol 196:57-73.
Culmsee C, Zhu X, Yu QS, Chan SL, Camandola S, Guo Z, Greig NH, Mattson MP (2001) A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. J Neurochem 77:220-228.
Cuzzocrea S, Costantino G, Gitto E, Mazzon E, Fulia F, Serraino I, Cordaro S, Barberi I, De Sarro A, Caputi AP (2000) Protective effects of melatonin in ischemic brain injury. J Pineal Res 29:217-227.
Daadi MM, Lee SH, Arac A, Grueter BA, Bhatnagar R, Maag AL, Schaar B, Malenka RC, Palmer TD, Steinberg GK (2009) Functional engraftment of the medial ganglionic eminence cells in experimental stroke model. Cell Transplant 18:815-826.
Darsalia V, Allison SJ, Cusulin C, Monni E, Kuzdas D, Kallur T, Lindvall O, Kokaia Z (2011) Cell number and timing of transplantation determine survival of human neural stem cell grafts in stroke-damaged rat brain. J Cereb Blood Flow Metab 31:235-242.
Dave KR, Bhattacharya SK, Saul I, DeFazio RA, Dezfulian C, Lin HW, Raval AP, Perez-Pinzon MA (2011) Activation of protein kinase C delta following cerebral ischemia leads to release of cytochrome C from the mitochondria via bad pathway. PLoS One 6:e22057.
Dawson LA, Djali S, Gonzales C, Vinegra MA, Zaleska MM (2000) Characterization of transient focal ischemia-induced increases in extracellular glutamate and aspartate in spontaneously hypertensive rats. Brain Res Bull 53:767-776.
DeFazio RA, Raval AP, Lin HW, Dave KR, Della-Morte D, Perez-Pinzon MA (2009) GABA synapses mediate neuroprotection after ischemic and epsilonPKC preconditioning in rat hippocampal slice cultures. J Cereb Blood Flow Metab 29:375-384.
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112-119.
Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4:313-321.
Dempsey RJ, Sailor KA, Bowen KK, Tureyen K, Vemuganti R (2003) Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-1 and GDNF. J Neurochem 87:586-597.
Dietrich WD, Busto R, Halley M, Valdes I (1990) The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 49:486-497.
Dietrich WD, Halley M, Valdes I, Busto R (1991) Interrelationships between increased vascular permeability and acute neuronal damage following temperature-controlled brain ischemia in rats. Acta Neuropathol 81:615-625.
Dietrich WD, Busto R, Alonso O, Globus MY, Ginsberg MD (1993) Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rats. J Cereb Blood Flow Metab 13:541-549.
Dietrich WD, Alonso O, Busto R, Globus MY, Ginsberg MD (1994) Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat. Acta Neuropathol 87:250-258.
do Carmo Cunha J, de Freitas Azevedo Levy B, de Luca BA, de Andrade MS, Gomide VC, Chadi G (2007) Responses of reactive astrocytes containing S100beta protein and fibroblast growth factor-2 in the border and in the adjacent preserved tissue after a contusion injury of the spinal cord in rats: implications for wound repair and neuroregeneration. Wound Repair Regen 15:134-146.
Doetsch F, Petreanu L, Caille I, Garcia-Verdugo JM, Alvarez-Buylla A (2002) EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36:1021-1034.
Dong W, Li N, Gao D, Zhen H, Zhang X, Li F (2008) Resveratrol attenuates ischemic brain damage in the delayed phase after stroke and induces messenger RNA and protein express for angiogenic factors. J Vasc Surg 48:709-714.
Drejer J, Benveniste H, Diemer NH, Schousboe A (1985) Cellular origin of ischemia-induced glutamate release from brain tissue in vivo and in vitro. J Neurochem 45:145-151.
Eliasziw M, Kennedy J, Hill MD, Buchan AM, Barnett HJ, North American Symptomatic Carotid Endarterectomy Trial G (2004) Early risk of stroke after a transient ischemic attack in patients with internal carotid artery disease. CMAJ 170:1105-1109.
Els T, Oehm E, Voigt S, Klisch J, Hetzel A, Kassubek J (2006) Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke. Cerebrovasc Dis 21:79-85.
Eltzschig HK, Eckle T (2011) Ischemia and reperfusion--from mechanism to translation. Nat Med 17:1391-1401.
Erickson MA, Banks WA (2011) Cytokine and chemokine responses in serum and brain after single and repeated injections of lipopolysaccharide: multiplex quantification with path analysis. Brain Behav Immun 25:1637-1648.
Fang L, Gao H, Zhang W, Zhang W, Wang Y (2015) Resveratrol alleviates nerve injury after cerebral ischemia and reperfusion in mice by inhibiting inflammation and apoptosis. Int J Clin Exp Med 8:3219-3226.
Farbu E, Kurz KD, Kurz MW (2011) Ischemic stroke--novel therapeutic strategies. Acta Neurol Scand Suppl:28-37.
Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V (2009) Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 8:355-369.
Fitch MT, Silver J (1997) Activated macrophages and the blood-brain barrier: inflammation after CNS injury leads to increases in putative inhibitory molecules. Exp Neurol 148:587-603.
Gage FH (2000) Mammalian neural stem cells. Science 287:1433-1438.
Garry PS, Ezra M, Rowland MJ, Westbrook J, Pattinson KT (2015) The role of the nitric oxide pathway in brain injury and its treatment--from bench to bedside. Exp Neurol 263:235-243.
Gautier JC, Pullicino P (1985) A clinical approach to cerebrovascular disease. Neuroradiology 27:452-459.
Ghibelli L, Diederich M (2010) Multistep and multitask Bax activation. Mitochondrion 10:604-613.
Gilad E, Cuzzocrea S, Zingarelli B, Salzman AL, Szabo C (1997) Melatonin is a scavenger of peroxynitrite. Life Sci 60:PL169-174.
Globus MY, Alonso O, Dietrich WD, Busto R, Ginsberg MD (1995) Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia. J Neurochem 65:1704-1711.
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, et al. (2014) Heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation 129:e28-e292.
Goldman SA, Nottebohm F (1983) Neuronal production, migration, and differentiation in a vocal control nucleus of the adult female canary brain. Proc Natl Acad Sci U S A 80:2390-2394.
Gonzalvez F, Pariselli F, Dupaigne P, Budihardjo I, Lutter M, Antonsson B, Diolez P, Manon S, Martinou JC, Goubern M, Wang X, Bernard S, Petit PX (2005) tBid interaction with cardiolipin primarily orchestrates mitochondrial dysfunctions and subsequently activates Bax and Bak. Cell Death Differ 12:614-626.
Grysiewicz RA, Thomas K, Pandey DK (2008) Epidemiology of ischemic and hemorrhagic stroke: incidence, prevalence, mortality, and risk factors. Neurol Clin 26:871-895, vii.
Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D, Investigators E (2008) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359:1317-1329.
Hagberg H, Lehmann A, Sandberg M, Nystrom B, Jacobson I, Hamberger A (1985) Ischemia-induced shift of inhibitory and excitatory amino acids from intra- to extracellular compartments. J Cereb Blood Flow Metab 5:413-419.
Hall ED (1997) Brain attack. Acute therapeutic interventions. Free radical scavengers and antioxidants. Neurosurg Clin N Am 8:195-206.
He Q, Li Z, Wang Y, Hou Y, Li L, Zhao J (2017) Resveratrol alleviates cerebral ischemia/reperfusion injury in rats by inhibiting NLRP3 inflammasome activation through Sirt1-dependent autophagy induction. Int Immunopharmacol 50:208-215.
He Y, Liu J, Grossman D, Durrant D, Sweatman T, Lothstein L, Epand RF, Epand RM, Lee RM (2007) Phosphorylation of mitochondrial phospholipid scramblase 3 by protein kinase C-delta induces its activation and facilitates mitochondrial targeting of tBid. J Cell Biochem 101:1210-1221.
Herdegen T, Claret FX, Kallunki T, Martin-Villalba A, Winter C, Hunter T, Karin M (1998) Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury. J Neurosci 18:5124-5135.
Hernandez-Ontiveros DG, Tajiri N, Acosta S, Giunta B, Tan J, Borlongan CV (2013) Microglia activation as a biomarker for traumatic brain injury. Front Neurol 4:30.
Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1:489-495.
Hong JM, Lee JS, Song HJ, Jeong HS, Choi HA, Lee K (2014) Therapeutic hypothermia after recanalization in patients with acute ischemic stroke. Stroke 45:134-140.
Hong LZ, Zhao XY, Zhang HL (2010) p53-mediated neuronal cell death in ischemic brain injury. Neurosci Bull 26:232-240.
Hsieh ST, Kidd GJ, Crawford TO, Xu Z, Lin WM, Trapp BD, Cleveland DW, Griffin JW (1994) Regional modulation of neurofilament organization by myelination in normal axons. J Neurosci 14:6392-6401.
Huang J, Ye X, You Y, Liu W, Gao Y, Yang S, Peng J, Hong Z, Tao J, Chen L (2014a) Electroacupuncture promotes neural cell proliferation in vivo through activation of the ERK1/2 signaling pathway. Int J Mol Med 33:1547-1553.
Huang L, Wu ZB, Zhuge Q, Zheng W, Shao B, Wang B, Sun F, Jin K (2014b) Glial scar formation occurs in the human brain after ischemic stroke. Int J Med Sci 11:344-348.
Huang W, Zhou Z, Wan B, Chen G, Li J (2017) Nuclear Factor kB and Inhibitor of kB: Acupuncture Protection Against Acute Focal Cerebral Ischemia in Rodents. Altern Ther Health Med 23:20-28.
Huang ZJ, He SA, Lei B (2014c) Clinical analysis of acute cerebral infarction by Dengzhanhua injection and Xiongqin injection combined with Xuesaitong treatment. Zhong Yao Cai 37:1093-1095.
Irving EA, Bamford M (2002) Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 22:631-647.
Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, Eisenbarth SC, Florquin S, Flavell RA, Leemans JC, Sutterwala FS (2009) Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A 106:20388-20393.
Jagtap P, Szabo C (2005) Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 4:421-440.
Janardhan V, Qureshi AI (2004) Mechanisms of ischemic brain injury. Curr Cardiol Rep 6:117-123.
Jancso G, Karcsu S, Kiraly E, Szebeni A, Toth L, Bacsy E, Joo F, Parducz A (1984) Neurotoxin induced nerve cell degeneration: possible involvement of calcium. Brain Res 295:211-216.
Jiang MQ, Zhao YY, Cao W, Wei ZZ, Gu X, Wei L, Yu SP (2017) Long-term survival and regeneration of neuronal and vasculature cells inside the core region after ischemic stroke in adult mice. Brain Pathol 27:480-498.
Jin-qiao S, Bin S, Wen-hao Z, Yi Y (2009) Basic fibroblast growth factor stimulates the proliferation and differentiation of neural stem cells in neonatal rats after ischemic brain injury. Brain Dev 31:331-340.
Jin K, Mao X, Xie L, Galvan V, Lai B, Wang Y, Gorostiza O, Wang X, Greenberg DA (2010) Transplantation of human neural precursor cells in Matrigel scaffolding improves outcome from focal cerebral ischemia after delayed postischemic treatment in rats. J Cereb Blood Flow Metab 30:534-544.
Kabadi SV, Faden AI (2014) Neuroprotective strategies for traumatic brain injury: improving clinical translation. Int J Mol Sci 15:1216-1236.
Kanazawa M, Takahashi T, Nishizawa M, Shimohata T (2017) Therapeutic Strategies to Attenuate Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment for Acute Ischemic Stroke. J Atheroscler Thromb 24:240-253.
Keep RF, Hua Y, Xi G (2012) Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol 11:720-731.
Kietadisorn R, Juni RP, Moens AL (2012) Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities. Am J Physiol Endocrinol Metab 302:E481-495.
Kilic E, Kilic U, Reiter RJ, Bassetti CL, Hermann DM (2004) Prophylactic use of melatonin protects against focal cerebral ischemia in mice: role of endothelin converting enzyme-1. J Pineal Res 37:247-251.
Kim JH, Choi KH, Jang YJ, Bae SS, Shin BC, Choi BT, Shin HK (2013a) Electroacupuncture acutely improves cerebral blood flow and attenuates moderate ischemic injury via an endothelial mechanism in mice. PLoS One 8:e56736.
Kim SJ, Lee SR (2014) Protective effect of melatonin against transient global cerebral ischemia-induced neuronal cell damage via inhibition of matrix metalloproteinase-9. Life Sci 94:8-16.
Kim YR, Kim HN, Ahn SM, Choi YH, Shin HK, Choi BT (2014) Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia. PLoS One 9:e90000.
Kim YR, Kim HN, Jang JY, Park C, Lee JH, Shin HK, Choi YH, Choi BT (2013b) Effects of electroacupuncture on apoptotic pathways in a rat model of focal cerebral ischemia. Int J Mol Med 32:1303-1310.
Kiprianova I, Schindowski K, von Bohlen und Halbach O, Krause S, Dono R, Schwaninger M, Unsicker K (2004) Enlarged infarct volume and loss of BDNF mRNA induction following brain ischemia in mice lacking FGF-2. Exp Neurol 189:252-260.
Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57-69.
Kirton A (2017) Advancing non-invasive neuromodulation clinical trials in children: Lessons from perinatal stroke. Eur J Paediatr Neurol 21:75-103.
