Hebei Key Laboratory for Neurology

Shijiazhuang, China

Hebei Key Laboratory for Neurology

Shijiazhuang, China

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Zhang J.,Hebei Medical University | Fu B.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Institute of Cardio Cerebral Vascular Diseases | And 8 more authors.
Brain Research | Year: 2013

Background Inflammatory damage aggravates the cerebral ischemic pathological process and may pave a new way for treatment. Bicyclol has been proved to elicit a series of biologic effects through its anti-inflammatory property in treating hepatitis and hepatic ischemic/reperfusion injury. Whether this protective effect applies to cerebral ischemic injury, we therefore investigated the potential neuroprotective role of bicyclol and the underlying mechanisms. Methods: Male Sprague-Dawley rats were randomly assigned to five groups: permanent middle cerebral artery occlusion (pMCAO), Vehicle (pMCAO+0.5% sodium carboxymethylcellulose), By-L (Vehicle+bicyclol 50 mg/kg), By-H (Vehicle+bicyclol 100 mg/kg) and Sham operated group. Bicyclol was administered intragastrically once a day for 3 days, after 1 h of bicyclol pretreatment on the third day; rat brain ischemia was induced by pMCAO. Neurological deficit, infarct volume, and brain edema were measured at 24 h after stroke. Immunohistochemistry, Western blot and real-time quantitative PCR were used to detect the expression of TLR4, TLR9, TRAF6, NF-κB and MMP-9, claudin-5. Results: Compared with pMCAO group, bicyclol significantly ameliorated neurological deficit, decreased infarct volume and edema, and down-regulated the expression of TLR4, TLR9, TRAF6, NF-κB and MMP-9 (P<0.05). Meanwhile, the expression of claudin-5 was increased (P<0.05). Conclusions: Bicyclol has neuroprotective effect on cerebral ischemia, and this protection may be through down-regulating TLR4, TLR9, TRAF6, NF-κB, MMP-9 and up-regulating claudin-5 expression. © 2013 Elsevier B.V.


Li L.,Hebei Medical University | Li L.,Hebei General Hospital | Zhang X.,Hebei Medical University | Zhang X.,Hebei Institute of Cardio Cerebral Vascular Diseases | And 6 more authors.
Brain Research | Year: 2013

Background: Oxidative and inflammatory damages have been suggested to play an important role in cerebral ischemic pathogenesis, and provide promising therapeutic strategies for stroke. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a pleiotropic transcription factor, has been shown to play a key role in protecting cells against oxidative injury in cerebral ischemia. In this study, we demonstrated the hypothesis that ursolic acid (UA), a natural pentacyclic triterpenoid acid, isolated from edible plants in the Oleaceae family, a well-known anti-oxidative and anti-inflammatory reagent, protects the brain against ischemic injury by activating the Nrf2 pathway. Methods: Nrf2 -/- and wild-type (WT) mice were induced into focal cerebral ischemia by transient middle cerebral artery occlusion (MCAO), and received UA treatment immediately after MCAO. The behavioral dysfunction, infarct size, and the expression of Nrf2, HO-1 and inflammatory factors (TLR4 and NF-κB) in ischemic brain were measured at 24 h after stroke. Results: UA treatment significantly improved neurological deficit and reduced infarct size in WT mice after MCAO. Administration of UA also decreased the product of lipid peroxidation, promoted the activation of Nrf2 pathway and decreased the expression of TLR4 and NF-KB after stroke in WT mice. However, Nrf2 -/- mice demonstrated more severe neurologic deficits, infarct size and inflammatory damage after MCAO, and did not benefit from the protective effect of UA. Conclusion: The results indicated that UA protected the brain against ischemic injury in mice by anti-oxidative and anti-inflammatory effects after MCAO. Activation of the Nrf2 pathway contributes to the neuroprotective effects induced by UA in cerebral ischemia. © 2012 Elsevier B.V.


