Key Laboratory of Neurological Diseases

Wuhan, China

Key Laboratory of Neurological Diseases

Wuhan, China
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Wang X.,Huazhong University of Science and Technology | Wang Z.-H.,Huazhong University of Science and Technology | Wu Y.-Y.,Huazhong University of Science and Technology | Tang H.,Huazhong University of Science and Technology | And 9 more authors.
Molecular Neurobiology | Year: 2013

Alzheimer's disease (AD) is the most prevalent type of dementia in elderly people. There are decreased melatonin levels in the serum of AD patients, and melatonin supplements are able to reverse AD pathology and memory deficits in many animal experiments and clinical trials. However, the underlying mechanism regarding how melatonin rescues the AD-like memory/synaptic disorder remains unknown. Here, we use the Morris water maze, step-down inhibitory avoidance task, in vivo long-term potentiation recording, and Golgi staining and report that intraperitoneal injection of melatonin (1 mg/kg/day) for 14 days in rats effectively reverses the memory and synaptic impairment in scopolamine-induced amnesia, a well-recognized dementia animal model. Using real-time polymerase chain reaction and western blotting experiments, we further determined that melatonin rescues the EPACs/miR-124/Egr1 signal pathway, which is important in learning and memory, as reported recently. Our studies provide a novel underlying epigenetic mechanism for melatonin to attenuate the synaptic disorder and could benefit drug discovery in neurodegenerative diseases. © 2012 Springer Science+Business Media New York.

Zhang H.,Huazhong University of Science and Technology | Li X.,Huazhong University of Science and Technology | Li X.,Key Laboratory of Neurological Diseases | Gong J.,Huazhong University of Science and Technology | And 7 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2017

The degeneration of retinal ganglion cells (RGCs) has been identified as a major problem in glaucoma. Previous studies have indicated an association between annexin A1 (ANXA1) and neuronal cell apoptosis, and RGCs apoptosis in acute ischemia-reperfusion was attributed to an increased production of IL-1β. We found that the expression and nuclear translocation of ANXA1 were upregulated in models of acute ischemia-reperfusion in RGCs in vivo. ANXA1 was found to have a promoting effect on the expression of IL-1β in primary cultured RGCs, which could be inhibited by treatment with ANXA1 shRNA or the p65 inhibitor BAY 11-7082. ANXA1 interacted with p65, and recruited it into the nucleus. Chromatin immunoprecipitation assay revealed that ANXA1 accumulated at the IL-1β gene promoter. The reduction of p65 nuclear translocation using a membrane-permeable ANXA1 peptide containing a Ser5Ala mutation led to a decrease in the expression of IL-1β, and acute ischemia-reperfusion induced RGCs apoptosis in vivo. These results indicate that in RGCs, ANXA1 increases IL-1β expression by recruiting p65 to the nucleus, which induces cell apoptosis. The obtained results may help the development of a novel treatment strategy against RGCs apoptosis in acute ischemia-reperfusion injury. © 2017 The Author(s)

Xiong Y.-S.,Huazhong University of Science and Technology | Wang D.-L.,Huazhong University of Science and Technology | Tan L.,Huazhong University of Science and Technology | Wang X.,Huazhong University of Science and Technology | And 7 more authors.
CNS and Neurological Disorders - Drug Targets | Year: 2013

One of the neuropathological hallmarks of Alzheimer's disease (AD) is the occurrence of neurofibrillary tangles (NFTs) that are composed of abnormally hyperphosphorylated microtubule-associated protein tau. Abnormal tau hyperphosphorylation is mainly induced due to the imbalance between protein kinases and phosphatases. In the tanglerich subregions of the hippocampus and parietal cortex in the brain of AD patients, the levels of the phosphorylationdependent protein peptidyl-prolyl cis-trans isomerase (Pin1) were found to be low. Although Pin1 can regulate tau phosphorylation, it is not clear whether the inhibition of glycogen synthase kinase 3 (GSK-3), the primary mediator of tau phosphorylation in AD, could reverse tau hyperphosphorylation induced due to the down-regulation of Pin1. We found that while suppression of Pin1, either by using its inhibitor Juglone or a shRNA plasmid against Pin1, induces tau hyperphosphorylation and GSK-3β activation both in vivo and in vitro, inhibition of GSK-3β by SB216763 or LiCl reverses tau hyperphosphorylation. Our data suggest that GSK-3β activation plays an important role in tau hyperphosphorylation induced by the down-regulation of Pin1, and the inhibition of GSK-3β might be a potential therapeutic approach for AD pathology. © 2013 Bentham Science Publishers.

