|Year : 2019 | Volume
| Issue : 9 | Page : 1494-1498
More than anti-malarial agents: therapeutic potential of artemisinins in neurodegeneration
Bing-Wen Lu1, Larry Baum2, Kwok-Fai So3, Kin Chiu PhD 4, Li-Ke Xie MD 5
1 Department of Ophthalmology, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing; Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administration Region, China
2 State Key Laboratory of Brain and Cognitive Sciences; Center for Genomic Sciences, Li Ka Shing Faculty of Medicine; Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong Special Administration Region, China
3 Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong; Center for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong Special Administration Region; GHM Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
4 Department of Ophthalmology, Li Ka Shing Faculty of Medicine; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong Special Administration Region, China
5 Department of Ophthalmology, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing, China
|Date of Submission||29-Dec-2018|
|Date of Acceptance||13-Feb-2019|
|Date of Web Publication||9-May-2019|
Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administration Region, China; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong Special Administration Region
Department of Ophthalmology, Eye Hospital, China Academy of Chinese Medical Sciences, Beijing
Source of Support: This work was supported by the Natural Science Foundation of Beijing of China, No. 7192235 (to LKX), Conflict of Interest: None
Artemisinin, also called qinghaosu, is originally derived from the sweet wormwood plant (Artemisia annua), which is used in traditional Chinese medicine. Artemisinin and its derivatives (artemisinins) have been widely used for many years as anti-malarial agents, with few adverse side effects. Interestingly, evidence has recently shown that artemisinins might have a therapeutic value for several other diseases beyond malaria, including cancers, inflammatory diseases, and autoimmune disorders. Neurodegeneration is a challenging age-associated neurological disorder characterized by deterioration of neuronal structures as well as functions, whereas neuroinflammation has been considered to be an underlying factor in the development of various neurodegenerative disorders, including Alzheimer’s disease. Recently discovered properties of artemisinins suggested that they might be used to treat neurodegenerative disorders by decreasing oxidation, inflammation, and amyloid beta protein (Aβ). In this review, we will introduce artemisinins and highlight the possible mechanisms of their neuroprotective activities, suggesting that artemisinins might have therapeutic potential in neurodegenerative disorders.
Keywords: artemisinin; inflammation; neuroinflammation; neurodegeneration; Alzheimer’s disease; Parkinson’s disease; Aβ; anti-oxidation; neuroprotection; neural regeneration
|How to cite this article:|
Lu BW, Baum L, So KF, Chiu K, Xie LK. More than anti-malarial agents: therapeutic potential of artemisinins in neurodegeneration. Neural Regen Res 2019;14:1494-8
|How to cite this URL:|
Lu BW, Baum L, So KF, Chiu K, Xie LK. More than anti-malarial agents: therapeutic potential of artemisinins in neurodegeneration. Neural Regen Res [serial online] 2019 [cited 2019 May 27];14:1494-8. Available from: http://www.nrronline.org/text.asp?2019/14/9/1494/255960
| Introduction|| |
Artemisinin and its derivatives from the sweet wormwood plant (Artemisia annua, Asteraceae) are called artemisinins; they have been used in traditional Chinese medicine for a long time (Tu, 2011; Guo, 2016; Wong et al., 2017). The plant was first recognized by the Chinese physician Hong Ge (born in the year 283) for its fever-reducing property (Efferth, 2017). Youyou Tu, at the China Academy of Traditional Chinese Medicine, isolated artemisinin (Artemisinin structure research collaboration group, 1977; Tu, 2011; Guo, 2016) and tested it in clinical trials (Tu, 2016). Studies conducted in humans during 1980s–1990s led to the designation of artemisinins as a first-line treatment for malaria and helped Youyou Tu win the 2015 Nobel Prize in Physiology or Medicine (Chen, 2016). Artemisinin-based combination therapies have joined the currently established standard treatments of malarial parasites around the world (Qin et al., 2017). Interestingly, abundant evidence has recently accumulated demonstrating that artemisinins might also be useful for many other diseases beyond malaria, including cancers, inflammatory diseases, and autoimmune disorders (Raffetin et al., 2018).