Yang Y.,Hebei Medical University | Yang Y.,Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease | Yang Y.,Hebei Key Laboratory for Neurology | Zhang X.,Hebei Medical University | And 12 more authors.
Neuroscience Letters | Year: 2014

Apelin has been proved to protect the heart against ischemia/reperfusion (I/R) injury via the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) signaling pathways. Whether this protective effect applies to brain I/R injury needed to be explored. We therefore investigated the potential neuroprotective role of Apelin-13 and the underlying mechanisms. Focal transient cerebral I/R model in male ICR mice was induced by 60. min of ischemia followed by reperfusion. Apelin-13 intracerebroventricular injection was performed 15. min before reperfusion. Neurological function, infarct volume, brain edema and apoptosis were measured at 24. h after stroke. To further test the mechanism of Apelin-13, PI3K inhibitor LY294002 and ERK1/2 inhibitor PD98059 were injected into the lateral cerebral ventricle 15. min before ischemia. Compared with the Vehicle group, Apelin-13 significantly ameliorated neurological deficit, infarct volume, brain edema and reduced TUNEL-positive cells. Bax, caspase-3 and cleaved caspase-3 were down-regulated and Bcl-2 up-regulated. While, the effect of Apelin-13 on Bax, Bcl-2, caspase-3 and cleaved caspase-3 was attenuated by LY294002 and PD98059. Apelin protected the brain against I/R insult injury, and this effect may be through activation of PI3K/Akt and ERK1/2 signaling pathways. © 2014 Elsevier Ireland Ltd.


Zhang N.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Collaborative Innovation Center for Cardio Cerebrovascular Disease | Zhang X.,Hebei Key Laboratory for Neurology | And 6 more authors.
Mediators of Inflammation | Year: 2014

The most effective way to contain cerebral ischemic injury is reperfusion; however, reperfusion itself may result in tissue injury, for which inflammatory damage is one of the main causative factors. NALP3 inflammasome is a multiprotein complex. It consists of NALP3, ASC, and caspase-1, whose function is to switch on the inflammatory process. Chrysophanol is an extract from plants of Rheum genus and it possesses many pharmacological effects including its anti-inflammation activity. In this study, the effects of chrysophanol in cerebral ischemia/reperfusion and the potential mechanisms were investigated. Male CD1 mice were subject to transient middle cerebral artery occlusion (tMCAO). The NALP3 inflammasome activation status and its dynamic expression during the natural inflammatory response induced by tMCAO were first profiled. The neuroprotective effects of chrysophanol were then assessed and the potential mechanisms mediating the observed neuroprotection were then explored. Physical parameters including neurological deficit, infarct size, brain edema, and BBB permeability were measured at 24 h after tMCAO. Confocal microscopy, Western blotting, immunohistochemistry, and qRT-PCR techniques were utilized to analyze the expression of NALP3 inflammasome and IL-1β. Our results indicated that the brain tissue damage during cerebral ischemia/reperfusion is accompanied by NALP3 inflammasome activation. Chrysophanol could inhibit the activation of NALP3 inflammasome and protect cerebral ischemic stroke. © 2014 Nan Zhang et al.


Bai X.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Collaborative Innovation Center for Cardio Cerebrovascular Disease | Zhang X.,Hebei Key Laboratory for Neurology | And 6 more authors.
Neurochemical Research | Year: 2014

Inflammatory damage plays a pivotal, mainly detrimental role in cerebral ischemic pathogenesis and may represent a promising target for treatment. Naringenin (NG) has gained growing appreciation for its beneficial biological effects through its anti-inflammatory property. Whether this protective effect applies to cerebral ischemic injury, we therefore investigate the potential neuroprotective role of NG and the underlying mechanisms. Focal cerebral ischemia in male Sprague-Dawley rats was induced by permanent middle cerebral artery occlusion (pMCAO) and NG was pre-administered intragastrically once daily for four consecutive days before surgery. Neurological deficit, brain water content and infarct volume were measured at 24 h after stroke. Immunohistochemistry, Western blot and RT-qPCR were used to explore the anti-inflammatory potential of NG in the regulation of NOD2, RIP2 and NF-κB in ischemic cerebral cortex. Additionally, the activities of MMP-9 and claudin-5 were analyzed to detect NG's influence on blood-brain barrier. Compared with pMCAO and Vehicle groups, NG noticeably improved neurological deficit, decreased infarct volume and edema at 24 h after ischemic insult. Consistent with these results, our data also indicated that NG significantly downregulated the expression of NOD2, RIP2, NF-κB and MMP-9, and upregulated the expression of claudin-5 (P < 0.05). The results provided a neuroprotective profile of NG in cerebral ischemia, this effect was likely exerted by down-regulated NOD2, RIP2, NF-κB, MMP-9 and up-regulated claudin-5 expression. © 2014 Springer Science+Business Media.