Wen Z.,Huazhong University of Science and Technology | Wen Z.,Key Laboratory of Neurological Diseases | Gao C.,Huazhong University of Science and Technology | Gao C.,Key Laboratory of Neurological Diseases | And 5 more authors.
Journal of Molecular Neuroscience | Year: 2014

Neurons establish interactions with target cells via elongation and guidance of axons, and the growth cone plays pivotal roles in this process. Cyclin-dependent kinase 5 (Cdk5) is a key regulator of nervous system development. Cdk5 regulates several significant events by phosphorylating substrates that are involved in neurogenesis, and previous studies of Cdk5 have typically focused on single substrates. Here, we took a new approach to investigate Cdk5 substrates using mass spectrometry and bioinformatics analyses. Axonal growth cones were isolated and analyzed by HPLC-MALDI-MS/MS. In total, 178,617 MS/MS spectra were detected. Candidates were analyzed by GPS 2.1 and Scansite 3, which predicted that 2,664 and 275 sites, respectively, were potential phosphorylation sites of Cdk5. There were 190 overlapped phosphorylation sites, corresponding to 89 proteins. Those proteins correlated with axonal functions were classified, and two of them were verified using a classic site-specific mutation strategy. This is the first study in which the phosphoproteome of axonal growth cones was identified. The systematic examination of Cdk5 substrates could provide a reference for further study of molecular mechanisms of axonal growth cones, and new insights into treatments of neuronal disorders. © 2013 Springer Science+Business Media New York.

Wang W.,Huazhong University of Science and Technology | Wang F.,Huazhong University of Science and Technology | Wang F.,Key Laboratory of Neurological Diseases | Yang Y.-J.,Huazhong University of Science and Technology | And 9 more authors.
British Journal of Pharmacology | Year: 2011

Background and Purpose There is growing interest in the physiological functions of flavonoids, especially in their effects on cognitive function and on neurodegenerative diseases. The aim of the current investigation was to evaluate the role of the flavonoid baicalein in long-term potentiation (LTP) in the hippocampal CA1 region and cognitive behavioural performance. EXPERIMENTAL APPROACH Effects of baicalein on LTP in rat hippocampal slices were investigated by electrophysiological methods. Phosphorylation of Akt (at Ser 473), the extracellular signal-regulated kinase (ERK1/2) and the transcription factor cAMP response element-binding protein (CREB) (at Ser 133) were analysed by Western blot. Fear conditioning was used to determine whether baicalein could improve learning and memory in rats. KEY RESULTS Baicalein enhanced the N-methyl-d-aspartate glutamate receptor-dependent LTP in a bell-shaped concentration-dependent manner. Addition of the lipoxygenase metabolites 12(S)-HETE and 12(S)-HPETE did not reverse these effects of baicalein. Baicalein treatment enhanced phosphorylation of Akt during induction of LTP with the same bell-shaped dose-response curve. LTP potentiation induced by baicalein was blocked by inhibitors of phosphoinositide 3-kinase. CREB phosphorylation was also increased in the CA1 region of baicalein-treated slices. Baicalein-treated rats performed significantly better than controls in a hippocampus-dependent contextual fear conditioning task. Furthermore, baicalein treatment selectively increased the phosphorylation of Akt and CREB in the CA1 region of hippocampus, but not in the prefrontal cortex, after fear conditioning training. CONCLUSIONS AND IMPLICATIONS Our results demonstrate that the flavonoid baicalein can facilitate memory, and therefore it might be useful in the treatment of patients with memory disorders. © 2011 The British Pharmacological Society.

Wang W.,Huazhong University of Science and Technology | Zheng L.-L.,Huazhong University of Science and Technology | Wang F.,Huazhong University of Science and Technology | Wang F.,Key Laboratory of Neurological Diseases | And 6 more authors.
Journal of Ethnopharmacology | Year: 2011

Aim of the study: Tanshinone IIA (Tan IIA) is one of the key components of Salvia miltiorrhiza Bunge that has been widely used for various cardiovascular and cerebrovascular disorders in Asian countries. Many studies have reported that Tan IIA has antioxidative properties, but whether Tan IIA can rescue neurons from oxidative insult has never been reported. The present study was undertaken to evaluate the possible neuroprotective effects of Tan IIA on hydrogen peroxide (H2O2)-induced oxidative stress in rats. Materials and methods: H2O2-induced cytotoxicity was evaluated by the cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and flow cytometry with PI staining. Calcium imaging experiments were carried out to measure intracellular free calcium concentration. Western blotting was used to determine the expression of Bax and Bcl-2 protein. Electrophysiological studies in hippocampal slices were performed to investigate the effect of Tan IIA on synaptic function and cognitive impairment caused by H2O2. Results: It was found that pretreatment with Tan IIA protected primary rat cortical neurons against H 2O2-induced cytotoxicity. Furthermore, Tan IIA markedly reduced the elevation of [Ca2+]i evoked by H 2O2. Western blot analysis indicated that pretreatment with Tan IIA prevented the increase in Bax/Bcl-2 ratio induced by H 2O2. In addition, preincubation of Tan IIA 20 min prior to H2O2 exposure could reverse H2O 2-induced hippocampal LTP impairment, but without significant alteration in basal synaptic transmission and LTP induction. Conclusions: These findings demonstrate that Tan IIA might serve as a novel promising therapeutic agent for oxidative stress injury in neurodegenerative diseases. © 2010 Elsevier Ireland Ltd.

