The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression.
(1) The monoamine hypothesis has long stood as the major research focus in the pathogenesis of depression. The majority of antidepressant drugs exert their effects by increasing the concentration of synaptic monoamine transmitters through the regulation of signal transduction pathways and transcription factors.
(2) The neural plasticity hypothesis postulates that depression occurs not only because of receptor levels, but also their activation of signaling pathways, the initiation of gene transcription, and a change in the level of downstream target gene expression.
(3) We focus on the extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway and explore the function of this pathway by discussing evidence from molecular biology studies.
Neuroacanthocytosis is an autosomal recessive or dominant inherited disease characterized by widespread, non-specific nervous system symptoms, or spiculated “acanthocytic” red blood cells. The clinical manifestations typically involve chorea and dystonia, or a range of other movement disorders. Psychiatric and cognitive symptoms may also be present. The two core neuroacanthocytosis syndromes, in which acanthocytosis is atypical, are autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome. Acanthocytes are found in a smaller proportion of patients with Huntington's disease-like 2 and pantothenate kinase-associated neurodegeneration. Because the clinical manifestations are diverse and complicated, in this review we present features of inheritance, age of onset, neuroimaging and laboratory findings, as well as the spectrum of central and peripheral neurological abnormalities and extraneuronal involvement to help distinguish the four specific syndromes.
Features of inheritance, age of onset, neuroimaging, laboratory findings, and the spectrum of central and peripheral neurological abnormalities and extraneuronal involvement of neuroacanthocytosis are reviewed to help guide research and instruct clinical diagnosis.
A total of 30 students scoring between 12 and 20 on the Test Anxiety Scale who had been exhibiting an anxious state > 24 hours, and 30 normal control students were recruited. Indices of heart rate variability were recorded using an Actiheart electrocardiogram recorder at 10 minutes before auricular pressing, in the first half of stimulation and in the second half of stimulation. The results revealed that the standard deviation of all normal to normal intervals and the root mean square of standard deviation of normal to normal intervals were significantly increased after stimulation. The heart rate variability triangular index, very-low-frequency power, low-frequency power, and the ratio of low-frequency to high-frequency power were increased to different degrees after stimulation. Compared with normal controls, the root mean square of standard deviation of normal to normal intervals was significantly increased in anxious students following auricular pressing. These results indicated that auricular pressing can elevate heart rate variability, especially the root mean square of standard deviation of normal to normal intervals in students with pre-exam anxiety.
(1) Immediate stimulation of auricular pressing elevated heart rate variability among students with pre-exam anxiety and normal controls.
(2) Auricular pressing transiently restored balance between sympathetic and vagus nerves in students with pre-exam anxiety.
(3) Auricular pressing was able to simultaneously excite sympathetic and vagus nerves in normal students.
(4) Compared with normal controls, auricular pressing increased the root mean square of standard deviation of normal to normal intervals and vagus nerve excitation in students with pre-exam anxiety.
(5) Elevation of heart rate variability appears to be a potential mechanism for auricular pressing to treat pre-exam anxiety.
Animal models of cerebral palsy established by simple infection or the hypoxia/ischemia method cannot effectively simulate the brain injury of a premature infant. Healthy 17-day-pregnant Wistar rats were intraperitoneally injected with lipopolysaccharide then subjected to hypoxia. The pups were used for this study at 4 weeks of age. Simultaneously, a hypoxia/ischemia group and a control group were used for comparison. The results of the footprint test, the balance beam test, the water maze test, neuroelectrophysiological examination and neuropathological examination demonstrated that, at 4 weeks after birth, footprint repeat space became larger between the forelimbs and hindlimbs of the rats, the latency period on the balance beam and in the Morris water maze was longer, place navigation and ability were poorer, and the stimulus intensity that induced the maximal wave amplitude of the compound muscle action potential was greater in the lipopolysaccharide/hypoxia and hypoxia/ischemia groups than in the control group. We observed irregular cells around the periventricular area, periventricular leukomalacia and breakage of the nuclear membrane in the lipopolysaccharide/hypoxia and hypoxia/ischemia groups. These results indicate that we successfully established a Wistar rat pup model of cerebral palsy by intraperitoneal injection of lipopolysaccharide and hypoxia.