Neurodegeneration is a type of neurological disorder that mainly occurs in the aging population and is characterized by deterioration of neuronal structures as well as functions (Kreiner, 2018). Neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease, are currently major challenges around the world (Olanow et al., 2009). The causes for neurodegenerative disorders are still not fully known, but might include excitotoxicity, oxidative stress, inflammation, and apoptosis (Alexander, 2017; Feldmann et al., 2019; Toosi et al., 2019). Signs of neuroinflammation have been proven in many AD mouse models before Aβ accumulation (Camara and De-Souza, 2018). Thus, neuroinflammation is now widely regarded as an important pathogenic factor of neurodegenerative disorders (Braidy and Grant, 2017; McCauley and Baloh, 2018; Niranjan, 2018).
Newly discovered properties of artemisinins suggest that they might be able to treat neurodegenerative diseases (Okorji et al., 2016; Zheng et al., 2016; Yan et al., 2017; Zeng et al., 2017). This review will explore this evidence.
A literature review was conducted in February 2019 using the PubMed. Using the key word “artemisinins”, 632 relevant publications published from 1956 to 2019 were retrieved. Among them, around 60 publications were examined using the key words “inflammation” OR “neuro-” OR “oxidation”.
| Chemical Structures and Pharmacological Actions of Artemisinins|| |
It was Youyou Tu who first deduced the structure of artemisinin. Using mass spectroscopy, spectrophotometry and X-ray crystallography, she discovered that artemisinin is a sesquiterpene lactone endoperoxide (Tu, 2016). The clinically important artemisinins include artesunate, artemether, and dihydroartemisin (DHA) [Figure 1], which were discovered and developed in 1986 (Nair et al., 1986). Today, these derivatives are more commonly used than artemisinin itself to treat malaria because of the minimal adverse effects, as well as their better efficacy and tolerability (Pinheiro et al., 2018). Artesunate is the most important analog, displaying a more favorable pharmacological profile than artemisinin because of its greater water-solubility and higher oral bioavailability that enable it to act more rapidly (Pinheiro et al., 2018). Recently, novel artemisinin derivatives have also been designed. These are named SM, each with a specific number to identify it [Figure 2].
|Figure 2: Chemical structures of newly developed artemisinin derivatives.|
SM735: 3-(12-β-ARTEMISININOXY) phenoxyl succinic acid (Zhou et al., 2005); SM905: 1-(12-β-dihydroartemisinoxy)-2-hydroxy-3-tert-butylaminopropane maleate (Wang et al., 2007); SM933: ethyl 2-[4-(12-β-artemisininoxy)] phenoxylpropionate (Zhao et al., 2012); SM934: 2’-aminoarteether (β)maleate (Hou et al., 2009).
Click here to view
| Neuroprotective Activity of Artemisinins|| |
Artemisinins have been shown to have neuroprotective effects, and therefore they are potential candidates for the treatment of neurodegenerative disorders (Okorji et al., 2016; Zheng et al., 2016; Yan et al., 2017; Zeng et al., 2017). Other factors in their favor as potential treatments are their abilities to cross the blood-brain barrier as small lipophilic molecules and to protect against oxidative stress (Zheng et al., 2016).
Artemisinin has been shown to have a neuroprotective effect on sodium nitroprusside-induced oxidative insult to PC12 cells and brain primary cortical neurons (Zheng et al., 2016). PC12 cells were pretreated with artemisinin of different concentrations (3.1–100 μM) before their exposure to sodium nitroprusside (800 μM). Cell viability was protected in a concentration-dependent manner with artemisinin pretreatment, as measured by MTT assay, caspase 3/7 activities, and by lactate dehydrogenase release. Extracellular signal-regulated kinases (ERK) is part of the mitogen-activated protein kinase (MAPK) family, one of the oldest families of serine/threonine protein kinases responsible for intracellular signaling (Bohush et al., 2018). Their results demonstrated that the ERK pathway could be activated by artemisinin (25 μM), as shown by western blot analysis, whereas PD98059, an ERK inhibitor, could block the protective effect displayed by artemisinin (Zheng et al., 2016).
Previous studies proposed dysfunctional cyclic-AMP response element binding protein (CREB) signaling in various mouse models of AD (Bartolotti et al., 2016; Ettcheto et al., 2018). Many potential therapeutic approaches targeting CREB signaling have been studied for treatment of neurodegenerative disorders (Motaghinejad et al., 2017). Chong and Zheng (2016) demonstrated that artemisinin was able to suppress oxidative stress induced by hydrogen peroxide (H2O2) in D407 retinal pigment epithelial cells and that activation of ERK/CREB signaling was involved. Yan et al. (2017) demonstrated that artemisinin was able to protect retinal neuronal cells RGC-5 against oxidative insult induced by H2O2 via activation of the ERK1/2 pathway. Their flash electroretinogram results also interestingly found that, in a concentration-dependent manner, artemisinin injected intravitreally could protect retinal function damaged by light exposure.
