Hebei Key Laboratory for Neurology

Shijiazhuang, China

Hebei Key Laboratory for Neurology

Shijiazhuang, China
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Du Y.,Hebei Medical University | Du Y.,The First Hospital of Shijiazhuang City | Zhang X.,Hebei Medical University | Zhang X.,Hebei Institute of Cardio Cerebral Vascular Diseases | And 6 more authors.
Neuroscience Letters | Year: 2012

Inflammation and oxidative stress play an important role in cerebral ischemic pathogenesis. It has been well established that atorvastatin and probucol could elicit a variety of biological effects through its anti-inflammatory and anti-oxidant properties respectively. This study was to examine whether probucol and atorvastatin in combination had the enhanced protective effect against cerebral ischemia. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAO). Experiment 1 was used to evaluate the time course expression of Peroxiredoxin2 (Prx2) and Foxo3a after cerebral ischemia. Experiment 2 was used to detect neuroprotective effect of atorvastatin and probucol in cerebral ischemia. At 24. h or 72. h, neurologic deficit, brain water content and infarct size were measured. Immunohistochemistry, RT-PCR, Western blot and confocal microscope were used to analyze the expressions of Prx2, Foxo3a and nuclear factor erythroid 2-related factor 2 (Nrf2). Compared with the normal-control group, the expressions of Prx2 and Foxo3a were down-regulated in ischemic brain. Compared with the use of probucol or atorvastatin alone, the combined treatment dramatically reduced the brain water content and the infarct volume (P< 0.05). Meanwhile, the decrease of Prx2, Foxo3a and Nrf2 was significantly alleviated in combined treatment group. Probucol combined with atorvastatin can get the augmented neuroprotection from the damage caused by MCAO, this effect may be through up-regulation of Prx2, Foxo3a and Nrf2. © 2012 Elsevier Ireland Ltd.


Ji 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 6 more authors.
Brain Research Bulletin | Year: 2012

Inflammation and oxidative stress play an important role in cerebral ischemic pathogenesis. Polydatin has been proved to elicit numerous biological effects through its anti-inflammatory and anti-oxidant properties. However, little is known regard to the mechanism of polydatin's neuroprotection in ischemic stroke. We therefore investigated the potential neuroprotective effects of polydatin and explored the underlying mechanisms. Male, Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (pMCAO). Experiment 1 was used to evaluate the expression of glioma-associated oncogene homolog1 (Gli1), Patched-1 (Ptch1) and Superoxide dismutase 1 (SOD1) after pMCAO, six time points were included. Experiment 2 was used to detect polydatin's neuroprotection after pMCAO. Neurological deficit, brain water content and infarct size were measured at 24. h and 72. h after pMCAO. Immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR), Western Blotting, activity assay and confocal microscope were used to analyse the expression of Gli1, Ptch1, SOD1 and nuclear factor-kappa B (NF-κB). Experiment 3 was used to detect polydatin's influence on blood-brain barrier (BBB). Compared with Sham group, the expression of Gli1, Ptch1 and SOD1 were up-regulated shortly after pMCAO (P<. 0.05). Compared with Vehicle group, high dose of polydatin (50. mg/kg) up-regulated Gli1, Ptch1, SOD1 and down-regulated NF-κB, and reduced infarct volume, brain water content and behavioral deficits (P<. 0.05). Meanwhile, BBB permeability was also ameliorated. The results indicated that polydatin protected the brain from damage caused by pMCAO, and this effect may be through up-regulating the expression of Gli1, Ptch1 and SOD1 and down-regulating the expression of NF-κB, and ameliorating BBB permeability. © 2011 Elsevier Inc.


Zhang L.,Hebei Medical University | Zhao H.,First Hospital of Shijiazhuang City | Zhang X.,Hebei Medical University | Zhang X.,Hebei Institute of Cardio Cerebral Vascular Diseases | And 5 more authors.
Brain Research Bulletin | Year: 2013