(1) This study successfully established a Wistar rat pup model of cerebral palsy by intraperitoneal injection of lipopolysaccharide and hypoxia.
(2) The brain injuries of the rat pup models were evaluated by behavioral, cognitive, neuroelectrophysiological and neuropathological examinations.
Previous studies addressing the protection of tea polyphenols against cerebral ischemia/reperfusion injury often use focal cerebral ischemia models, and the optimal dose is not unified. In this experiment, a cerebral ischemia/reperfusion injury rat model was established using a modified four-vessel occlusion method. Rats were treated with different doses of tea polyphenols (25, 50, 100, 150, 200 mg/kg) via intraperitoneal injection. Results showed that after 2, 6, 12, 24, 48 and 72 hours of reperfusion, peroxide dismutase activity and total antioxidant capacity in brain tissue gradually increased, while malondialdehyde content gradually decreased after tea polyphenol intervention. Tea polyphenols at 200 mg/kg resulted in the most apparent changes. Terminal deoxynucleotidyl transferase-mediated nick end labeling and flow cytometry showed that 200 mg/kg tea polyphenols significantly reduced the number and percentage of apoptotic cells in the hippocampal CA1 region of rats after cerebral ischemia/reperfusion injury. The open field test and elevated plus maze experiments showed that tea polyphenols at 200 mg/kg strengthened exploratory behavior and reduced anxiety of cerebral ischemia/reperfusion injured rats. Experimental findings indicate that tea polyphenols protected rats against cerebral ischemia/reperfusion injury and 200 mg/kg is regarded as the optimal dose.
(1) Tea polyphenols have anti-inflammatory, antitumor and neuroprotective effects. However, the optimal dose required to exert a protective effect remains unclear.
(2) Previous studies have mainly used a focal cerebral ischemia model, this study established global cerebral ischemia/reperfusion injury in rats, in a broader attempt to optimize the protective dose of tea polyphenols on global cerebral ischemia/reperfusion injury in rats.
(3) We found that tea polyphenols can significantly reduce oxidative stress injury and apoptosis of nerve cells, and that the optimal protective dose is 200 mg/kg.
Electroacupuncture at Shangjuxu (ST37) and Tianshu (ST25) can improve visceral hypersensitivity in rats. Colorectal distension was used to establish a rat model of chronic visceral hypersensitivity. Immunohistochemistry was used to detect P2X2 and P2X3 receptor expression in dorsal root ganglia from rats with chronic visceral hypersensitivity. Results demonstrated that abdominal withdrawal reflex scores obviously increased following establishment of the model, indicating visceral hypersensitivity. Simultaneously, P2X2 and P2X3 receptor expression increased in dorsal root ganglia. After bilateral electroacupuncture at Shangjuxu and Tianshu, abdominal withdrawal reflex scores and P2X2 and P2X3 receptor expression decreased in rats with visceral hypersensitivity. These results indicated that electroacupuncture treatment improved visceral hypersensitivity in rats with irritable bowel syndrome by reducing P2X2 and P2X3 receptor expression in dorsal root ganglia.
(1) P2X2 and P2X3 receptors participated in visceral hypersensitivity in primary afferent neurons of dorsal root ganglia in rats.
(2) Electroacupuncture reduced visceral hypersensitivity in rats with chronic visceral hypersensitivity.
(3) Electroacupuncture improved visceral hypersensitivity in rats with chronic visceral hypersensitivity by regulating P2X2 and P2X3 receptor expression in dorsal root ganglia.