Kizmazoglu C, Aydin HE, Sevin IE, Kalemci O, Yuceer N, Atasoy MA (2015) Neuroprotective effect of resveratrol on acute brain ischemia reperfusion injury by measuring annexin V, p53, Bcl-2 levels in rats. J Korean Neurosurg Soc 58:508-512.
Kleim JA, Bruneau R, VandenBerg P, MacDonald E, Mulrooney R, Pocock D (2003) Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurol Res 25:789-793.
Kobayashi T, Ahlenius H, Thored P, Kobayashi R, Kokaia Z, Lindvall O (2006) Intracerebral infusion of glial cell line-derived neurotrophic factor promotes striatal neurogenesis after stroke in adult rats. Stroke 37:2361-2367.
Koh PO (2008) Melatonin attenuates the cerebral ischemic injury via the MEK/ERK/p90RSK/bad signaling cascade. J Vet Med Sci 70:1219-1223.
Kollmar R, Blank T, Han JL, Georgiadis D, Schwab S (2007) Different degrees of hypothermia after experimental stroke: short- and long-term outcome. Stroke 38:1585-1589.
Kondziolka D, Wechsler L, Goldstein S, Meltzer C, Thulborn KR, Gebel J, Jannetta P, DeCesare S, Elder EM, McGrogan M, Reitman MA, Bynum L (2000) Transplantation of cultured human neuronal cells for patients with stroke. Neurology 55:565-569.
Kondziolka D, Steinberg GK, Wechsler L, Meltzer CC, Elder E, Gebel J, Decesare S, Jovin T, Zafonte R, Lebowitz J, Flickinger JC, Tong D, Marks MP, Jamieson C, Luu D, Bell-Stephens T, Teraoka J (2005) Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg 103:38-45.
Koronowski KB, Dave KR, Saul I, Camarena V, Thompson JW, Neumann JT, Young JI, Perez-Pinzon MA (2015) Resveratrol preconditioning induces a novel extended window of ischemic tolerance in the mouse brain. Stroke 46:2293-2298.
Kumar A, Loane DJ (2012) Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav Immun 26:1191-1201.
Lai TW, Zhang S, Wang YT (2014) Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115:157-188.
Lang D, Kiewert C, Mdzinarishvili A, Schwarzkopf TM, Sumbria R, Hartmann J, Klein J (2011) Neuroprotective effects of bilobalide are accompanied by a reduction of ischemia-induced glutamate release in vivo. Brain Res 1425:155-163.
Laudon M, Frydman-Marom A (2014) Therapeutic effects of melatonin receptor agonists on sleep and comorbid disorders. Int J Mol Sci 15:15924-15950.
Lee DG, Lee DY (2015) Effects of adjustment of transcranial direct current stimulation on motor function of the upper extremity in stroke patients. J Phys Ther Sci 27:3511-3513.
Lee JH, Wei ZZ, Cao W, Won S, Gu X, Winter M, Dix TA, Wei L, Yu SP (2016) Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice. Neurobiol Dis 96:248-260.
Lee RH, Couto ESA, Lerner FM, Wilkins CS, Valido SE, Klein DD, Wu CY, Neumann JT, Della-Morte D, Koslow SH, Minagar A, Lin HW (2017) Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia. Am J Physiol Heart Circ Physiol 312:H182-H188.
Leker RR, Soldner F, Velasco I, Gavin DK, Androutsellis-Theotokis A, McKay RD (2007) Long-lasting regeneration after ischemia in the cerebral cortex. Stroke 38:153-161.
Li H, Wang D (2011) Mild hypothermia improves ischemic brain function via attenuating neuronal apoptosis. Brain Res 1368:59-64.
Li J, Yuan J (2008) Caspases in apoptosis and beyond. Oncogene 27:6194-6206.
Li J, Zhang H, Zhang C (2012) Role of inflammation in the regulation of coronary blood flow in ischemia and reperfusion: mechanisms and therapeutic implications. J Mol Cell Cardiol 52:865-872.
Li JG, Wang LQ, Yang XY, Chen Z, Lai LYW, Xu H, Liu JP (2017) Chinese herbal medicine Dengzhan Xixin injection for acute ischemic stroke: A systematic review and meta-analysis of randomised controlled trials. Complement Ther Med 34:74-85.
Li W, Huang R, Shetty RA, Thangthaeng N, Liu R, Chen Z, Sumien N, Rutledge M, Dillon GH, Yuan F, Forster MJ, Simpkins JW, Yang SH (2013) Transient focal cerebral ischemia induces long-term cognitive function deficit in an experimental ischemic stroke model. Neurobiol Dis 59:18-25.
Li Y, Chopp M, Chen J, Wang L, Gautam SC, Xu YX, Zhang Z (2000) Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab 20:1311-1319.
Liauw J, Hoang S, Choi M, Eroglu C, Choi M, Sun GH, Percy M, Wildman-Tobriner B, Bliss T, Guzman RG, Barres BA, Steinberg GK (2008) Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab 28:1722-1732.
Lin HW, Saul I, Gresia VL, Neumann JT, Dave KR, Perez-Pinzon MA (2014) Fatty acid methyl esters and Solutol HS 15 confer neuroprotection after focal and global cerebral ischemia. Transl Stroke Res 5:109-117.
Lin HW, Liu CZ, Cao D, Chen PY, Chen MF, Lin SZ, Mozayan M, Chen AF, Premkumar LS, Torry DS, Lee TJ (2008) Endogenous methyl palmitate modulates nicotinic receptor-mediated transmission in the superior cervical ganglion. Proc Natl Acad Sci U S A 105:19526-19531.
Lin HW, Della-Morte D, Thompson JW, Gresia VL, Narayanan SV, Defazio RA, Raval AP, Saul I, Dave KR, Morris KC, Si ML, Perez-Pinzon MA (2012) Differential effects of delta and epsilon protein kinase C in modulation of postischemic cerebral blood flow. Adv Exp Med Biol 737:63-69.
Lindenberg R, Renga V, Zhu LL, Nair D, Schlaug G (2010) Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients. Neurology 75:2176-2184.
Liu AJ, Li JH, Li HQ, Fu DL, Lu L, Bian ZX, Zheng GQ (2015) Electroacupuncture for Acute Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials. Am J Chin Med 43:1541-1566.
Liu D, Gharavi R, Pitta M, Gleichmann M, Mattson MP (2009) Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons. Neuromolecular Med 11:28-42.
Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ (2006) Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 367:1747-1757.
Lu L, Zhang XG, Zhong LL, Chen ZX, Li Y, Zheng GQ, Bian ZX (2016) Acupuncture for neurogenesis in experimental ischemic stroke: a systematic review and meta-analysis. Sci Rep 6:19521.