There is cumulative evidence that the serine-threonine kinase Akt and its downstream nuclear transcription factor CREB are involved in neuronal survival and protection. The Akt activates and phosphorylates CREB at Ser133, resulting in the up-regulation of pro-survival CREB target genes such as BDNF and Bcl-2. Thus, Akt/CREB signaling pathway may be one propitious target for treatment of ischemic cerebral injury. Nobiletin (NOB) exhibits a wide spectrum of beneficial biological properties including anti-inflammatory, antioxidant, anti-carcinogenic actions and contributes to reverse learning impairment in Alzheimer's disease rat. However, little is currently known regarding the exact role of NOB in ischemic stroke. Here, we designed to evaluate its possible therapeutic effect on cerebral ischemia. Adult male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (pMCAO) and randomly divided into five groups: Sham (sham-operated. + 0.05% Tween-80), MCAO (pMCAO + 0.9% saline), Vehicle group (pMCAO + 0.05% Tween-80), NOB-L (pMCAO + NOB 10. mg/kg) and NOB-H (pMCAO + NOB 25. mg/kg) groups. Rats were pre-administered intraperitoneally once daily for 3 days before surgery and then received once again immediately after surgery. Neurological deficit scores, brain water content and infarct volume were evaluated at 24. h after stroke. Additionally, the activities of Akt, CREB, BDNF, Bcl-2 and claudin-5 in ischemic brain cortex were analyzed by the methods of immunohistochemistry, western blot and RT-qPCR. Compared with Vehicle group, neurological deficits and brain edema were relieved in NOB-H group ( P < 0.05), infarct volume was lessened in both NOB-L and NOB-H groups ( P < 0.05) at 24. h after stroke. Immunohistochemistry, western blot and RT-qPCR analysis indicated that NOB dramatically promoted the activities of Akt, CREB, BDNF and Bcl-2 ( P < 0.05). Meanwhile, claudin-5 expression was also enhanced. On the basis of these findings, we concluded that NOB protected the brain from ischemic damage and it maybe through activating the Akt/CREB signaling pathway and ameliorating BBB permeability. © 2013 Elsevier Inc.


Fu B.,Hebei Medical University | Zhang J.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease | And 9 more authors.
Neuroscience | Year: 2014

Background and object: Silent mating type information regulation 2 homolog 1 (SIRT1) is a class III histone deacetylase and activates peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) which attenuates oxidative damage. Alpha-lipoic acid (ALA) has been proven to protect the rat brain against cerebral ischemia injury by reducing oxidative stress. However, the underlying mechanisms are poorly understood. In this study, we investigated the potential neuroprotection and the possible role of ALA in SIRT1 pathway. Methods: Male CD-1 mice were randomly assigned to three groups: Sham, permanent middle cerebral artery occlusion (pMCAO) and ALA group (ALA, 50. mg/kg). ALA was administered intraperitoneally 30. min prior to ischemia in the ALA group. Neurological deficit, infarct volume, and brain edema were detected at 24. h after cerebral ischemia. Immunohistochemistry, western blot and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect the expression of SIRT1 and PGC-1α. Activities of superoxide dismutase (SOD) were measured by assay kits. Results: Compared with the pMCAO group, the ALA group significantly ameliorated neurological deficit, lessened infarct volume and brain edema, increased the expression of SIRT1, PGC-1α and activities of SOD (P<. 0.05). Conclusions: ALA protected the mouse brain against ischemic damage, and this protection may be through up-regulating SIRT1-dependent PGC-1α expression. © 2014 IBRO.


Zhang J.,Hebei Medical University | Fu B.,Hebei Medical University | Zhang X.,Hebei Medical University | Zhang X.,Hebei Collaborative Innovation Center for Cardio cerebrovascular Disease | And 11 more authors.
Brain Research Bulletin | Year: 2014

Oxidative damage plays a detrimental role in the pathophysiology of cerebral ischemia and may represent a therapeutic target. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) controls the coordinated expression of the important antioxidant and detoxification genes through a promotor sequence termed the antioxidant response element. Bicyclol has been proved to elicit a variety of biological effects through its antioxidant and anti-inflammatory properties. But the underlying mechanisms are poorly understood. In this study, the role of bicyclol in cerebral ischemia and its potential mechanism were investigated. Methods: Male Sprague-Dawley rats were randomly assigned to five groups: MCAO (middle cerebral artery occlusion), Vehicle (MCAO. +. 0.5% sodium carboxymethylcellulose), By-L (Vehicle. +. bicyclol 50. mg/kg), By-H (Vehicle. +. bicyclol 100. mg/kg) and Sham operated groups. Bicyclol was administered intragastrically once a day for 3 consecutive days; after 1. h of bicyclol pretreatment on the third day, rat ischemic stroke was induced by MCAO. Neurological deficit, infarct volume, and brain edema were detected at 24. h after stroke. Western blot and RT-qPCR were used to measure the expression of Nrf2, HO-1 and SOD1. MDA was detected by the spectrophotometer. Results: Compared with MCAO group, By-H group significantly ameliorated neurological deficit, lessened the infarct volume and brain edema, increased the expression of Nrf2, HO-1 and SOD1 (P< 0.05), and decreased the content of MDA (P< 0.05). Conclusions: Bicyclol protected the rat brain from ischemic damage caused by MCAO, and this effect may be through the upregulation of the transcription factor Nrf2 expression. © 2013 Elsevier Inc.


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.


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.


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.

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