Aging and Cognition Neuroscience Laboratory of Hebei Province

Shijiazhuang, China

Aging and Cognition Neuroscience Laboratory of Hebei Province

Shijiazhuang, China
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Liu Y.-X.,Hebei Medical University | Zhang M.,Hebei Medical University | Liu L.-Z.,Hebei Medical University | Cui X.,Hebei Medical University | And 3 more authors.
GLIA | Year: 2012

This study was undertaken to determine the role of glutamate transporter-1a (GLT-1a), one of the splice variants of glutamate transporter-1, in the induction of brain ischemic tolerance by cerebral ischemic preconditioning (CIP). We used a rat global cerebral ischemic model and assessed changes by neuropathological evaluation, Western blot analysis, immunohistochemistry, real-time PCR, in vivo brain microdialysis, and high performance liquid chromatography. We found that CIP induced a significant upregulation of GLT-1a expression in the CA1 hippocampus in a time course corresponding to that of neuroprotection of CIP against brain ischemia. Severe brain ischemia for 8 min induced delayed downregulation of GLT-1a, an obvious increase in glutamate concentration and delayed neuronal death of the pyramidal neurons in the CA1 hippocampus. When the animals were pretreated with CIP before the severe ischemia, the above changes normally induced by the severe ischemia were effectively prevented. Importantly, such a preventive effect of CIP on these changes was significantly inhibited by intracerebroventricular administration of GLT-1a antisense oligodeoxynucleotides, which have been proven to specifically inhibit the expression of GLT-1a protein and mRNA, and had no effect on the expression of GLT-1b. In addition, the concentration of aspartate was also elevated after severe brain ischemic insult. However, CIP had no effect on the elevated aspartate concentrations. These results indicate that GLT-1a participated in the brain ischemic tolerance induced by CIP in rats. © 2011 Wiley Periodicals, Inc.


Sun X.-C.,Hebei Medical University | Xian X.-H.,Aging and Cognition Neuroscience Laboratory of Hebei Province | Li W.-B.,Aging and Cognition Neuroscience Laboratory of Hebei Province | Li W.-B.,Hebei Medical University | And 4 more authors.
Experimental Neurology | Year: 2010

This study investigates whether activation of p38 MAPK by the up-regulation of HSP 70 participates in the induction of brain ischemic tolerance by limb ischemic preconditioning (LIP). Western blot and immunohistochemical assays indicated that p38 MAPK activation occurred earlier than HSP 70 induction in the CA1 region of the hippocampus after LIP. P-p38 MAPK expression was up-regulated at 6. h and reached its peak 12. h after LIP, while HSP 70 expression was not significantly increased until 1. day and peaked 2. days after LIP. Neuropathological evaluation by thionin staining showed that quercetin (4. ml/kg, 50. mg/kg, intraperitoneal injection), an inhibitor of HSP 70, blocked the protective effect of LIP against delayed neuronal death that is normally induced by lethal brain ischemic insult, indicating that HSP 70 participates in the induction of brain ischemic tolerance by LIP. Furthermore, SB 203580, an inhibitor of HSP 70, inhibited HSP 70 activation in the CA1 region of the hippocampus induced by LIP either with or without the presence of subsequent brain ischemic insult. Based on the above results, it can be concluded that activation of p38 MAPK participates in the brain ischemic tolerance induced by LIP at least partly by the up-regulation of HSP 70 expression. © 2010 Elsevier Inc.


Cui X.,Hebei Medical University | Li L.,Hebei Medical University | Hu Y.-Y.,Hebei Medical University | Ren S.,Hebei Medical University | And 3 more authors.
Molecular Neurobiology | Year: 2015