Zhao T.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease | Zhang X.,Hebei Key Laboratory for Neurology | And 8 more authors.
Neurochemical Research | Year: 2014

Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Evodiamine (Evo) has been proved to elicit a variety of biological effects through its anti-inflammatory property in the treatment of infectious disease, Alzheimer's disease and hypoxia-induced inflammatory response. Whether this protective effect applies to cerebral ischemic injury, we therefore investigated the potential neuroprotective role of Evo and the underlying mechanisms. Male Institute of Cancer Research (ICR) mice were subjected to permanent middle cerebral artery occlusion (pMCAO) and randomly divided into five groups: Sham (sham-operated + 1 % DMSO + 0.5 % tween80), pMCAO (pMCAO + 0.9 % saline), Vehicle (pMCAO + 1 % DMSO + 0.5 % tween80), Evo-L (Vehicle + Evo 50 mg/kg) and Evo-H (Vehicle + Evo 100 mg/kg) groups. Evo was administered intragastrically twice daily for 3 days, and once again 30 min before mouse brain ischemia was induced by pMCAO. Neurological deficit, brain water content and infarct size were measured at 24 h after stroke. The expression of pAkt, pGSK3β, NF-κB and claudin-5 in ischemic cerebral cortex was analyzed by western blot and qRT-PCR. Compared with Vehicle group, Evo significantly ameliorated neurological deficit, brain water content and infarct size, upregulated the expression of pAkt, pGSK3β and claudin-5, and downregulated the nuclear accumulation of NF-κB (P < 0.05). Evo protected the brain from ischemic damage caused by pMCAO; this effect may be through upregulation of pAkt, pGSK3β and claudin-5, and downregulation of NF-κB expression. © 2014 Springer Science+Business Media.


Zhao Y.,Hebei Medical University | Fu B.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Collaborative Innovation Center for Cerebrovascular Disease | And 9 more authors.
Brain Research Bulletin | Year: 2014

Background: Oxidative damage plays a pivotal role in the pathogenesis of cerebral ischemic stroke and may represent a target for treatment. Our previous studies have proved that nuclear factor E2-related factor 2 (Nrf2) and its downstream genes served as a key mechanism for protection against oxidative stress. Paeonol (PN) is reputed to possess a broad range of therapeutic properties probably by virtue of its antioxidative ability. However little is elucidated regarding the underlying mechanisms in ischemic stroke. The aim of this study was to explore PNs effect in ischemic injury and the role of the pAkt, Nrf2 and hemeoxygenase-1 (HO-1) in the mice brains of permanent middle cerebral artery occlusion (pMCAO). Methods: Male CD-1 mice were subjected to pMCAO and randomly divided into five groups: Sham (sham-operated. + 0.9% saline), pMCAO (pMCAO + 0.9% saline), Vehicle (pMCAO + vehicle), PN-L (pMCAO + PN 30. mg/kg) and PN-H (pMCAO + PN 60. mg/kg) groups. PN was pre-administered intragastrically once daily for 3 days and with the last administration at 30. min before the operation in the fourth day. Neurological deficit scores, brain water content and infarct volume were measured at 24. h after pMCAO. Western blot and qRT-PCR were employed to determine the expressions of pAkt, Nrf2, HO-1 and claudin-5. Superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by spectrophotometer. Results: Compared with Vehicle group, PN significantly alleviated neurological deficit, infarct volume and brain edema (P< 0.05), upregulated the expression of pAkt, Nrf2, HO-1and SOD (P< 0.05), decreased the level of MDA (P< 0.05). Meanwhile, the expression of claudin-5 was also enhanced. Conclusions: PN reduced ischemic brain injury after pMCAO; this effect may be accompanied with upregulation of pAkt, Nrf2, HO-1 and ameliorating BBB permeability. © 2014 Elsevier Inc..