Artemisinin has also been shown to protect neuronal HT-22 mouse hippocampal cells from glutamate-induced neuronal oxidative damage and cell death (Lin et al., 2018), with 25 μM producing the optimum protective effect. Their results further suggest that pretreatment of artemisinin could activate protein kinase B (Akt)/Bcl-2 signaling because MK2206, an Akt inhibitor, could block its protective effect.
Besides being linked with memory consolidation (Horwood et al., 2006), phosphoinositide 3-kinase/Akt (which artemisinins inhibit) is associated with a number of metabolic functions that are essential for neuronal viability but dysfunctional in AD (Cheng et al., 2011; De Felice, 2013). Moreover, mammalian target of rapamycin (mTOR) signaling is activated by Akt and strongly correlated with the presence of Aβ and tau protein that accumulate in AD (Caccamo et al., 2011). However, the role of mTOR in AD remains controversial because increased Aβ concentrations might increase mTOR signaling, but even higher Aβ concentrations can decrease mTOR signaling (Lafay-Chebassier et al., 2005).
Artesunate could mimic caloric restriction and extend lifespan in yeast (Wang et al., 2015). Downregulation of MAPK signaling was observed in their study, indicating a relationship between cytochrome c oxidase activation and artesunate-heme conjugation.
To sum up, the above results indicate that artemisinin may have neuroprotective effects against oxidative stress through modulating various signaling pathways, most importantly, the ERK, CREB, MAPK, and Akt/mTOR pathways.
Suppression of inflammation is another effect of artemisinin derivatives. Because of the favorable pharmacological actions of artemisinins on various signaling pathways as well as their relatively safe properties, they have been recently studied in various models of inflammatory disorders (Shi et al., 2015; Tu, 2016).
Artemisinins have been demonstrated to suppress inflammatory responses through the suppression of many pro-inflammatory cytokines (Lin et al., 2016; Feng et al., 2017; Li et al., 2018; Lu et al., 2018; Qiang et al., 2018; Sun et al., 2018).
Nuclear factor kappa B (NF-κB) is involved in neurodegenerative disorders such as AD (He et al., 2018). Aβ neurotoxicity has been found to be closely linked to NF-κB activation (Bourne et al., 2007). Therefore, inhibiting NF-κB might treat neurodegenerative disorders (Kim et al., 2017; Subedi et al., 2017; Zhang and Xu, 2018). Another recent study showed that artemisinin B, an artemisinin derivative without a dioxygen bridge, could alleviate learning and memory impairment in AD through inhibiting neuro-inflammatory responses (Qiang et al., 2018). Both the in vivo and in vitro studies have demonstrated that artemisinin B might play its anti-neuroinflammatory role through regulating the toll-like receptor 4-myeloid differentiation factor 88/NF-κB pathway.
In a mouse model of experimental cerebral ischemia/reperfusion injury, a water-soluble derivative of artemisinin, artesunate (10–40 mg/kg) was shown to attenuate inflammatory processes through activating nuclear factor erythroid 2-related factor 2 (Nrf2), which is an important transcription factor that activates anti-oxidation leading to neuroprotection, as well as through suppressing ROS-dependent p38 MARK (Lu et al., 2018).
Nrf2 activation and the up-regulation of antioxidant and anti-inflammatory genes have been suggested by a variety of studies to be attractive therapeutic targets to prevent neurodegenerative disorders (Abdalkader et al., 2018; Morroni et al., 2018). In a study of BV2 microglia, a lipid-soluble derivative of artemisinin, artemether, has been shown to induce Nrf2 activity via increasing its nuclear translocation as well as its binding to antioxidant response elements, suggesting a possible therapeutic neuroprotective effect (Okorji et al., 2016). Pretreatment by artemether (5–40 μM) was found to reduce, in a dose-dependent fashion, the production of nitrite as well as the expression of tumor necrosis factor-alpha, prostaglandin E2, and interleukin-6 in lipopolysaccharide-stimulated BV2 microglia co-cultured with HT22 neuronal cells. Also, their findings suggested that artemether might exert its anti-inflammatory effect through suppressing NF-κB and p38 MAPK signaling.