The study was undertaken to investigate whether sulbactam protects cerebral neurons against ischemia and whether the protection is mediated by regulating the expression and uptake activity of glial glutamate transporter-1 (GLT1) in a rat global brain ischemia model. The CA1 hippocampus was selected as the observing target. Real time quantitative PCR, Western blot and immunohistochemistry assays were used to detect GLT1 expression. Neuropathological evaluation was performed after thionin staining to determine the extent of the delayed neuronal death (DND) of pyramidal neurons. It was found that cerebral ischemia for 8 min induced obvious DND of pyramidal neurons and GLT1 downregulation. Sulbactam pretreatment significantly upregulated GLT1 expression in sham rats and prevented or reversed the GLT1 downregulation normally induced in the ischemic rat brain. Meanwhile, sulbactam pretreatment effectively prevented the DND of pyramidal neurons normally induced by brain ischemia in a dose-dependent manner. Sulbactam posttreatment also protected pyramidal neurons against DND induced by brain ischemia although the magnitude of the protective effect was weaker than that in sulbactam pretreatment. Furthermore, either antisense knockdown of GLT1 expression or inhibition of the GLT1 uptake activity with dihydrokainate, a selective inhibitor of GLT1, significantly blocked the neuronal protective effect of sulbactam. These findings indicate that sulbactam has a neuronal protective effect though upregulating GLT1. © 2014, Springer Science+Business Media New York.


Zhang M.,Hebei Medical University | Gong J.-X.,Hebei Medical University | Wang J.-L.,Hebei Medical University | Jiang M.-Y.,Hebei Medical University | And 9 more authors.
Molecular Neurobiology | Year: 2017

Our previous study has proved that the up-regulation of glial glutamate transporter 1 (GLT-1) played an important role in the acquisition of brain ischemic tolerance after cerebral ischemic preconditioning (CIP) in rats. However, little is known about the mechanism involved in the up-regulation of GLT-1 in the process. The present study investigates whether p38 MAPK, ERK1/2, and/or JNK participates in the up-regulation of GLT-1 during the induction of brain ischemic tolerance by CIP. It was found that CIP significantly enhanced the expression of p-p38 MAPK without altering p-ERK1/2 and p-JNK expression in the CA1 hippocampus. Inhibition of p38 MAPK function by its selective inhibitor SB203580 or knockdown p38 MAPK expression by its antisense oligodeoxynucleotides (AS-ODNs) suppressed the induction of brain ischemic tolerance. Furthermore, p38 MAPK was activated earlier than the up-regulation of GLT-1 in the CA1 hippocampus after CIP. Meanwhile, the expression of p-p38 MAPK by astrocytes was increased, and p38 MAPK AS-ODNs dose-dependently inhibited the up-regulation of GLT-1 after CIP. Taken together, it could be concluded that p38 MAPK participates in the mediation of GLT-1 up-regulation during the induction of brain ischemic tolerance after CIP. © 2016, Springer Science+Business Media New York.


Hu Y.,Hebei Medical University | Li W.,Hebei Medical University | Li W.,Aging and Cognition Neuroscience Laboratory of Hebei Province | Lu L.,Hebei Medical University | And 5 more authors.
Pain | Year: 2010

Glial glutamate transporter-1 (GLT-1) plays an essential role in the maintenance of glutamate homeostasis and is involved in the development and maintenance of pathological pain. The present study was undertaken (1) to observe the anti-nociceptive effects of ceftriaxone (Cef) in a chronic neuropathic pain model induced by chronic constrictive nerve injury (CCI) of the sciatic nerve and (2) to identify the role of spinal GLT-1 in the process. CCI induced significant thermal hyperalgesia and mechanical allodynia, which began from postoperative day 3 and lasted to day 21. This long-term hyperalgesia was accompanied by significant down-regulation of GLT-1 expression in the L4-L6 segments of the spinal dorsal horn, as revealed by immunohistochemistry and Western blot. Intraperitoneal preventive and therapeutic administration of Cef effectively prevented or reversed, respectively, the development of thermal hyperalgesia, mechanical allodynia, and GLT-1 down-regulation in the spinal dorsal horn. To further determine whether the above anti-nociceptive effects of Cef are a result of the up-regulation of spinal GLT-1 expression and its function, we further observed the effects of intrathecal administration of Cef in the same model. It was found that intrathecal administration of Cef led to the specific up-regulation of GLT-1 expression and glutamate uptake (3H-glutamate) in the spinal dorsal horn, and similar anti-nociceptive effects to those of intraperitoneal administration of Cef. The above effects of intrathecal Cef administration were all significantly inhibited by intrathecal administration of GLT-1 antisense oligodeoxynucleotides (As-ODNs). These results indicate that Cef plays an anti-nociceptive role by up-regulating spinal GLT-1 expression and its function. © 2009 International Association for the Study of Pain.