Qiao H.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Institute of Cardio Cerebral Vascular Diseases | Zhang X.,Hebei Key Laboratory for Neurology | And 9 more authors.
Brain Research | Year: 2012

Background: Inflammatory damage is known to be involved in ischemic stroke. Luteolin has been proved to elicit a series of biologic effects through its anti-inflammatory property in multiple sclerosis and rheumatoid arthritis. Whether this protective effect applies to ischemic injury in brain is still unknown, we therefore investigate the potential neuroprotective role of luteolin in ischemic stroke and the underlying mechanisms. Methods: Male Sprague-Dawley rats were subjected to pMCAO and luteolin was administered intraperitoneally immediately after surgery, then once daily thereafter. Neurological deficit, infarct volume, and brain water content were measured at 24 h and 72 h after stroke. The expression of TLR4, TLR5, and NF-κB were measured by real-time PCR, immunohistochemical staining (IHC), and Western blot. P38MAPK and extracellular signal-regulated kinase (ERK) were detected by IHC, and Western blot. Results: Compared with pMCAO group, luteolin significantly alleviated neurological deficit, decreased infarct volume and suppressed edema after ischemic stroke, which were accompanied with decreased expression of TLR4, TLR5, NF-κB and p-p38MAPK. Meanwhile, luteolin activated the expression of p-ERK1/2 (P < 0.05). Conclusions: Luteolin protected the brain from the damage caused by pMCAO, and this effect may be through downregulation of TLR4, TLR5, NF-κB, p38MAPK and upregulation of ERK expression. © 2012 Elsevier B.V. All rights reserved.


Qiao H.,Hebei Medical University | Dong L.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Institute of Cardio Cerebral Vascular Diseases | And 10 more authors.
Neurochemical Research | Year: 2012

Luteolin recently has been proved to elicit a vanity of biological effects through its antioxidant and antiapoptosis properties. Oxidative and apoptosis damage play an important role in cerebral ischemic pathogenesis and may represent a target for treatment. The aim of this study was to evaluate the neuroprotective effects of luteolin and the underlying mechanisms in cerebral ischemia. Focal cerebral ischemia was induced in adult male Sprague- Dawley rats by permanent middle cerebral artery occlusion (pMCAO). Luteolin was injected intraperitoneally at different doses of 10 or 25 mg/kg immediately after pMCAO. Experiment 1, luteolin's neuroprotective effect was analyzed. Neurological deficits, brain water content and infarct volume were evaluated at 24 and 72 h after pMCAO. SOD1, Bcl-2, and Bax expression were measured by immunohistochemistry, western blot and reverse transcription- polymerase chain reaction. Experiment 2, luteolin's anti-oxidative activities were evaluated. SOD1, CAT activities, and MDA content were measured by spectrophotometer. Experiment 3, the influence of luteolin on claudin-5 was detected. Compared with MCAO group, luteolin significantly increased the activities of SOD1, CAT, Bcl-2 and claudin-5 (P<0.05), decreased the levels of MDA and Bax (P<0.05), and alleviated the neurological deficits, infarct volume and brain water content (P<0.05). The results indicated that luteolin protected the brain from ischemic damage, and this effect may be through reduction of oxidative stress and apoptosis, and upregulation of the expressions of claudin-5.


Zhao J.,Hebei Medical University | Zhao J.,Hebei General Hospital | Zhang X.,Hebei Medical University | Zhang X.,Hebei Key Laboratory for Neurology | And 3 more authors.
Current Neuropharmacology | Year: 2014

Stroke is the third leading cause of human death. Endothelial dysfunction, thrombogenesis, inflammatory and oxidative stress damage, and angiogenesis play an important role in cerebral ischemic pathogenesis and represent a target for prevention and treatment. Statins have been found to improve endothelial function, modulate thrombogenesis, attenuate inflammatory and oxidative stress damage, and facilitate angiogenesis far beyond lowering cholesterol levels. Statins have also been proved to significantly decrease cardiovascular risk and to improve clinical outcome. Could statins be the new candidate agent for the prevention and therapy in ischemic stroke? In recent years, a vast expansion in the understanding of the pathophysiology of ischemic stroke and the pleiotropic effects of statins has occurred and clinical trials involving statins for the prevention and treatment of ischemic stroke have begun. These facts force us to revisit ischemic stroke and consider new strategies for prevention and treatment. Here, we survey the important developments in the non-lipid dependent pleiotropic effects and clinical effects of statins in ischemic stroke. ©2014 Bentham Science Publishers.

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