Aβ peptide, which accumulates in AD, can be neurotoxic. Artemisinin can protect or rescue PC12 cells from cell death induced by a toxic fragment, Aβ 25–35 (Zeng et al., 2017). Treatment with 12.5 or 25 μM artemisinin for 1 hour reduced the death of PC12 cells after subsequent exposure to Aβ 25–35 for 24 hours. Reversing the order of exposure also reduces cell death, with 25 or 50 μM artemisinin for 24 hours rescuing PC12 cells that had been incubated with 0.1, 0.3, or 1 μM Aβ 25–35 for 30 minutes. Further study showed that low-concentration artemisinin might be able to promote neuronal differentiation of PC12 cells through activating the ERK1/2 and p38 MAPK signaling pathway (Sarina et al., 2013). These results suggest the potential application of artemisinin as a novel treatment of neurodegenerative disorders, especially AD.
| Challenges for Use of Artemisinins in Neurodegeneration|| |
Although artemisinin seems to be a pluripotent drug with possible clinical value in anti-malarial, anti-tumor, anti-inflammatory and anti-neurodegenerative roles, there are potential pitfalls (Yuan et al., 2017). In contrast to short-term high-dose artemisinin treatment against malaria, long-term treatment with low-dose artemisinin has generally been investigated for treatment of other diseases (Wang et al., 2015). However, long-term low-dose exposure to artemisinin might induce free radical scavengers that can destroy the vulnerable endoperoxide bridge structure within artemisinin (Sun and Zhou, 2017). Furthermore, unexpected metabolic dysfunctions or other abnormalities, including neurotoxicity, or genotoxicity due to sperm DNA damage, might also emerge upon excessive artemisinin use (Singh et al., 2015). Therefore, the effects of artemisinin on neurodegeneration, either positive or negative, should be assessed and thorough long-term toxicity testing is performed to ensure safety at the appropriate dose.
| Prospect|| |
In the words of the discoverer of artemisinin at the conclusion of her Nobel Lecture, “Expanding clinical applications of artimisinin is also of interest to public health. We know what it can do, we need to know why and how it does it, what else it can do, and how it can do better.” (Tu, 2016). Artemisinins have been demonstrated to alleviate neurodegeneration through reducing oxidation, inflammation, and Aβ toxicity, in both direct and indirect manners. However, research on artemisinins in neurodegenerative disorders is still limited, and much more will need to be studied. A better understanding of the neuroprotective activities of artemisinins might improve treatments of neurodegenerative disorders. 
Author contributions: Manuscript writing: BWL; providing suggestions for the manuscript and manuscript revision: LB; discussions: KC, LKX, KFS; approval of final manuscript for publication: all authors.
Conflicts of interest: There are no conflicts of interest associated with this manuscript.
Financial support: This work was supported by the Natural Science Foundation of Beijing of China, No. 7192235 (to LKX). The funding body played no role in the manuscript preparation other than providing funding.
Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.
Plagiarism check: Checked twice by iThenticate.
Peer review: Externally peer reviewed.
Funding: This work was supported by the Natural Science Foundation of Beijing of China, No. 7192235 (to LKX).
| References|| |
Abdalkader M, Lampinen R, Kanninen KM, Malm TM, Liddell JR (2018) Targeting Nrf2 to suppress ferroptosis and mitochondrial dysfunction in neurodegeneration. Front Neurosci 12:466.
Alexander RW (2017) Use of PIXYL software analysis of brain MRI (with & without contrast) as valuable metric in clinical trial tracking in study of multiple sclerosis (MS) and related neurodegenerative processes. Clin Trials Degener Dis 2:1-6.
Artemisinin structure research collaboration group (1977) A new type of galacterpene lactone—artimisinin. Kexue Tongbao 22:142.
Bartolotti N, Bennett DA, Lazarov O (2016) Reduced pCREB in Alzheimer’s disease prefrontal cortex is reflected in peripheral blood mononuclear cells. Mol Psychiatry 21:1158-1166.
Bohush A, Niewiadomska G, Filipek A (2018) Role of mitogen activated protein kinase signaling in Parkinson’s disease. Int J Mol Sci 19:E2973.