Wen Z.,Huazhong University of Science and Technology | Wen Z.,Key Laboratory of Neurological Diseases | Shu Y.,Huazhong University of Science and Technology | Shu Y.,Key Laboratory of Neurological Diseases | And 13 more authors.
Neurobiology of Aging | Year: 2014

Raf kinase inhibitor protein (RKIP) is a major negative mediator of the extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. The downregulation of RKIP is correlated with many cancers, but the mechanisms that underlie this downregulation and its roles in the nervous system remain unclear. Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif "KLYEQ" in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA). Furthermore, in the brain sample of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride-induced and transgenic PD models, we demonstrate that CDK5-mediated phosphorylation and autophagy of RKIP are involved in the overactivation of the ERK/MAPK cascade, leading to S-phase reentry and neuronal loss. These findings provide evidence for the role of the CDK5/RKIP/ERK pathway in PD pathogenesis and suggest that this pathway may be a suitable therapeutic target in PD. © 2014 Elsevier Inc.

Xu S.-B.,Key Laboratory of Neurological Diseases | Huang B.,Key Laboratory of Neurological Diseases | Zhang C.-Y.,Key Laboratory of Neurological Diseases | Du P.,Fudan University | And 7 more authors.
CMAJ | Year: 2013

Background: The traditional Chinese theory of acupuncture emphasizes that the intensity of acupuncture must reach a threshold to generate de qi, which is necessary to achieve the best therapeutic effect. De qi is an internal compound sensation of soreness, tingling, fullness, aching, cool, warmth and heaviness, and a radiating sensation at and around the acupoints. However, the notion that de qi must be achieved for maximum benefit has not been confirmed by modern scientific evidence. Methods: We performed a prospective multicentre randomized controlled trial involving patients with Bell palsy. Patients were randomly assigned to the de qi (n = 167) or control (n = 171) group. Both groups received acupuncture: in the de qi group, the needles were manipulated manually until de qi was reached, whereas in the control group, the needles were inserted without any manipulation. All patients received prednisone as a basic treatment. The primary outcome was facial nerve function at month 6. We also assessed disability and quality of life 6 months after randomization. Results: After 6 months, patients in the de qi group had better facial function (adjusted odds ratio [OR] 4.16, 95% confidence interval [CI] 2.23-7.78), better disability assessment (differences of least squares means 9.80, 95% CI 6.29-13.30) and better quality of life (differences of least squares means 29.86, 95% CI 22.33-37.38). Logistic regression analysis showed a positive effect of the de qi score on facial-nerve function (adjusted OR 1.07, 95% CI 1.04-1.09). Interpretation: Among patients with Bell palsy, acupuncture with strong stimulation that elicited de qi had a greater therapeutic effect, and stronger intensity of de qi was associated with the better therapeutic effects. Trial registration: no. NCT00685789. © 2013 Canadian Medical Association or its licensors.

Liu R.-L.,Huazhong University of Science and Technology | Liu R.-L.,Xinxiang Medical University | Xiong Q.-J.,Huazhong University of Science and Technology | Shu Q.,Huazhong University of Science and Technology | And 10 more authors.
Brain Research | Year: 2012

Hyperoside is a flavonoid compound and widely used in clinic to relieve pain and improve cardiovascular functions. However, the effects of hyperoside on ischemic neurons and the molecular mechanisms remain unclear. Here, we used an in vitro ischemic model of oxygen-glucose deprivation followed by reperfusion (OGD-R) to investigate the protective effects of hyperoside on ischemic neuron injury and further explore the possible related mechanisms. Our results demonstrated that hyperoside protected cultured cortical neurons from OGD-R injury, it also relieved glutamate-induced neuronal injury and NMDA-induced [Ca2]i elevation. As for the mechanisms, hyperoside firstly attenuated the phosphorylation of CaMKII caused by OGD-R lesions. Meanwhile, hyperoside lessened iNOS expression induced by OGD-R via inhibition of NF-κB activation. Furthermore, ameliorating of ERK, JNK and Bcl-2 family-related apoptotic signaling pathways were also involved in the neuroprotection of hyperoside. Taken together, these studies revealed that hyperoside had protective effects on neuronal ischemia-reperfusion impairment, which was related to the regulation of nitric oxide signaling pathway. © 2012 Elsevier B.V.

Zhang P.,Huazhong University of Science and Technology | Zhang P.,Key Laboratory of Neurological Diseases | Tian B.,Huazhong University of Science and Technology | Tian B.,Key Laboratory of Neurological Diseases
Oxidative Medicine and Cellular Longevity | Year: 2014

Metabolic syndrome is becoming commoner due to a rise in obesity rates among adults. Generally speaking, a person with metabolic syndrome is twice as likely to develop cardiovascular disease and five times as likely to develop diabetes as someone without metabolic syndrome. Increasing oxidative stress in metabolic syndrome and Parkinson's disease is mentioned in the comprehensive articles; however, the system review about clear relation between metabolic syndrome and Parkinson's disease is deficient. In this review, we will focus on the analysis that the metabolic syndrome may be a risk factor for Parkinson's disease and the preventions that reduce the incident of Parkinson's disease by regulating the oxidative stress. © 2014 Pei Zhang and Bo Tian.

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