Liu A.-J.,Hebei Medical University | Hu Y.-Y.,Hebei Medical University | Li W.-B.,Hebei Medical University | Li W.-B.,Aging and Cognition Neuroscience Laboratory of Hebei Province | And 2 more authors.
Journal of Neurochemistry | Year: 2011

Glial glutamate transporter-1 (GLT-1) is the predominant subtype of glutamate transporters which are responsible for the homeostasis of extracellular glutamate. Our previous studies have shown that up-regulation in GLT-1 protein expression matches brain ischemic tolerance induced by cerebral ischemic preconditioning (CIP). To specify the role of functional changes of GLT-1 in the induction of brain ischemic tolerance by CIP, the present study was undertaken to examine changes in the binding properties of GLT-1 (including maximum binding and affinity for glutamate) and in GLT-1 mediated glutamate uptake, using L- 3H-glutamate assay in the rat hippocampus. The results indicated that CIP was able to increase the maximum binding and affinity, and uptake of GLT-1 for glutamate in hippocampal CA1 subfield either with or without the presence of the subsequent severe brain ischemic insult. Simultaneously, accompanied with the above changes, CIP significantly reduced the delayed neuronal death (DND) in this region induced by lethal global cerebral ischemia. It could be concluded that up-regulation in the maximum binding and affinity and glutamate uptake of GLT-1 contributed to the neuronal protection of CIP against global cerebral ischemic insult. © 2011 International Society for Neurochemistry.


Zhang M.,Hebei Medical University | Li W.-B.,Hebei Medical University | Li W.-B.,Aging and Cognition Neuroscience Laboratory of Hebei Province | Liu Y.-X.,Hebei Medical University | And 7 more authors.
Neurochemistry International | Year: 2011

It is well known that neurons in the CA3 and dentate gyrus (DG) subfields of the hippocampus are resistant to short period of ischemia which is usually lethal to pyramidal neurons in hippocampal CA1 subfield. The present study was undertaken to clarify whether the inherent higher resistance of neurons in CA3 and DG to ischemia is associated with glial glutamate transporter-1 (GLT-1) in rats. Western blot analysis and immunohistochemistry assay showed that the basal expressions of GLT-1 in both CA3 and DG were much higher than that in CA1 subfield. Mild global brain ischemia for 8 min induced delayed death of almost all CA1 pyramidal neurons and marked GLT-1 down-regulation in the CA1 subfield, but it was not lethal to the neurons in either CA3 or DG and induced GLT-1 up-regulation and astrocyte activation showed normal soma and aplenty slender processes in the both areas. When the global brain ischemia was prolonged to 25 min, neuronal death was clearly observed in CA3 and DG accompanied with down-regulation of GLT-1 expression and abnormal astrocytes represented with hypertrophic somas, but shortened processes. After down-regulating of GLT-1 expression and function by its antisense oligodeoxynucleotides or inhibiting GLT-1 function by dihydrokainate, an inhibitor of GLT-1, the mild global brain ischemia for 8 min, which usually was not lethal to CA3 and DG neurons, induced the neuronal death in CA3 and DG subfields. Taken together, the higher expression of GLT-1 in the CA3 and DG contributes to their inherent resistance to ischemia. © 2011 Elsevier B.V. All rights reserved.


Hu Y.-Y.,Hebei Medical University | Xu J.,Hebei Medical University | Zhang M.,Hebei Medical University | Wang D.,Hebei Medical University | And 3 more authors.
Journal of Neurochemistry | Year: 2015

Ceftriaxone(Cef) selectively increases the expression of glial glutamate transporter-1 (GLT-1), which was thought to be neuroprotective in some circumstances. However, the effect of Cef on glutamate uptake of GLT-1 was mostly assayed using in vitro studies such as primary neuron/astrocyte cultures or brain slices. In addition, the effect of Cef on neurons in different ischemic models was still discrepant. Therefore, this study was undertaken to observe the effect of Cef on neurons in global brain ischemia in rats, and especially to provide direct evidence of the up-regulation of GLT-1 uptake for glutamate contributing to the neuronal protection of Cef against brain ischemia. Neuropathological evaluation indicated that administration of Cef, especially pre-treatment protocols, significantly prevented delayed neuronal death in hippocampal CA1 subregion normally induced by global brain ischemia. Simultaneously, pre-administration of Cef significantly up-regulated the expression of GLT-1. Particularly, GLT-1 uptake assay with 3H-glutamate in living cells from adult rats showed that up-regulation in glutamate uptake accompanied up-regulated GLT-1 expression. Inhibition of GLT-1 by antisense oligodeoxynucleotides or dihydrokainate significantly inhibited the Cef-induced up-regulation in GLT-1 uptake and the neuroprotective effect against global ischemia. Thus, we may conclude that Cef protects neurons against global brain ischemia via up-regulation of the expression and glutamate uptake of GLT-1. © 2014 International Society for Neurochemistry.