Bourne KZ, Ferrari DC, Lange-Dohna C, Rossner S, Wood TG, Perez-Polo JR (2007) Differential regulation of BACE1 promoter activity by nuclear factor-kappaB in neurons and glia upon exposure to beta-amyloid peptides. J Neurosci Res 85:1194-1204.
Braidy N, Grant R (2017) Kynurenine pathway metabolism and neuroinflammatory disease. Neural Regen Res 12:39-42.
Caccamo A, Maldonado MA, Majumder S, Medina DX, Holbein W, Magrí A, Oddo S (2011) Naturally secreted amyloid-beta increases mammalian target of rapamycin (mTOR) activity via a PRAS40-mediated mechanism. J Biol Chem 286:8924-8932.
Camara H, De-Souza EA (2018) Beta-amyloid accumulation slows earlier than expected in preclinical Alzheimer’s disease patients. J Neurosci 38:9123-9125.
Chen WJ (2016) Honoring antiparasitics: The 2015 Nobel Prize in Physiology or Medicine. Biomed J 39:93-97.
Cheng C, Ho WE, Goh FY, Guan SP, Kong LR, Lai WQ, Leung BP, Wong WS (2011) Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway. PLoS One 6:e20932.
Chong CM, Zheng W (2016) Artemisinin protects human retinal pigment epithelial cells from hydrogen peroxide-induced oxidative damage through activation of ERK/CREB signaling. Redox Biol 9:50-56.
De Felice FG (2013) Alzheimer’s disease and insulin resistance: translating basic science into clinical applications. J Clin Invest 123:531-539.
Efferth T (2017) Cancer combination therapy of the sesquiterpenoid artesunate and the selective EGFR-tyrosine kinase inhibitor erlotinib. Phytomedicine 37:58-61.
Ettcheto M, Abad S, Petrov D, Pedrós I, Busquets O, Sánchez-López E, Casadesús G, Beas-Zarate C, Carro E, Auladell C, Olloquequi J, Pallàs M, Folch J, Camins A (2018) Early preclinical changes in hippocampal CREB-binding protein expression in a mouse model of familial Alzheimer’s disease. Mol Neurobiol 55:4885-4895.
Feldmann KG, Chowdhury A, Becker JL, McAlpin N, Ahmed T, Haider S, Richard Xia JX, Diaz K, Mehta MG, Mano I (2019) Non-canonical activation of CREB mediates neuroprotection in a Caenorhabditis elegans model of excitotoxic necrosis. J Neurochem 148:531-549.
Feng X, Chen W, Xiao L, Gu F, Huang J, Tsao BP, Sun L (2017) Artesunate inhibits type I interferon-induced production of macrophage migration inhibitory factor in patients with systemic lupus erythematosus. Lupus 26:62-72.
Guo Z (2016) Artemisinin anti-malarial drugs in China. Acta Pharm Sin B 6:115-124.
He P, Yan S, Zheng J, Gao Y, Zhang S, Liu Z, Liu X, Xiao C (2018) Eriodictyol attenuates LPS-induced neuroinflammation, amyloidogenesis, and cognitive impairments via the inhibition of NF-kappaB in male C57BL/6J mice and BV2 microglial cells. J Agric Food Chem 66:10205-10214.
Horwood JM, Dufour F, Laroche S, Davis S (2006) Signalling mechanisms mediated by the phosphoinositide 3-kinase/Akt cascade in synaptic plasticity and memory in the rat. Eur J Neurosci 23:3375-3384.
Hou LF, He SJ, Wang JX, Yang Y, Zhu FH, Zhou Y, He PL, Zhang Y, Yang YF, Li Y, Tang W, Zuo JP (2009) SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivo. Int Immunopharmacol 9:1509-1517.
Kim MJ, Rehman SU, Amin FU, Kim MO (2017) Enhanced neuroprotection of anthocyanin-loaded PEG-gold nanoparticles against Aβ1-42-induced neuroinflammation and neurodegeneration via the NF-KB /JNK/GSK3β signaling pathway. Nanomedicine 13:2533-2544.
Kreiner G (2018) What have we learned recently from transgenic mouse models about neurodegeneration? The most promising discoveries of this millennium. Pharmacol Rep 70:1105-1115.
Lafay-Chebassier C, Paccalin M, Page G, Barc-Pain S, Perault-Pochat MC, Gil R, Pradier L, Hugon J (2005) mTOR/p70S6k signalling alteration by Abeta exposure as well as in APP-PS1 transgenic models and in patients with Alzheimer’s disease. J Neurochem 94:215-225.