Ma J, Luo Y (2008) Effects of electroacupuncture on expressions of angiogenesis factors and anti-angiogenesis factors in brain of experimental cerebral ischemic rats after reperfusion. J Tradit Chin Med 28:217-222.
McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, Beck PL, Muruve DA, Kubes P (2010) Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330:362-366.
McKeon RJ, Schreiber RC, Rudge JS, Silver J (1991) Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. J Neurosci 11:3398-3411.
McKerracher L, David S, Jackson DL, Kottis V, Dunn RJ, Braun PE (1994) Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron 13:805-811.
Mok VC, Wong A, Lam WW, Fan YH, Tang WK, Kwok T, Hui AC, Wong KS (2004) Cognitive impairment and functional outcome after stroke associated with small vessel disease. J Neurol Neurosurg Psychiatry 75:560-566.
Morikawa E, Ginsberg MD, Dietrich WD, Duncan RC, Kraydieh S, Globus MY, Busto R (1992) The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 12:380-389.
Mrschtik M, Ryan KM (2015) Lysosomal proteins in cell death and autophagy. FEBS J 282:1858-1870.
Mu Q, Liu P, Hu X, Gao H, Zheng X, Huang H (2014) Neuroprotective effects of Buyang Huanwu decoction on cerebral ischemia-induced neuronal damage. Neural Regen Res 9:1621-1627.
Mukhopadhyay G, Doherty P, Walsh FS, Crocker PR, Filbin MT (1994) A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration. Neuron 13:757-767.
Naeser MA, Martin PI, Nicholas M, Baker EH, Seekins H, Kobayashi M, Theoret H, Fregni F, Maria-Tormos J, Kurland J, Doron KW, Pascual-Leone A (2005) Improved picture naming in chronic aphasia after TMS to part of right Broca’s area: an open-protocol study. Brain Lang 93:95-105.
Narayanan SV, Dave KR, Saul I, Perez-Pinzon MA (2015) Resveratrol preconditioning protects against cerebral ischemic injury via nuclear erythroid 2-related factor 2. Stroke 46:1626-1632.
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581-1587.
Nguyen T, Mehta NR, Conant K, Kim KJ, Jones M, Calabresi PA, Melli G, Hoke A, Schnaar RL, Ming GL, Song H, Keswani SC, Griffin JW (2009) Axonal protective effects of the myelin-associated glycoprotein. J Neurosci 29:630-637.
Nitkunan A, Lanfranconi S, Charlton RA, Barrick TR, Markus HS (2011) Brain atrophy and cerebral small vessel disease: a prospective follow-up study. Stroke 42:133-138.
No authors listed (1990) Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke 21:637-676.
Nour M, Scalzo F, Liebeskind DS (2013) Ischemia-reperfusion injury in stroke. Interv Neurol 1:185-199.
Okuno S, Saito A, Hayashi T, Chan PH (2004) The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 24:7879-7887.
Olmez I, Ozyurt H (2012) Reactive oxygen species and ischemic cerebrovascular disease. Neurochem Int 60:208-212.
Ovbiagele B, Nguyen-Huynh MN (2011) Stroke epidemiology: advancing our understanding of disease mechanism and therapy. Neurotherapeutics 8:319-329.
Ovbiagele B, Cruz-Flores S, Lynn MJ, Chimowitz MI, Warfarin-Aspirin Symptomatic Intracranial Disease Study G (2008) Early stroke risk after transient ischemic attack among individuals with symptomatic intracranial artery stenosis. Arch Neurol 65:733-737.
Ovbiagele B, Goldstein LB, Higashida RT, Howard VJ, Johnston SC, Khavjou OA, Lackland DT, Lichtman JH, Mohl S, Sacco RL, Saver JL, Trogdon JG; American Heart Association Advocacy Coordinating Committee and Stroke Council (2013) Forecasting the future of stroke in the United States: a policy statement from the American Heart Association and American Stroke Association. Stroke 44:2361-2375.
Pantoni L, Gorelick PB (2014) Cerebral Small Vessel Disease. Cambridge, United Kingdom: Cambridge University Press.
Park SM, Choi MS, Sohn NW, Shin JW (2012) Ginsenoside Rg3 attenuates microglia activation following systemic lipopolysaccharide treatment in mice. Biol Pharm Bull 35:1546-1552.
Pei Z, Pang SF, Cheung RT (2003) Administration of melatonin after onset of ischemia reduces the volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model. Stroke 34:770-775.
Peters O, Back T, Lindauer U, Busch C, Megow D, Dreier J, Dirnagl U (1998) Increased formation of reactive oxygen species after permanent and reversible middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 18:196-205.
Picard-Riera N, Nait-Oumesmar B, Baron-Van Evercooren A (2004) Endogenous adult neural stem cells: limits and potential to repair the injured central nervous system. J Neurosci Res 76:223-231.
Plautz EJ, Barbay S, Frost SB, Friel KM, Dancause N, Zoubina EV, Stowe AM, Quaney BM, Nudo RJ (2003) Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: a feasibility study in primates. Neurol Res 25:801-810.
Poeggeler B, Saarela S, Reiter RJ, Tan DX, Chen LD, Manchester LC, Barlow-Walden LR (1994) Melatonin--a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. Ann N Y Acad Sci 738:419-420.
Polymeri A, Giannobile WV, Kaigler D (2016) Bone Marrow Stromal Stem Cells in Tissue Engineering and Regenerative Medicine. Horm Metab Res 48:700-713.
Pozo D, Reiter RJ, Calvo JR, Guerrero JM (1994) Physiological concentrations of melatonin inhibit nitric oxide synthase in rat cerebellum. Life Sci 55:PL455-460.
Prakasa Babu P, Yoshida Y, Su M, Segura M, Kawamura S, Yasui N (2000) Immunohistochemical expression of Bcl-2, Bax and cytochrome c following focal cerebral ischemia and effect of hypothermia in rat. Neurosci Lett 291:196-200.
Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B, Alix S, Youle RJ, LaMarche A, Maroney AC, Johnson EM Jr (2003) JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38:899-914.
Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453-462.
Raval AP, Dave KR, Mochly-Rosen D, Sick TJ, Perez-Pinzon MA (2003) Epsilon PKC is required for the induction of tolerance by ischemic and NMDA-mediated preconditioning in the organotypic hippocampal slice. J Neurosci 23:384-391.
Reier PJ, Houle JD (1988) The glial scar: its bearing on axonal elongation and transplantation approaches to CNS repair. Adv Neurol 47:87-138.
Reiter RJ (1991) Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev 12:151-180.
Riva MA, Gale K, Mocchetti I (1992) Basic fibroblast growth factor mRNA increases in specific brain regions following convulsive seizures. Brain Res Mol Brain Res 15:311-318.