The arrangement of various biological structures should generally ensure the safety of crucial structures and increase their working efficiency; however, other principles governing the relative positions of structures in humans have not been reported. The present study therefore investigated other principles using nerves and their companion vessels in the human body as an example. Nerves and blood vessels usually travel together and in the most direct way towards their targets. Human embryology, histology, and gross anatomy suggest that there are many possible positions for these structures during development. However, for mechanical reasons, tougher or stronger structures should take priority. Nerves are tougher than most other structures, followed by arteries, veins, and lymphatic vessels. Nerves should therefore follow the most direct route, and be followed by the arteries, veins, and lymphatic vessels. This general principle should be applicable to all living things.
This study used nerves and their companion vessels in the human body as examples to investigate the principles governing the relative positioning of structures within organisms. Tougher or stronger structures take priority for mechanical reasons. The results can help to explain the arrangements of local blood vessels and nerves.
The glucose-inhibited neurons present in the lateral hypothalamic area are regarded as glucose detectors. This structure is involved in the regulation of food intake through extracellular blood glucose concentrations, and plays a crucial role in obesity onset. In the present study, obesity models established with high fat feeding were treated with electroacupuncture at Zusanli (ST36)/Inner Court (ST44) on the left side and Tianshu (ST25) bilaterally. We found that electroacupuncture could effectively reduce body weight and the fat-weight ratio, and decrease serum leptin, resistin, tumor necrosis factor alpha, and neuropeptide Y levels, while increase serum adiponectin and cholecystokinin-8 levels. This treatment altered the electrical activity of glucose-inhibited neurons in the lateral hypothalamic area, with electroacupuncture at Zusanlil Inner Court exerting an inhibitory effect, while electroacupuncture at bilateral Tianshu exerting an excitatory effect. These data suggest that electroacupuncture at the lower limbs and abdominal cavity is an effective means for regulating the activity of glucose-inhibited neurons in the lateral hypothalamic area and for improving the secretory function of adipose tissue.
(1) Electroacupuncture at the lower limbs and abdominal cavity is an effective means for fat weight loss and improvement of secretion function of adipose tissue.
(2) Glucose-inhibited neurons are present in the lateral hypothalamic area, and can be regulated by electroacupuncture treatment at the lower limbs and abdominal cavity. This regulatory action may be one of the mechanisms underlying acupuncture treatment for simple obesity.
(3) Electroacupuncture at different acupoints exerts various effects on the glucose-inhibited neurons in the lateral hypothalamic area.
A total of 64 patients with acute lacunar infarction were enrolled within 24 hours of onset. The patients received conventional therapy (antiplatelet drugs and hypolipidemic drugs) alone or conventional therapy plus 450 mg Xueshuantong once a day. The main ingredient of the Xueshuantong lyophilized powder used for injection was Panax notoginseng saponins. Assessments were made at admission and at discharge using the National Institutes of Health Stroke Scale, the Activity of Daily Living and the Mini-Mental State Examination. Additionally, the relative cerebral blood flow, relative cerebral blood volume and relative mean transit time in the region of interest were calculated within 24 hours after the onset of lacunar infarction, using dynamic susceptibility contrast magnetic resonance perfusion imaging technology. Patients underwent a follow-up MRI scan after 4 weeks of treatment. There was an improvement in the Activity of Daily Living scores and a greater reduction in the scores on the National Institutes of Health Stroke Scale in the treatment group than in the control group. However, the Mini-Mental State Examination scores showed no significant differences after 4 weeks of treatment. Compared with the control group, the relative cerebral blood flow at discharge had increased and showed a greater improvement in the treatment group. Furthermore, there was a reduction in the relative mean transit time at discharge and the value was lower in the treatment group than in the control group. The experimental findings indicate that Xueshuantong treatment improves neurological deficits in elderly patients with lacunar infarction, and the mechanism may be related to increased cerebral perfusion.
(1) A prospective randomized double-blind controlled clinical trial was performed to evaluate the therapeutic effect of Xueshuantong in elderly patients with lacunar infarction. The results show a potential for clinical application.