Li T, Zeng Q, Chen X, Wang G, Zhang H, Yu A, Wang H, Hu Y (2018) The therapeutic effect of artesunate on rosacea through the inhibition of the JAK/STAT signaling pathway. Mol Med Rep 17:8385-8390.
Lin SP, Li W, Winters A, Liu R, Yang SH (2018) Artemisinin prevents glutamate-induced neuronal cell death via Akt pathway activation. Front Cell Neurosci 12:108.
Lin ZM, Yang XQ, Zhu FH, He SJ, Tang W, Zuo JP (2016) Artemisinin analogue SM934 attenuate collagen-induced arthritis by suppressing T follicular helper cells and T helper 17 cells. Sci Rep 6:38115.
Lu H, Wang B, Cui N, Zhang Y (2018) Artesunate suppresses oxidative and inflammatory processes by activating Nrf2 and ROS dependent p38 MAPK and protects against cerebral ischemiareperfusion injury. Mol Med Rep 17:6639-6646.
McCauley ME, Baloh RH (2018) Inflammation in ALS/FTD pathogenesis. Acta Neuropathol doi: 10.1007/s00401-018-1933-9.
Morroni F, Sita G, Graziosi A, Turrini E, Fimognari C, Tarozzi A, Hrelia P (2018) Neuroprotective effect of caffeic acid phenethyl ester in a mouse model of Alzheimer’s disease involves Nrf2/HO-1 pathway. Aging Dis 9:605-622.
Motaghinejad M, Motevalian M, Fatima S, Faraji F, Mozaffari S (2017) The neuroprotective effect of curcumin against nicotine-induced neurotoxicity is mediated by CREB-BDNF signaling pathway. Neurochem Res 42:2921-2932.
Nair MS, Acton N, Klayman DL, Kendrick K, Basile DV, Mante S (1986) Production of artemisinin in tissue cultures of Artemisia annua. J Nat Prod 49:504-507.
Niranjan R (2018) Recent advances in the mechanisms of neuroinflammation and their roles in neurodegeneration. Neurochem Int 120:13-20.
Okorji UP, Velagapudi R, El-Bakoush A, Fiebich BL, Olajide OA (2016) Antimalarial drug artemether inhibits neuroinflammation in BV2 microglia through Nrf2-dependent mechanisms. Mol Neurobiol 53:6426-6443.
Olanow CW, Stern MB, Sethi K (2009) The scientific and clinical basis for the treatment of Parkinson disease (2009). Neurology 72:S1-136.
Pinheiro LCS, Feitosa LM, Silveira FFD, Boechat N (2018) Current antimalarial therapies and advances in the development of semi-synthetic artemisinin derivatives. An Acad Bras Cienc 90:1251-1271.
Qiang W, Cai W, Yang Q, Yang L, Dai Y, Zhao Z, Yin J, Li Y, Li Q, Wang Y, Weng X, Zhang D, Chen Y, Zhu X (2018) Artemisinin B improves learning and memory impairment in AD dementia mice by suppressing neuroinflammation. Neuroscience 395:1-12.
Qin Y, Yang G, Li M, Liu HJ, Zhong WL, Yan XQ, Qiao KL, Yang JH, Zhai DH, Yang W, Chen S, Zhou HG, Sun T, Yang C (2017) Dihydroartemisinin inhibits EMT induced by platinum-based drugs via Akt-Snail pathway. Oncotarget 8:103815-103827.
Raffetin A, Bruneel F, Roussel C, Thellier M, Buffet P, Caumes E, Jauréguiberry S (2018) Use of artesunate in non-malarial indications. Med Mal Infect 48:238-249.
Sarina, Yagi Y, Nakano O, Hashimoto T, Kimura K, Asakawa Y, Zhong M, Narimatsu S, Gohda E (2013) Induction of neurite outgrowth in PC12 cells by artemisinin through activation of ERK and p38 MAPK signaling pathways. Brain Res 1490:61-71.
Shi C, Li H, Yang Y, Hou L (2015) Anti-inflammatory and immunoregulatory functions of artemisinin and its derivatives. Mediators Inflamm 2015:435713.
Singh S, Giri A, Giri S (2015) The antimalarial agent artesunate causes sperm DNA damage and hepatic antioxidant defense in mice. Mutat Res Genet Toxicol Environ Mutagen 777:1-6.