Rocha S, Silva E, Foerster A, Wiesiolek C, Chagas AP, Machado G, Baltar A, Monte-Silva K (2016) The impact of transcranial direct current stimulation (tDCS) combined with modified constraint-induced movement therapy (mCIMT) on upper limb function in chronic stroke: a double-blind randomized controlled trial. Disabil Rehabil 38:653-660.
Rodriguez F, Bonacasa B, Fenoy FJ, Salom MG (2013) Reactive oxygen and nitrogen species in the renal ischemia/reperfusion injury. Curr Pharm Des 19:2776-2794.
Rolls A, Shechter R, Schwartz M (2009) The bright side of the glial scar in CNS repair. Nat Rev Neurosci 10:235-241.
Rong Z, Fu X, Wang M, Xu Y (2012) A scalable approach to prevent teratoma formation of human embryonic stem cells. J Biol Chem 287:32338-32345.
Ryan JM, Barry FP, Murphy JM, Mahon BP (2005) Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (Lond) 2:8.
Schaller B, Graf R (2004) Cerebral ischemia and reperfusion: the pathophysiologic concept as a basis for clinical therapy. J Cereb Blood Flow Metab 24:351-371.
Schielke GP, Yang GY, Shivers BD, Betz AL (1998) Reduced ischemic brain injury in interleukin-1 beta converting enzyme-deficient mice. J Cereb Blood Flow Metab 18:180-185.
Schmidt OI, Heyde CE, Ertel W, Stahel PF (2005) Closed head injury--an inflammatory disease? Brain Res Brain Res Rev 48:388-399.
Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W (1998) Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 29:2461-2466.
Schwartz JP, Nishiyama N (1994) Neurotrophic factor gene expression in astrocytes during development and following injury. Brain Res Bull 35:403-407.
Semple PF (1995) Difficult hypertension: practical management and decision making. BMJ 311:205.
Shen J, Qiu X, Jiang B, Zhang D, Xin W, Fung PC, Zhao B (2003) Nitric oxide and oxygen radicals induced apoptosis via bcl-2 and p53 pathway in hypoxia-reoxygenated cardiomyocytes. Sci China C Life Sci 46:28-39.
Shen J, Zhu Y, Yu H, Fan ZX, Xiao F, Wu P, Zhang QH, Xiong XX, Pan JW, Zhan RY (2014) Buyang Huanwu decoction increases angiopoietin-1 expression and promotes angiogenesis and functional outcome after focal cerebral ischemia. J Zhejiang Univ Sci B 15:272-280.
Shimohata T, Zhao H, Steinberg GK (2007a) Epsilon PKC may contribute to the protective effect of hypothermia in a rat focal cerebral ischemia model. Stroke 38:375-380.
Shimohata T, Zhao H, Sung JH, Sun G, Mochly-Rosen D, Steinberg GK (2007b) Suppression of deltaPKC activation after focal cerebral ischemia contributes to the protective effect of hypothermia. J Cereb Blood Flow Metab 27:1463-1475.
Siegel CS, McCullough LD (2013) NAD+ and nicotinamide: sex differences in cerebral ischemia. Neuroscience 237:223-231.
Silver J, Miller JH (2004) Regeneration beyond the glial scar. Nat Rev Neurosci 5:146-156.
Silverstein FS, Buchanan K, Johnston MV (1986) Perinatal hypoxia-ischemia disrupts striatal high-affinity [3H]glutamate uptake into synaptosomes. J Neurochem 47:1614-1619.
Song M, Mohamad O, Gu X, Wei L, Yu SP (2013) Restoration of intracortical and thalamocortical circuits after transplantation of bone marrow mesenchymal stem cells into the ischemic brain of mice. Cell Transplant 22:2001-2015.
Speliotes EK, Caday CG, Do T, Weise J, Kowall NW, Finklestein SP (1996) Increased expression of basic fibroblast growth factor (bFGF) following focal cerebral infarction in the rat. Brain Res Mol Brain Res 39:31-42.
Staquicini FI, Dias-Neto E, Li J, Snyder EY, Sidman RL, Pasqualini R, Arap W (2009) Discovery of a functional protein complex of netrin-4, laminin gamma1 chain, and integrin alpha6beta1 in mouse neural stem cells. Proc Natl Acad Sci U S A 106:2903-2908.
Stroemer P, Patel S, Hope A, Oliveira C, Pollock K, Sinden J (2009) The neural stem cell line CTX0E03 promotes behavioral recovery and endogenous neurogenesis after experimental stroke in a dose-dependent fashion. Neurorehabil Neural Repair 23:895-909.
Takami K, Kiyota Y, Iwane M, Miyamoto M, Tsukuda R, Igarashi K, Shino A, Wanaka A, Shiosaka S, Tohyama M (1993) Upregulation of fibroblast growth factor-receptor messenger RNA expression in rat brain following transient forebrain ischemia. Exp Brain Res 97:185-194.
Tan F, Wang X, Li HQ, Lu L, Li M, Li JH, Fang M, Meng D, Zheng GQ (2013) A randomized controlled pilot study of the triple stimulation technique in the assessment of electroacupuncture for motor function recovery in patients with acute ischemic stroke. Evid Based Complement Alternat Med 2013:431986.
Teskey GC, Flynn C, Goertzen CD, Monfils MH, Young NA (2003) Cortical stimulation improves skilled forelimb use following a focal ischemic infarct in the rat. Neurol Res 25:794-800.
Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C (2017) Melatonin: Pharmacology, Functions and Therapeutic Benefits. Curr Neuropharmacol 15:434-443.
Treggiari MM, Romand JA, Martin JB, Reverdin A, Rufenacht DA, de Tribolet N (2003) Cervical sympathetic block to reverse delayed ischemic neurological deficits after aneurysmal subarachnoid hemorrhage. Stroke 34:961-967.
Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011) The role of microglia in the healthy brain. J Neurosci 31:16064-16069.
Triccas LT, Burridge JH, Hughes A, Verheyden G, Desikan M, Rothwell J (2015) A double-blinded randomised controlled trial exploring the effect of anodal transcranial direct current stimulation and uni-lateral robot therapy for the impaired upper limb in sub-acute and chronic stroke. NeuroRehabilitation 37:181-191.
Trounson A, McDonald C (2015) Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17:11-22.
Tsai SK, Hung LM, Fu YT, Cheng H, Nien MW, Liu HY, Zhang FB, Huang SS (2007) Resveratrol neuroprotective effects during focal cerebral ischemia injury via nitric oxide mechanism in rats. J Vasc Surg 46:346-353.
van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ (2010) Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 9:167-176.
Vitturi DA, Patel RP (2011) Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy. Free Radic Biol Med 51:805-812.
Wagner JP, Black IB, DiCicco-Bloom E (1999) Stimulation of neonatal and adult brain neurogenesis by subcutaneous injection of basic fibroblast growth factor. J Neurosci 19:6006-6016.
