OBJECTIVE Progressive isch⁃emic stroke is characterized by aggravation of neurological dysfunction and poor prognosis.Neuroinflammation is involved in the pathological process of cerebral ischemia.Inflammasomes-activa...OBJECTIVE Progressive isch⁃emic stroke is characterized by aggravation of neurological dysfunction and poor prognosis.Neuroinflammation is involved in the pathological process of cerebral ischemia.Inflammasomes-activated caspase-1 has thus been considered a promising target for stroke therapy.However,it remains not fully understood how caspase-1 ag⁃gravates progressive functional impairment.We previously identified a novel caspase-1 inhibitor CZL-80,the present study is to explore whether CZL-80 protects against progressive ischemic stroke.METHODS Male C57/BL6 mice and cas⁃pase-1-/-mice were subjected to photothrombotic(PT)-induced cerebral ischemia.CZL-80 was in⁃traperitoneally injected daily during 1-7 d,1-4 d,4-7 d after PT.The grid-walking task and the cyl⁃inder task were used to determine the motor function.RESULTS Mice developed primary and the secondary neurological dysfunction at 1 d and 4-7 d after PT onset.The activation of cas⁃pase-1 peaked at 7 d after ischemic stroke and caspase-1 was mainly derived from activated microglia.Treatment with CZL-80(30 mg·kg-1)during 1-7 d significantly improved motor func⁃tion.Administration of CZL-80 during 1-4 d could not ameliorate motor function loss while administration during 4-7 d after PT onset signifi⁃cantly reduced foot faults and forelimb symme⁃try.Remarkably,treatment with CZL-80 during 4-7 d showed no significant difference in efficacy compared with the its administration during 1-7 d,which indicated a key therapeutic window.More⁃over,the neuroprotective effect of CZL-80 during 4-7 d was available at least until 43 d after isch⁃emic stroke,indicating CZL-80 can improve the long-term neurological function after cerebral ischemia.Furthermore,administration of CZL-80(30 mg·kg-1)during 4-7 d after PT onset in cas⁃pase-1-/-mice failed to improve the motor func⁃tion,which suggested that the neuroprotective effect of CZL-80 was caspase-1-dependent.The results showed that CZL-80 did not inhibit the expression of GSDMD and failed to reduce neu⁃ronal loss after ischemia.These results indicated the effect of CZL-80 was not attributable to inhib⁃it pyroptosis.We further found that CZL-80 signif⁃icantly reduced the number of activated microglia in the peri-infarct brain cortex after ischemic stroke,which might be involved in its neuropro⁃tective effect.CONCLUSION CZL-80,a novel caspase-1 inhibitor,improved motor function after progressive ischemic stroke in mice.The effective therapeutic window of CZL-80 would be 4-7 d after ischemia,when the secondary neuro⁃logical dysfunction occurred.Therefore,the inter⁃vention by targeting caspase-1 in this window phase provides a novel strategy for the function⁃al recovery of stroke survivors.展开更多
OBJECTIVE: To investigate the effect of brain functional recovery decoction(BFRD) on expression of vascular endothelial growth factor(VEGF) and angiopoietin-1(Ang-1) protein in rats with cerebral ischemia reperfusion ...OBJECTIVE: To investigate the effect of brain functional recovery decoction(BFRD) on expression of vascular endothelial growth factor(VEGF) and angiopoietin-1(Ang-1) protein in rats with cerebral ischemia reperfusion injury, and to explore the mechanism of action of BFRD.METHODS: Using the suture-occlusion method, a Wistar rat model of focal cerebral ischemia reperfusion was established. The rats were randomly divided into treatment group, model group, and sham operation group. The treatment group was administered BFRD. In situ hybridization was used to detect VEGF m RNA expression. Immunohistochemistry was used to observe expression of Ang-1 protein.RESULTS: VEGF mRNA expression was greater in the model group compared with the sham operation group(P < 0.05); Ang-1 protein expression was more obvious in the treatment group than the model group(P < 0.05).CONCLUSION: BFRD promoted VEGF m RNA and Ang-1 protein expression in the brains of rats with cerebral ischemia, suggesting increased angiogenesis.展开更多