Subedi L, Kwon OW, Pak C, Lee G, Lee K, Kim H, Kim SY (2017) N,N-disubstituted azines attenuate LPS-mediated neuroinflammation in microglia and neuronal apoptosis via inhibiting MAPK signaling pathways. BMC Neurosci 18:82.
Sun C, Zhou B (2017) The antimalarial drug artemisinin induces an additional, Sod1-supressible anti-mitochondrial action in yeast. Biochim Biophys Acta Mol Cell Res 1864:1285-1294.
Sun Z, Ma Y, Chen F, Wang S, Chen B, Shi J (2018) Artesunate ameliorates high glucose-induced rat glomerular mesangial cell injury by suppressing the TLR4/NF-kappaB/NLRP3 inflammasome pathway. Chem Biol Interact 293:11-19.
Toosi A, Shajiee H, Khaksari M, Vaezi G, Hojati V (2019) Obestatin improve spatial memory impairment in a rat model of fetal alcohol spectrum disorders via inhibiting apoptosis and neuroinflammation. Neuropeptides doi: 10.1016/j.npep.2019.01.001.
Tu Y (2011) The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med 17:1217-1220.
Tu Y (2016) Artemisinin-A gift from traditional Chinese medicine to the world (Nobel Lecture). Angew Chem Int Ed Engl 55:10210-10226.
Wang D, Wu M, Li S, Gao Q, Zeng Q (2015) Artemisinin mimics calorie restriction to extend yeast lifespan via a dual-phase mode: a conclusion drawn from global transcriptome profiling. Sci China Life Sci 58:451-465.
Wang JX, Tang W, Yang ZS, Wan J, Shi LP, Zhang Y, Zhou R, Ni J, Hou LF, Zhou Y, He PL, Yang YF, Li Y, Zuo JP (2007) Suppressive effect of a novel water-soluble artemisinin derivative SM905 on T cell activation and proliferation in vitro and in vivo. Eur J Pharmacol 564:211-218.
Wong YK, Xu C, Kalesh KA, He Y, Lin Q, Wong WSF, Shen HM, Wang J (2017) Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action. Med Res Rev 37:1492-1517.
Yan F, Wang H, Gao Y, Xu J, Zheng W (2017) Artemisinin protects retinal neuronal cells against oxidative stress and restores rat retinal physiological function from light exposed damage. ACS Chem Neurosci 8:1713-1723.
Yuan DS, Chen YP, Tan LL, Huang SQ, Li CQ, Wang Q, Zeng QP (2017) Artemisinin: a panacea eligible for unrestrictive use? Front Pharmacol 8:737.
Zeng Z, Xu J, Zheng W (2017) Artemisinin protects PC12 cells against beta-amyloid-induced apoptosis through activation of the ERK1/2 signaling pathway. Redox Biol 12:625-633.
Zhang FX, Xu RS (2018) Juglanin ameliorates LPS-induced neuroinflammation in animal models of Parkinson’s disease and cell culture via inactivating TLR4/NF-kappaB pathway. Biomed Pharmacother 97:1011-1019.
Zhao YG, Wang Y, Guo Z, Gu AD, Dan HC, Baldwin AS, Hao W, Wan YY (2012) Dihydroartemisinin ameliorates inflammatory disease by its reciprocal effects on Th and regulatory T cell function via modulating the mammalian target of rapamycin pathway. J Immunol 189:4417-4425.
Zheng W, Chong CM, Wang H, Zhou X, Zhang L, Wang R, Meng Q, Lazarovici P, Fang J (2016) Artemisinin conferred ERK mediated neuroprotection to PC12 cells and cortical neurons exposed to sodium nitroprusside-induced oxidative insult. Free Radic Biol Med 97:158-167.
Zhou WL, Wu JM, Wu QL, Wang JX, Zhou Y, Zhou R, He PL, Li XY, Yang YF, Zhang Y, Li Y, Zuo JP (2005) A novel artemisinin derivative, 3-(12-beta-artemisininoxy) phenoxyl succinic acid (SM735), mediates immunosuppressive effects in vitro and in vivo. Acta Pharmacol Sin 26:1352-1358.
C-Editor: Zhao M; S-Editors: Yu J, Li CH; L-Editor: Song LP; T-Editor: Jia Y
[Figure 1], [Figure 2]