Wang J, Xie Y, Zhao S, Zhang J, Chai Y, Li Y, Liao X (2017) Dengzhanxixin injection for cerebral infarction: A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 96:e7674.
Wang L, Jiang DM (2009) Neuroprotective effect of Buyang Huanwu Decoction on spinal ischemia/reperfusion injury in rats. J Ethnopharmacol 124:219-223.
Wang SJ, Omori N, Li F, Jin G, Zhang WR, Hamakawa Y, Sato K, Nagano I, Shoji M, Abe K (2002) Potentiation of Akt and suppression of caspase-9 activations by electroacupuncture after transient middle cerebral artery occlusion in rats. Neurosci Lett 331:115-118.
Wang ZL, Cheng SM, Ma MM, Ma YP, Yang JP, Xu GL, Liu XF (2008) Intranasally delivered bFGF enhances neurogenesis in adult rats following cerebral ischemia. Neurosci Lett 446:30-35.
Wardlaw JM, Smith C, Dichgans M (2013a) Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 12:483-497.
Wardlaw JM et al. (2013b) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12:822-838.
White BC, Grossman LI, O’Neil BJ, DeGracia DJ, Neumar RW, Rafols JA, Krause GS (1996) Global brain ischemia and reperfusion. Ann Emerg Med 27:588-594.
White RE, Yin FQ, Jakeman LB (2008) TGF-alpha increases astrocyte invasion and promotes axonal growth into the lesion following spinal cord injury in mice. Exp Neurol 214:10-24.
Wu VW, Nishiyama N, Schwartz JP (1998) A culture model of reactive astrocytes: increased nerve growth factor synthesis and reexpression of cytokine responsiveness. J Neurochem 71:749-756.
Xanthos DN, Sandkuhler J (2014) Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci 15:43-53.
Xie G, Yang S, Chen A, Lan L, Lin Z, Gao Y, Huang J, Lin J, Peng J, Tao J, Chen L (2013) Electroacupuncture at Quchi and Zusanli treats cerebral ischemia-reperfusion injury through activation of ERK signaling. Exp Ther Med 5:1593-1597.
Xie Z, Chen F, Li WA, Geng X, Li C, Meng X, Feng Y, Liu W, Yu F (2017) A review of sleep disorders and melatonin. Neurol Res 39:559-565.
Xin H, Li Y, Cui Y, Yang JJ, Zhang ZG, Chopp M (2013a) Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 33:1711-1715.
Xin N, Yang FJ, Li Y, Li YJ, Dai RJ, Meng WW, Chen Y, Deng YL (2013b) Dragon’s blood dropping pills have protective effects on focal cerebral ischemia rats model. Phytomedicine 21:68-74.
Xu K, Tavernarakis N, Driscoll M (2001) Necrotic cell death in C. elegans requires the function of calreticulin and regulators of Ca(2+) release from the endoplasmic reticulum. Neuron 31:957-971.
Yamada N, Kakuda W, Kondo T, Shimizu M, Sageshima M, Mitani S, Abo M (2014) Continuous theta-burst stimulation combined with occupational therapy for upper limb hemiparesis after stroke: a preliminary study. Acta Neurol Belg 114:279-284.
Yamashima T (2004) Ca2+-dependent proteases in ischemic neuronal death: a conserved ‘calpain-cathepsin cascade’ from nematodes to primates. Cell Calcium 36:285-293.
Yang ZX, Xie JH, Liu DD (2017) Xingnao Kaiqiao needling method for acute ischemic stroke: a meta-analysis of safety and efficacy. Neural Regen Res 12:1308-1314.
Yenari MA, Han HS (2012) Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 13:267-278.
Yin X, Crawford TO, Griffin JW, Tu P, Lee VM, Li C, Roder J, Trapp BD (1998) Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J Neurosci 18:1953-1962.
Ying W (2006) NAD+ and NADH in cellular functions and cell death. Front Biosci 11:3129-3148.
Yiu G, He Z (2006) Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7:617-627.
Yoo SW, Kim SS, Lee SY, Lee HS, Kim HS, Lee YD, Suh-Kim H (2008) Mesenchymal stem cells promote proliferation of endogenous neural stem cells and survival of newborn cells in a rat stroke model. Exp Mol Med 40:387-397.
Yoshimura S, Takagi Y, Harada J, Teramoto T, Thomas SS, Waeber C, Bakowska JC, Breakefield XO, Moskowitz MA (2001) FGF-2 regulation of neurogenesis in adult hippocampus after brain injury. Proc Natl Acad Sci U S A 98:5874-5879.
Yuan J (2009) Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis 14:469-477.
Zechel S, Werner S, Unsicker K, von Bohlen und Halbach O (2010) Expression and functions of fibroblast growth factor 2 (FGF-2) in hippocampal formation. Neuroscientist 16:357-373.
Zhang P, Lei X, Sun Y, Zhang H, Chang L, Li C, Liu D, Bhatta N, Zhang Z, Jiang C (2016) Regenerative repair of Pifithrin-alpha in cerebral ischemia via VEGF dependent manner. Sci Rep 6:26295.
Zhang S, Wu B, Liu M, Li N, Zeng X, Liu H, Yang Q, Han Z, Rao P, Wang D, all I (2015) Acupuncture efficacy on ischemic stroke recovery: multicenter randomized controlled trial in China. Stroke 46:1301-1306.
Zhao E, Xu H, Wang L, Kryczek I, Wu K, Hu Y, Wang G, Zou W (2012) Bone marrow and the control of immunity. Cell Mol Immunol 9:11-19.
Zhao H, Steinberg GK, Sapolsky RM (2007) General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage. J Cereb Blood Flow Metab 27:1879-1894.
Zhao Y, Guan YF, Zhou XM, Li GQ, Li ZY, Zhou CC, Wang P, Miao CY (2015) Regenerative neurogenesis after ischemic stroke promoted by nicotinamide phosphoribosyltransferase-nicotinamide adenine dinucleotide cascade. Stroke 46:1966-1974.
Zheng W, Honmou O, Miyata K, Harada K, Suzuki J, Liu H, Houkin K, Hamada H, Kocsis JD (2010) Therapeutic benefits of human mesenchymal stem cells derived from bone marrow after global cerebral ischemia. Brain Res 1310:8-16.