文摘OBJECTIVE Progressive isch⁃emic stroke is characterized by aggravation of neurological dysfunction and poor prognosis.Neuroinflammation is involved in the pathological process of cerebral ischemia.Inflammasomes-activated caspase-1 has thus been considered a promising target for stroke therapy.However,it remains not fully understood how caspase-1 ag⁃gravates progressive functional impairment.We previously identified a novel caspase-1 inhibitor CZL-80,the present study is to explore whether CZL-80 protects against progressive ischemic stroke.METHODS Male C57/BL6 mice and cas⁃pase-1-/-mice were subjected to photothrombotic(PT)-induced cerebral ischemia.CZL-80 was in⁃traperitoneally injected daily during 1-7 d,1-4 d,4-7 d after PT.The grid-walking task and the cyl⁃inder task were used to determine the motor function.RESULTS Mice developed primary and the secondary neurological dysfunction at 1 d and 4-7 d after PT onset.The activation of cas⁃pase-1 peaked at 7 d after ischemic stroke and caspase-1 was mainly derived from activated microglia.Treatment with CZL-80(30 mg·kg-1)during 1-7 d significantly improved motor func⁃tion.Administration of CZL-80 during 1-4 d could not ameliorate motor function loss while administration during 4-7 d after PT onset signifi⁃cantly reduced foot faults and forelimb symme⁃try.Remarkably,treatment with CZL-80 during 4-7 d showed no significant difference in efficacy compared with the its administration during 1-7 d,which indicated a key therapeutic window.More⁃over,the neuroprotective effect of CZL-80 during 4-7 d was available at least until 43 d after isch⁃emic stroke,indicating CZL-80 can improve the long-term neurological function after cerebral ischemia.Furthermore,administration of CZL-80(30 mg·kg-1)during 4-7 d after PT onset in cas⁃pase-1-/-mice failed to improve the motor func⁃tion,which suggested that the neuroprotective effect of CZL-80 was caspase-1-dependent.The results showed that CZL-80 did not inhibit the expression of GSDMD and failed to reduce neu⁃ronal loss after ischemia.These results indicated the effect of CZL-80 was not attributable to inhib⁃it pyroptosis.We further found that CZL-80 signif⁃icantly reduced the number of activated microglia in the peri-infarct brain cortex after ischemic stroke,which might be involved in its neuropro⁃tective effect.CONCLUSION CZL-80,a novel caspase-1 inhibitor,improved motor function after progressive ischemic stroke in mice.The effective therapeutic window of CZL-80 would be 4-7 d after ischemia,when the secondary neuro⁃logical dysfunction occurred.Therefore,the inter⁃vention by targeting caspase-1 in this window phase provides a novel strategy for the function⁃al recovery of stroke survivors.
基金International Cooperation Projects of Shaanxi Province(The Protection on Ischemia-reperfusion Rats and the influence of VEGF RNA Expression of Brain Functional Recovery Decoction,No.2012-Kw-33-02)
文摘OBJECTIVE: To investigate the effect of brain functional recovery decoction(BFRD) on expression of vascular endothelial growth factor(VEGF) and angiopoietin-1(Ang-1) protein in rats with cerebral ischemia reperfusion injury, and to explore the mechanism of action of BFRD.METHODS: Using the suture-occlusion method, a Wistar rat model of focal cerebral ischemia reperfusion was established. The rats were randomly divided into treatment group, model group, and sham operation group. The treatment group was administered BFRD. In situ hybridization was used to detect VEGF m RNA expression. Immunohistochemistry was used to observe expression of Ang-1 protein.RESULTS: VEGF mRNA expression was greater in the model group compared with the sham operation group(P < 0.05); Ang-1 protein expression was more obvious in the treatment group than the model group(P < 0.05).CONCLUSION: BFRD promoted VEGF m RNA and Ang-1 protein expression in the brains of rats with cerebral ischemia, suggesting increased angiogenesis.
