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Inflammatory response is an important mechanism of secondary nerve injury in ischemic stroke, which is still a research hotspot in the field of neuroscience at present. Astrocytes are characterized by extensive distribution in brain, strong hypoxia tolerance, and the ability to interact with almost all cells in neurovascular unit, thus becoming potential therapeutic targets for alleviating ischemic injury. After ischemic stroke, astrocytes quickly become reactive astrocytes, releasing a large number of inflammatory cytokines, promoting the activation and invasion of other inflammatory cells, triggering a cascade of inflammatory responses, and aggravating ischemic injury. A variety of basic studies have shown that inhibiting the astrocytes activation and astrocytosis can significantly reduce neuroinflammatory response and infarct volume, and significantly improve the neurological function recovery in a model of middle cerebral artery occlusion. In this paper, the research progress of inflammatory response of astrocytes after ischemic stroke was reviewed from the aspects of astrocyte activation and polarization, release of inflammatory cytokines, interaction of inflammatory cells and corresponding targeted therapy strategies.
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Objective To investigate the effect of donepezil on subventricular zone ( SVZ) neuro-genesis related neurotrophic factors after cerebral infarction. Methods Mice were randomly assigned into three groups: vehicle-treated sham group (Sham+vehicle,n=18),vehicle-treated middle cerebral artery oc-clusion (MCAO) group (MCAO + vehicle,n=30) and donepezil-treated MCAO group (MCAO+donepezil, n=30). Middle cerebral artery occlusion( MCAO) was induced by thread-occlusion method. Nissl staining was used to measure the infarct volume and the modified neurological severity score(mNSS) was used to as-sess neurologic function and brain water content was detected to assess brain edema degree. Proliferative cells and neuroblasts were labeled with 5-bromodeoxyuridine ( BrdU) and doublecortin ( DCX). The SVZ BrdU+/DCX+cells were detected by immunofluorescence. The expression of glial cell line-derived neurotro-phic factor (GDNF),brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were detec-ted by Western blot. Results The infarct volume of MCAO + donepezil group ((13. 33±4. 55)%) was sig-nificantly lower than that of MCAO + vehicle group ((31. 33±3. 93)%,t=7. 34,P<0. 05). The neurologic deficits were significantly ameliorated after donepezil treatment,and the brain water content of MCAO + done-pezil group ((71. 82±10. 18)%)was significantly less than that of MCAO + vehicle group ((85. 93± 7. 54)%,F=13. 480,P<0. 05). All differences were statistically significant (P<0. 05). The area of BrdU+/DCX+cells within SVZ of MCAO + vehicle group ((6. 16±1. 79)%) was significantly larger than that of sham + vehicle group ((2. 25±1. 09)%),and was fewer than that of MCAO+donepezil group ((16. 19± 2. 16)%,F=102. 756,P<0. 05). MCAO significantly promoted the expression of GDNF,BDNF and NGF within SVZ compared with sham operation,and donepezil increased these protein levels(F=15. 114,27. 121, 27. 398,P<0. 05). Conclusion Donepezil regulates neurogenesis via increasesing the expression of GDNF, BDNF and NGF within SVZ after cerebral infarction.
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Objective To investigate the effects of cholinergic signal on neural stem cell(NSC)differenti-ation in peri-infarction region after ischemic stroke. Methods Mice were randomly assigned into sham + vehicle group,middle cerebral artery occlusion(MCAO)+ vehicle group,MCAO + donepezil group and MCAO + atro-pine group(n = 25). MCAO was induced by thread-occlusion method. Modified neurological severity score (mNSS)was used to evaluate neurological function recovery,and the brain water content was measured by dry-wet weight method. NeuN/5-bromodeoxyuridine(BrdU),CNPase/BrdU,GFAP/BrdU double-labeled cells were tested by immunofluorescence. Results Brain water content of MCAO + vehicle group was significantly higher than that of sham operation group(P < 0.05). Donepezil-treated MCAO mice had lower neurologic deficit scores and brain water content than of MCAO + vehicle group(P < 0.05). On day 14 and day 28 after MCAO,the NeuN/BrdU, CNPase/BrdU and GFAP/BrdU immune-positive cells of MCAO + vehicle group were markedly increased as com-pared with that of sham+vehicle group(P<0.05).Compared with that of MCAO+vehicle group,the number of NeuN/BrdU-positive cells,CNPase/BrdU-positive cells and GFAP/BrdU-positive cells was higher in MCAO+done-pezil group,and the number of NeuN/BrdU-positive cells and CNPase/BrdU-positive cells of MCAO + atropine group was lower(P < 0.05). Conclusions Cholinergic signal could promote NSCs differentiation in peri-infarc-tion region,a lleviate cerebral edema,and improve the brain function restoration after stroke.