Zivin JA (2009) Acute stroke therapy with tissue plasminogen activator (tPA) since it was approved by the U.S. Food and Drug Administration (FDA). Ann Neurol 66:6-10
|This article has been cited by|
||Neuroprotective Effect of Danhong Injection on Cerebral Ischemia-Reperfusion Injury in Rats by Activation of the PI3K-Akt Pathway
| ||Chen Feng,Haofang Wan,Yangyang Zhang,Li Yu,Chongyu Shao,Yu He,Haitong Wan,Weifeng Jin |
| ||Frontiers in Pharmacology. 2020; 11 |
|[Pubmed] | [DOI]|
||High fructose diet-induced obesity worsens post-ischemic brain injury in the hippocampus of female rats
| ||P. A. Pérez-Corredor,J. A. Gutiérrez-Vargas,L. Ciro-Ramírez,Norman Balcazar,G. P. Cardona-Gómez |
| ||Nutritional Neuroscience. 2020; : 1 |
|[Pubmed] | [DOI]|
||Longshengzhi Capsules Improve Ischemic Stroke Outcomes and Reperfusion Injury via the Promotion of Anti-Inflammatory and Neuroprotective Effects in MCAO/R Rats
| ||Weinan Yang,Lincheng Zhang,Simiao Chen,Qigu Yao,Haihong Chen,Jing Zhou,Weiyan Chen,Lan He,Yuyan Zhang |
| ||Evidence-Based Complementary and Alternative Medicine. 2020; 2020: 1 |
|[Pubmed] | [DOI]|
||Metabolome Changes in Cerebral Ischemia
| ||Tae Hwan Shin,Da Yeon Lee,Shaherin Basith,Balachandran Manavalan,Man Jeong Paik,Igor Rybinnik,M. Maral Mouradian,Jung Hwan Ahn,Gwang Lee |
| ||Cells. 2020; 9(7): 1630 |
|[Pubmed] | [DOI]|
||Human placental trophoblast progenitor cells (hTPCs) promote angiogenesis and neurogenesis after focal cerebral ischemia in rats
| ||Muge Molbay,Eylem Özaydin-Goksu,Dijle Kipmen-Korgun,Ali Unal,Murat Ozekinci,Erhan Cebeci,Emin Maltepe,Emin Turkay Korgun |
| ||International Journal of Neuroscience. 2020; : 1 |
|[Pubmed] | [DOI]|
||Lycopene - a pleiotropic neuroprotective nutraceutical: Deciphering its therapeutic potentials in broad spectrum neurological disorders
| ||Rajib Paul,Muhammed Khairujjaman Mazumder,Joyobrato Nath,Satarupa Deb,Satinath Paul,Pallab Bhattacharya,Anupom Borah |
| ||Neurochemistry International. 2020; : 104823 |
|[Pubmed] | [DOI]|
||Hydroxysafflor Yellow A Together with Blood–Brain Barrier Regulator Lexiscan for Cerebral Ischemia Reperfusion Injury Treatment
| ||Liwei Tan,Yeye Wang,Yu Jiang,Rong Wang,Jingzhi Zu,Rui Tan |
| ||ACS Omega. 2020; 5(30): 19151 |
|[Pubmed] | [DOI]|
||NPD1 inhibits excessive autophagy by targeting RNF146 and wnt/ß-catenin pathway in cerebral ischemia-reperfusion injury
| ||Qiong Mu,Hailong Zhou,Yingning Xu,Qian He,Xiao Luo,Wansong Zhang,Haibing Li |
| ||Journal of Receptors and Signal Transduction. 2020; : 1 |
|[Pubmed] | [DOI]|
||Curcumin exerts protective effects against hypoxia-reoxygenation injury via the enhancement of apurinic/apyrimidinic endonuclease?1 in SH-SY5Y cells: Involvement of the PI3K/AKT pathway
| ||Lei Wu,Cao Jiang,Ying Kang,Yaji Dai,Wei Fang,Peng Huang |
| ||International Journal of Molecular Medicine. 2020; |
|[Pubmed] | [DOI]|
||Transcriptional activation of antioxidant gene expression by Nrf2 protects against mitochondrial dysfunction and neuronal death associated with acute and chronic neurodegeneration
| ||Molly J. Goodfellow,Apurva Borcar,Julie L. Proctor,Tiffany Greco,Robert E. Rosenthal,Gary Fiskum |
| ||Experimental Neurology. 2020; 328: 113247 |
|[Pubmed] | [DOI]|
||Stearic Acid Methyl Ester Affords Neuroprotection and Improves Functional Outcomes after Cardiac Arrest
| ||Po-Yi Chen,Celeste Yin-Chieh Wu,Garrett A. Clemons,Cristiane T. Citadin,Alexandre Couto e Silva,Harlee E. Possoit,Rinata Azizbayeva,Nathan E. Forren,Chin-Hung Liu,K.N. Shanaka Rao,David M. Krzywanski,Reggie Hui-Chao Lee,Jake T. Neumann,Hung Wen Lin |
| ||Prostaglandins, Leukotrienes and Essential Fatty Acids. 2020; : 102138 |
|[Pubmed] | [DOI]|
||An Inhibitor of the Sodium–Hydrogen Exchanger-1 (NHE-1), Amiloride, Reduced Zinc Accumulation and Hippocampal Neuronal Death after Ischemia
| ||Beom Seok Kang,Bo Young Choi,A Ra Kho,Song Hee Lee,Dae Ki Hong,Jeong Hyun Jeong,Dong Hyeon Kang,Min Kyu Park,Sang Won Suh |
| ||International Journal of Molecular Sciences. 2020; 21(12): 4232 |
|[Pubmed] | [DOI]|
||Pinosylvin provides neuroprotection against cerebral ischemia and reperfusion injury through enhancing PINK1/Parkin mediated mitophagy and Nrf2 pathway
| ||Hui Xu,Ruixia Deng,Edmund T.S. Li,Jiangang Shen,Mingfu Wang |
| ||Journal of Functional Foods. 2020; 71: 104019 |
|[Pubmed] | [DOI]|
||Extracellular vesicles derived from macrophage promote angiogenesis In vitro and accelerate new vasculature formation In vivo
| ||Prakash Gangadaran,Ramya Lakshmi Rajendran,Ji Min Oh,Chae Moon Hong,Shin Young Jeong,Sang-Woo Lee,Jaetae Lee,Byeong-Cheol Ahn |
| ||Experimental Cell Research. 2020; : 112146 |
|[Pubmed] | [DOI]|
||Neuroprotective effects of andrographolide on chronic cerebral hypoperfusion-induced hippocampal neuronal damage in rats possibly via PTEN/AKT signaling pathway
| ||Da-Peng Wang,Shu-Hui Chen,Di Wang,Kai Kang,Yi-Fang Wu,Shao-Hua Su,Ying-Ying Zhang,Jian Hai |
| ||Acta Histochemica. 2020; : 151514 |
|[Pubmed] | [DOI]|
