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Zhou J.,Tongji Medical College | Wu P.-F.,Tongji Medical College | Wang F.,Tongji Medical College | Wang F.,Huazhong University of Science and Technology | And 4 more authors.
Clinical and Experimental Pharmacology and Physiology | Year: 2012

Ischaemic brain injury is a leading cause of death and disability in many countries. However, the pathological mechanisms underlying ischaemic brain injury, including oxidative stress, calcium overload, excitotoxicity and neuronal apoptosis, are perplexing and this makes it difficult to find effective novel drugs for the treatment of the condition. Recently, gaseous molecules such as nitric oxide (NO), carbon monoxide (CO), hydrogen sulphide (H2S) and hydrogen (H2) have attracted considerable interest because of their physiological and pathophysiological roles in various body systems. Emerging evidence indicates that gaseous molecules are involved in the pathological processes of ischaemic brain damage. In the present review, we summarize evidence regarding the involvement of gaseous molecules in ischaemic brain injury and discuss the therapeutic potential of targeting gaseous molecules. Collectively, the available data suggest that the application of these biological gas molecules and their pharmacological regulators may be a potential therapeutic approach for the treatment of ischaemic brain injury. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd. Source


Liu C.,Xianning University | Wu J.,Xianning University | Xu K.,Xianning University | Cai F.,Xianning University | And 4 more authors.
Journal of Neurochemistry | Year: 2010

Recently more evidences support baicalein (Bai) is neuroprotective in models of ischemic stroke. This study was conducted to determine the molecular mechanisms involved in this effect. Either permanent or transient (2 h) middle cerebral artery occlusion (MCAO) was induced in rats in this study. Permanent MCAO led to larger infarct volumes in contrast to transient MCAO. Only in transient MCAO, Bai administration significantly reduced infarct size. Baicalein also markedly reduced apoptosis in the penumbra of transient MCAO rats. Additionally, oxygen and glucose deprivation (OGD) was used to mimic ischemic insult in primary cultured cortical neurons. A rapid increase in the intracellular reactive oxygen species level and nitrotyrosine formation induced by OGD was counteracted by Bai, which is parallel with attenuated cell injury. The reduction of phosphorylation Akt and glycogen synthase kinase-3β (GSK3β) induced by OGD was restored by Bai, which was associated with preserved levels of phosphorylation of PTEN, the phophatase that negatively regulates Akt. As a consequence, Bcl-2/Bcl-xL-associated death protein phosphorylation was increased and the protein level of Bcl-2 in motochondria was maintained, which subsequently antagonize cytochrome c released in cytosol. LY294002 blocked the increase in phospho-AKT evoked by Bai and abolished the associated protective effect. Together, these findings provide evidence that Bai protects neurons against ischemia injury and this neuroprotective effect involves PI3K/Akt and PTEN pathway. © 2010 International Society for Neurochemistry. Source


Yang J.,Huazhong University of Science and Technology | Luo X.,Huazhong University of Science and Technology | Huang X.,Huazhong University of Science and Technology | Ning Q.,Huazhong University of Science and Technology | And 4 more authors.
Journal of Neurochemistry | Year: 2014

Increasing evidence indicates that the Eph receptors and their ephrin ligands are involved in the regulation of interactions between neurons and astrocytes. Moreover, astrocytic ephrin-A3 reverse signaling mediated by EphA4 receptors is necessary for controlling the abundance of glial glutamate transporters. However, the role of ephrin-A3 reverse signaling in astrocytic function and neuronal death under ischemic conditions remains unclear. In the present study, we found that the EphA4 receptor and its ephrin-A3 ligand, which were distributed in neurons and astrocytes, respectively, in the hippocampus showed a coincident up-regulation of protein expression in the early stage of ischemia. Application of clustered EphA4 decreased the expressions of astrocytic glutamate transporters together with astrocytic glutamate uptake capacity through activating ephrin-A3 reverse signaling. In consequence, neuronal loss was aggravated in the CA1 region of the hippocampus accompanied by impaired hippocampus-dependent spatial memory when clustered EphA4 treatment was administered prior to transient global ischemia. These findings indicate that EphA4-mediated ephrin-A3 reverse signaling is a crucial mechanism for astrocytes to control glial glutamate transporters and prevent glutamate excitotoxicity under pathological conditions. © 2014 International Society for Neurochemistry. Source


Wu P.-F.,Huazhong University of Science and Technology | Zhang Z.,Huazhong University of Science and Technology | Wang F.,Huazhong University of Science and Technology | Wang F.,Key Laboratory of Neurological Diseases HUST | And 4 more authors.
Acta Pharmacologica Sinica | Year: 2010

More and more attention in the field of drug discovery has been focused on the neuroprotection of natural compounds from traditional medicinal herbs. Cerebral ischemia is a complex pathological process involving a series of mechanisms, and a framework for the development of neuroprotectants from traditional herb medicine is a promising treatment for cerebral ischemia. Natural compounds with the effects of anti-oxidation, anti-inflammation, calcium antagonization, anti-apoptosis, and neurofunctional regulation exhibit preventive or therapeutic effects on experimental ischemic brain injury. According to the pharmacological mechanisms underlying neuroprotection, we evaluated natural products from traditional medicinal herbs that exhibit protective effects on ischemic brain injury and characterized the promising targets. © 2010 CPS and SIMM All rights reserved. Source


Li Y.-K.,Huazhong University of Science and Technology | Wang F.,Huazhong University of Science and Technology | Wang F.,Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province | Wang F.,Key Laboratory of Neurological Diseases HUST | And 14 more authors.
Neuropsychopharmacology | Year: 2012

Astrocytes are implicated in information processing, signal transmission, and regulation of synaptic plasticity. Aquaporin-4 (AQP4) is the major water channel in adult brain and is primarily expressed in astrocytes. A growing body of evidence indicates that AQP4 is a potential molecular target for the regulation of astrocytic function. However, little is known about the role of AQP4 in synaptic plasticity in the amygdala. Therefore, we evaluated long-term potentiation (LTP) in the lateral amygdala (LA) and associative fear memory of AQP4 knockout (KO) and wild-type mice. We found that AQP4 deficiency impaired LTP in the thalamo-LA pathway and associative fear memory. Furthermore, AQP4 deficiency significantly downregulated glutamate transporter-1 (GLT-1) expression and selectively increased NMDA receptor (NMDAR)-mediated EPSCs in the LA. However, low concentration of NMDAR antagonist reversed the impairment of LTP in KO mice. Upregulating GLT-1 expression by chronic treatment with ceftriaxone also reversed the impairment of LTP and fear memory in KO mice. These findings imply a role for AQP4 in synaptic plasticity and associative fear memory in the amygdala by regulating GLT-1 expression. © 2012 American College of Neuropsychopharmacology. All rights reserved. Source

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