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Objective To investigate the role of Src signaling pathway in neurogenesis promoted by choline acetyltransferase (CHAT) + neurons in the subventricular zone (SVZ) after ischemic stroke.Methods The eighty-four mice were randomly assigned into four groups:sham-operated mice treated with vehicle (Sham+vehicle,n=18),middle cerebral artery occlusion (MCAO)-operated mice treated with vehicle (MCAO+vehicle,n=22),MCAO mice treated with donepezil (MCAO+donepezil,n=21),MCAO mice treated with donepezil and Src inhibitor KX2-391 (MCAO+donepezil+KX2-391,n=23).Mice were subjected to the temporary MCAO model of ischemic stroke.Modified neurological severity score (mNSS) was used to assess neurologic function of the mice.Proliferative cells were labeled with Ki67,and neuroblasts with doublecortin (DCX).The expression of Ki67+/DCX+ in the SVZ was detected by immunofluorescence.The expression of Ki67,phospho-epidermal growth factor receptor (p-EGFR),p-Raf,Src and p-Akt in the SVZ were quantified by Western blot.Results MCAO+donepezil+KX2-391 group showed worse performance in the mNSS test than MCAO+donepezil group (P＜0.05).Ten days after MCAO,the number of Ki67+/DCX+ cells in the SVZ of MCAO+donepezil group was 125.33± 13.71/area,which was 71.67± 18.35/area in MCAO+ donepezil+KX2-391 group (P＜0.05).What's more,the expression of proteins Ki67,p-EGFR,p-Raf,Src and p-Akt in mice of MCAO+donepezil group was markedly increased,which was (1.39±0.23),(1.42±0.19),(0.88±0.13),(1.14±0.19),(1.04±0.18) and it was decreased in MCAO+donepezil+KX2-391 group,which was 0.84±0.26,0.94±0.26,0.73±0.15,0.71±0.18,0.81±0.19(P＜0.05).Conclusion CHAT+ neurons in SVZ may promote neurogenesis after stroke via Src-epidermal growth factor receptor (EGFR) signaling pathway.
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Objective To observe the activities of ChAT + neurons in subventricular zone (SVZ) after ischemic stroke and their effects on angiogenesis in peri-infarction region and related signaling pathways. Methods C57BL/6 mice were randomly assigned into sham group,middle cerebral artery occlusion (MCAO) group and atropine group. Ischemic models were made by permanent coagulation of the distal middle cerebral artery. The expression of ChAT,AChE in SVZ and VEGF,VEGFR2,pERK in peripheral regions of ischemic injury was evaluated by Western blotting and immunofluorescence. 5-bromodeoxyuridine(BrdU)/CD31 double-labeled cells were also tested by immunofluorescence. Results At 14 d after the surgery,the ratio of ChAT/AChE in SVZ increased after stroke(P < 0.05). Compared with those in Sham group,the levels of VEGF,VEGFR2 and pERK were higher in MCAO group(P<0.05)and VEGFR2-positive and BrdU/CD31-positive cells increased significantly. However,lower expression of VEGF,VEGFR2 and pERK and less VEGFR2-positive and BrdU/CD31-positive cells were found in atropine group when compared with that in MCAO group. Conclusions The activities of ChAT +neurons in SVZ are enhanced after ischemic injury and they can promote angiogenesis in peripheral region of ischemic injury via upregulating VEGF-VEGFR2 signaling pathway and improving the brain function restoration.
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Objective To investigate the influence of donepezil on neurogenesis in the subventricular zone (SVZ) under the cerebral ischemic conditions. Methods Sixty mice were randomly assigned to a sham +vehicle group, a middle cerebral artery occlusion(MCAO) + vehicle group and a MCAO + donepezil group, 20 in each group. A model of MCAO was established. Neural stem cells/progenitor cells were labeled by Mash1, and neuroblasts were labeled by doublecortin (DCX). The expressions of DCX in the SVZ cells of each group were detected by immunofluorescence. The expressions of Mash1 and DCX in the SVZ cells of each group were quantified by Western blot. Results 10 days after MCAO was undergone, DCX-positive cells were seen in the SVZ of each group, and the expressions of DCX and Mash1 in MCAO + vehicle group were markedly increased as compared with the sham + vehicle group (P < 0.05), and that in MCAO + donepezil group were significantly increased as compared with the other two groups (P < 0.05). Conclusion As a kind of acetylcholinesterase inhibitors, donepezil can promote neurogenesis in SVZ under the cerebral ischemic conditions.
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Objective Recent researches indicate that Eph/ephrin signaling pathway is possibly related to adult neurogenesis after cerebral injury..With brief introduction of their structures and interactions,the review focus on their possible mechanism in adult neurogenesis.Methods The literatures between 2010 and 2015 were retrieved following online databases:PUBMED,ScienceDirect,Wanfang and CNKI database.The key words used in the reasearch were Eph,ephrin,cerebral injury,adult neurogenesisand so on.Results Totally 42 related articles were enrolled.And these papers discribed how researchers performed their experiments and further explained Eph/ephrin 's vital roles in adult neurogenesis.Conclusion Eph/ephrin signaling can influence adult neurogenesis after cerebral injury.positively or negatively.And Akt may be a downstream signaling molecule of Eph/ephrin that change the progress of adult neurogenesis.However,the detailed mechanisms remain to be further study.