||Inhibiting endogenous tissue plasminogen activator enhanced neuronal apoptosis and axonal injury after traumatic brain injury
| ||Jun-Jie Zhao,Zun-Wei Liu,Bo Wang,Ting-Qin Huang,Dan Guo,Yong-Lin Zhao,Jin-Ning Song |
| ||Neural Regeneration Research. 2020; 15(4): 667 |
|[Pubmed] | [DOI]|
||Fluoxetine mitigating late-stage cognition and neurobehavior impairment induced by cerebral ischemia reperfusion injury through inhibiting ERS-mediated neurons apoptosis in the hippocampus
| ||Feng Xu,Guixing Zhang,Jiangwen Yin,Qingtong Zhang,Ming-yue Ge,Li Peng,Sheng Wang,Yan Li |
| ||Behavioural Brain Research. 2019; 370: 111952 |
|[Pubmed] | [DOI]|
||Post-ischemic supplementation of folic acid improves neuronal survival and regeneration in vitro
| ||Charles K. Davis,G.K. Rajanikant |
| ||Nutrition Research. 2019; |
|[Pubmed] | [DOI]|
||Cysteinyl Leukotriene Receptor 2 is Involved in Inflammation and Neuronal Damage by Mediating Microglia M1/M2 Polarization through NF-?B Pathway
| ||Rui Zhao,Miaofa Ying,Shenglong Gu,Wei Yin,Yanwei Li,Hong Yuan,Sanhua Fang,Mingxing Li |
| ||Neuroscience. 2019; |
|[Pubmed] | [DOI]|
||Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti-inflammatory phenotype through STAT3 pathway
| ||Zong-Jian Liu,Yuan-Yuan Ran,Shu-Yan Qie,Wei-Jun Gong,Fu-Hai Gao,Zi-Tong Ding,Jia-Ning Xi |
| ||CNS Neuroscience & Therapeutics. 2019; 25(12): 1353 |
|[Pubmed] | [DOI]|
||Modes of Calcium Regulation in Ischemic Neuron
| ||Vineeta Singh,Vijaya Nath Mishra,Rameshwar Nath Chaurasia,Deepika Joshi,Vibha Pandey |
| ||Indian Journal of Clinical Biochemistry. 2019; |
|[Pubmed] | [DOI]|
||The role of neurogenesis in neurorepair after ischemic stroke
| ||Bruno L. Marques,Gustavo A. Carvalho,Elis M.M. Freitas,Raphaela A. Chiareli,Thiago G. Barbosa,Armani G.P. Di Araújo,Yanley L. Nogueira,Raul I. Ribeiro,Ricardo C. Parreira,Mariana S. Vieira,Rodrigo R. Resende,Renato S. Gomez,Onésia C. Oliveira-Lima,Mauro C.X. Pinto |
| ||Seminars in Cell & Developmental Biology. 2019; |
|[Pubmed] | [DOI]|
||Sappanone A prevents hypoxia-induced injury in PC-12 cells by down-regulation of miR-15a
| ||Chunyang Kang,Jian Gao,Mingyang Kang,Xiaoyang Liu,Yao Fu,Libo Wang |
| ||International Journal of Biological Macromolecules. 2019; 123: 35 |
|[Pubmed] | [DOI]|
||Neuroprotection of Resveratrol Against Focal Cerebral Ischemia/Reperfusion Injury in Mice Through a Mechanism Targeting Gut-Brain Axis
| ||Zhongci Dou,Xiongfei Rong,Erxian Zhao,Lixia Zhang,Yunqi Lv |
| ||Cellular and Molecular Neurobiology. 2019; |
|[Pubmed] | [DOI]|
||Ganoderic Acid A exerts the cytoprotection against hypoxia-triggered impairment in PC12 cells via elevating microRNA-153
| ||Hong Li,Bo Lou,Yingying Zhang,Changyuan Zhang |
| ||Phytotherapy Research. 2019; |
|[Pubmed] | [DOI]|
||Intranasal Erythropoietin Protects CA1 Hippocampal Cells, Modulated by Specific Time Pattern Molecular Changes After Ischemic Damage in Rats
| ||R. J. Macias-Velez,L. Fukushima-Díaz de León,C. Beas-Zárate,M. C. Rivera-Cervantes |
| ||Journal of Molecular Neuroscience. 2019; |
|[Pubmed] | [DOI]|
||Platycarya strobilacea leaf extract protects mice brain with focal cerebral ischemia by antioxidative property
| ||Ji Hye Lee,Ji Heun Jeong,Young-Gil Jeong,Do-Kyung Kim,Nam-Seob Lee,Chun Soo Na,Eun Soo Doh,Seung Yun Han |
| ||Anatomy & Cell Biology. 2019; 52(4): 486 |
|[Pubmed] | [DOI]|
||MiR-663, a MicroRNA Linked with Inflammation and Cancer That Is under the Influence of Resveratrol
| ||Jean-Jacques Michaille,Victoria Piurowski,Brooke Rigot,Hesham Kelani,Emily Fortman,Esmerina Tili |
| ||Medicines. 2018; 5(3): 74 |
|[Pubmed] | [DOI]|
||Activating Wnt/ß-catenin signaling pathway for disease therapy: Challenges and opportunities
| ||Piao Huang,Rong Yan,Xue Zhang,Lei Wang,Xisong Ke,Yi Qu |
| ||Pharmacology & Therapeutics. 2018; |
|[Pubmed] | [DOI]|
||MALAT1 lncRNA Induces Autophagy and Protects Brain Microvascular Endothelial Cells Against Oxygen–Glucose Deprivation by Binding to miR-200c-3p and Upregulating SIRT1 Expression
| ||Shan Wang,Xu Han,Zhengchun Mao,Yanming Xin,Surendra Maharjan,Bing Zhang |
| ||Neuroscience. 2018; |
|[Pubmed] | [DOI]|
||Palmitic acid methyl ester is a novel neuroprotective agent against cardiac arrest
| ||Reggie Hui-Chao Lee,Alexandre Couto e Silva,HarLee E. Possoit,Francesca M. Lerner,Po-Yi Chen,Rinata Azizbayeva,Cristiane T. Citadin,Celeste Yin-Chieh Wu,Jake T. Neumann,Hung Wen Lin |
| ||Prostaglandins, Leukotrienes and Essential Fatty Acids. 2018; |
|[Pubmed] | [DOI]|
||Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7
| ||Dae Hong,Bo Choi,A Kho,Song Lee,Jeong Jeong,Beom Kang,Dong Kang,Kyoung-Ha Park,Sang Suh |
| ||Cells. 2018; 7(12): 231 |
|[Pubmed] | [DOI]|
||Neuroprotection of Cytisine Against Cerebral Ischemia–Reperfusion Injury in Mice by Regulating NR2B-ERK/CREB Signal Pathway
| ||Peng Zhao,Jia-Mei Yang,Yong-Sheng Wang,Yin-Ju Hao,Yu-Xiang Li,Nan Li,Jing Wang,Yang Niu,Tao Sun,Jian-Qiang Yu |
| ||Neurochemical Research. 2018; |
|[Pubmed] | [DOI]|