Cao M.,Hebei Medical University | Zhang M.,Hebei Medical University | Zhang M.,Aging and Cognition Neuroscience Laboratory of Hebei Province | Zhang L.-W.,Hebei Medical University | And 4 more authors.
Archives Italiennes de Biologie | Year: 2013

Our previous study showed that 3-min cerebral ischemic preconditioning (CIP) up-regulated the expression of glial glutamate transporter-1 (GLT-1) protein, which protects pyramidal neurons, allowing them to survive an 8-min ischemic insult that usually induces severe delayed neuronal death in the hippocampal CA1 subfield. In the present study, in situ hybridization and immunohistochemistry were used to observe whether GLT-1 mRNA is modulated and whether actrocytes and/or neurons express GLT-1 mRNA during the induction of brain ischemic tolerance. We observed that GLT-1 mRNA is expressed in neurons and astrocytes in the hippocampal CA1 subfield. The expression of GLT-1 mRNA was significantly down-regulated in both neurons and astrocytes after the 8-min lethal ischemic insult. CIP for 3 min increased the expression of GLT-1 mRNA in neurons and astrocytes, and induced the elongation of the astrocytic processes around pyramidal neurons. It may be concluded that CIP performed 2 days before lethal ischemic insult activated astrocytes, which resulted in an increased number of lengthened processes expressing high levels of GLT-1, which protected the neurons and allowed them to survive 8-min ischemic insult that is usually lethal to neurons in the hippocampal CA1 subfield.


Zhang Y.-P.,Hebei Medical University | Li W.-B.,Hebei Medical University | Wang W.-L.,Hebei Medical University | Liu J.,Hebei Medical University | And 5 more authors.
Acta Pharmacologica Sinica | Year: 2012

Aim:Plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis. The present study was undertaken to examine the effects on pulmonary fibrosis of silencing PAI-1 expression with small interfering RNA (siRNA) and to assess the possible underlying mechanisms.Methods:Male Wistar rats were subjected to intratracheal injection of bleomycin (BLM, 5 mg/kg, 0.2 mL) to induce pulmonary fibrosis. Histopathological changes of lung tissue were examined with HE or Masson's trichrome staining. The expression levels of α-smooth muscle actin (α-SMA), collagen type-I and type-III, caspase-3, as well as p-ERK1/2 and PI3K/Akt in the lung tissue were evaluated using imunohistochemistry and Western blot analyses. The fibroblasts isolated from BLM-induced fibrotic lung tissue were cultured and transfected with pcDNA-PAI-1 or PAI-1siRNA. The expression level of PAI-1 in the fibroblasts was measured using real time RT-PCR and Western blot analysis. The fibroblast proliferation was evaluated using MTT assay.Results:Intratracheal injection of PAI-1-siRNA (7.5 nmoL/0.2 mL) significantly alleviated alveolitis and collagen deposition, reduced the expression of PAI-1, α-SMA, collagen type-I and collagen type-III, and increased the expression of caspase-3 in BLM-induced fibrotic lung tissue. In consistence with the in vivo results, the proliferation of the cultured fibroblasts from BLM-induced fibrotic lung tissue was inhibited by transfection with PAI-1-siRNA, and accelerated by overexpression of PAI-1 by transfection with pcDNA-PAI-1. The expression of caspase-3 was increased as a result of PAI-1 siRNA transfection, and decreased after transfection with pcDNA-PAI-1. In addition, the levels of p-ERK1/2 and PI3K/Akt in the fibrogenic lung tissue were reduced after treatment with PAI-1siRNA.Conclusion:The data demonstrate that PAI-1 siRNA inhibits alveolitis and pulmonary fibrosis in BLM-treated rats via inhibiting the proliferation and promoting the apoptosis of fibroblasts. Suppression ERK and AKT signalling pathways might have at least partly contributed to this process. Targeting PAI-1 is a promising therapeutic strategy for pulmonary fibrosis. © 2012 CPS and SIMM.

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