(2) After 4 weeks of treatment, Xueshuantong improved the clinical symptoms, increased relative cerebral blood flow, and decreased the relative mean transit time in the region of interest in elderly patients with lacunar infarction.
(3) After the risk factors such as gender, age and hypertension were excluded, Xueshuantong was shown to significantly reduce the patients’ scores on the National Institutes of Health Stroke Scale.
We hypothesized that the P2X7 receptor may be the target of isoflurane, so we investigated the roles of the P2X7 receptor and inositol triphosphate receptor in calcium overload and neuronal apoptosis induced by isoflurane in cultured embryonic rat hippocampal neurons. Results showed that isoflurane induced widespread neuronal apoptosis and significantly increased cytoplasmic Ca2+. Blockade of P2X7 receptors or removal of extracellular Ca2+ combined with blockade of inositol triphosphate receptors completely inhibited apoptosis or increase in cytoplasmic Ca2+. Removal of extracellular Ca2+ or blockade of inositol triphosphate receptor alone could partly inhibit these effects of isoflurane. Isoflurane could directly activate P2X7-gated channels and induce inward currents, but did not affect the expression of P2X7 receptor protein in neurons. These findings indicate that the mechanism by which isoflurane induced neuronal apoptosis in rat developing brain was mediated by intracellular calcium overload, which was caused by P2X7 receptor mediated calcium influx and inositol triphosphate receptor mediated calcium release.
(1) Many studies have focused on the neurotoxicity of isoflurane in recent years, but little is known about the mechanism involved in this neurotoxicity.
(2) This study focused on isoflurane-induced calcium overload to investigate the mechanism of isoflurane neurotoxicity.
(3) Results demonstrated that the neurotoxicity of isoflurane was mediated by the P2X7 receptor. Specifically, isoflurane induced neuronal apoptosis in developing rat brain by intracellular calcium overload caused by P2X7 receptor mediated calcium influx and inositol triphosphate receptor-mediated calcium release.
This study was designed to evaluate the neuroprotective effects of Morinda citrifolia L. (Rubiaceae), commonly known as noni, and memantine (a N-methy-D-aspartate receptor inhibitor) on hydrocephalus-induced neurodegenerative disorders. Kaolin was injected into the cistern magna of male adult New Zealand rabbits to establish a hydrocephalus animal model. Memantine (20 mg/kg, intraperitoneally; memantine-treated group) or noni (5 mL/kg, intragastrically; noni-treated group) was administered daily for 2 weeks. Microtubule-associated protein-2 and caspase-3 immunohistochemistry were performed to detect neuronal degeneration and apoptosis in the periventricular tissue of the fourth ventricle of rabbits. Microtubule-associated protein-2 staining density was significantly decreased in the hydrocephalic group, while the staining density was significantly increased in the memantine- and noni-treated groups, especially in the noni-treated group. Noni treatment decreased the number of caspase-3-positive cells in rabbits with hydrocephalus, while memantine had no effect. These findings suggest that noni exhibits more obvious inhibitory effects on hydrocephalus-induced neurodegenerative disorders than memantine in periventricular tissue of the fourth ventricle.
(1) Morinda citrifolia L. (Rubiaceae), known as noni, has been extensively used in folk medicine in Polynesia and tropical parts of eastern Asia and Australia, and contains some antioxidative or anti-inflammatory ingredients.
(2) This study monitored the microtubule-associated protein-2, a major component of the cytoskeleton, and the upregulation of caspase-3 as detection indices to validate that noni and memantine protect against hydrocephalus-induced neurodegenerative disorders.
(3) Memantine, a N-methyl-D-aspartate receptor inhibitor, has been used for the treatment of Alzheimer's disease. Results from this study demonstrate that memantine can alleviate hydrocephalus-induced neurodegenerative disorders.
(4) Noni exhibits more obvious inhibitory effects on hydrocephalus-induced neurodegenerative disorder than memantine in periventricular tissue of the fourth ventricle.