Caspase-8 plays an important role in the mediation of inflammation and the effect of its role in subarachnoid hemorrhage remains elusive.The nucleotide-binding oligomerization domain-like receptor protein 3 inflammaso...Caspase-8 plays an important role in the mediation of inflammation and the effect of its role in subarachnoid hemorrhage remains elusive.The nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome has been postulated to mediate inflammation during SAH.The aim of the present study was to investigate the effects of caspase-8 inhibition on SAH injury and further elucidate the molecular mechanisms.In this study,a subarachnoid hemorrhage model was established by endovascular perforation process in adult male Sprague-Dawley rats.Z-IETD-FMK(0.5,1,2 mg/kg;an inhibitor of caspase-8)was delivered via intravenous(tail vein)injection immediately after subarachnoid hemorrhage.After 12 hours of subarachnoid hemorrhage,western blot assay showed that the expression of cleaved caspase-8 was significantly increased at 12 hours,peaked at 24 hours,and then decreased at 72 hours after subarachnoid hemorrhage.Immunofluorescence staining demonstrated that caspase-8 was expressed in microglia after subarachnoid hemorrhage.Z-IETDFMK significantly improved neurological deficits and reduced brain water content 24 hours after subarachnoid hemorrhage.The Morris water maze and rotarod test confirmed that Z-IETD-FMK significantly improved spatial learning and memory abilities and motor coordination at 21–27 days after subarachnoid hemorrhage.Furthermore,inhibition of caspase-8 activation reduced the expression of pyrin domain-containing 3,caspase-1,and interleukin-1βafter subarachnoid hemorrhage.In conclusion,our findings suggest that caspase-8 inhibition alleviates subarachnoid hemorrhage-induced brain injuries by suppressing inflammation.The study was approved by the Institutional Animal Ethics Committee of the First Affiliated Hospital,School of Medicine,Zhejiang University,China(approval No.2016-193)on February 25,2016.展开更多
Dl-3n-butylphthalide can effectively treat cerebral ischemia;however,the mechanisms underlying the effects of dl-3n-butylphthalide on microcirculation disorders following diffuse brain injury remain unclear.In this st...Dl-3n-butylphthalide can effectively treat cerebral ischemia;however,the mechanisms underlying the effects of dl-3n-butylphthalide on microcirculation disorders following diffuse brain injury remain unclear.In this study,models of diffuse brain injury were established in Sprague-Dawley rats with the vertical impact method.Dl-3n-butylphthalide at 80 and 160 mg/kg was given via intraperitoneal injection immediately after diffuse brain injury.Ultrastructural changes in the cerebral cortex were observed using electron microscopy.Cerebral blood flow was measured by laser Doppler flowmetry,vascular density was marked by tannic acid-ferric chloride staining,vascular permeability was estimated by the Evans blue method,brain water content was measured using the dry-wet method,and rat behavior was measured by motor function and sensory function tests.At 6,24,48,and 72hours after administration of dl-3n-butylphthalide,reduced cerebral ultrastructure damage,increased vascular density and cerebral blood flow,and improved motor and sensory functions were observed.Our findings demonstrate that dl-3n-butylphthalide may have protective effects against diffuse brain injury by ameliorating microcirculation disorder and reducing blood-brain barrier damage and cerebral edema.展开更多
基金supported by Clinical Scientific Foundation of Zhejiang Medical Association of China,No.2018ZYC-A09(to HL)
文摘Caspase-8 plays an important role in the mediation of inflammation and the effect of its role in subarachnoid hemorrhage remains elusive.The nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome has been postulated to mediate inflammation during SAH.The aim of the present study was to investigate the effects of caspase-8 inhibition on SAH injury and further elucidate the molecular mechanisms.In this study,a subarachnoid hemorrhage model was established by endovascular perforation process in adult male Sprague-Dawley rats.Z-IETD-FMK(0.5,1,2 mg/kg;an inhibitor of caspase-8)was delivered via intravenous(tail vein)injection immediately after subarachnoid hemorrhage.After 12 hours of subarachnoid hemorrhage,western blot assay showed that the expression of cleaved caspase-8 was significantly increased at 12 hours,peaked at 24 hours,and then decreased at 72 hours after subarachnoid hemorrhage.Immunofluorescence staining demonstrated that caspase-8 was expressed in microglia after subarachnoid hemorrhage.Z-IETDFMK significantly improved neurological deficits and reduced brain water content 24 hours after subarachnoid hemorrhage.The Morris water maze and rotarod test confirmed that Z-IETD-FMK significantly improved spatial learning and memory abilities and motor coordination at 21–27 days after subarachnoid hemorrhage.Furthermore,inhibition of caspase-8 activation reduced the expression of pyrin domain-containing 3,caspase-1,and interleukin-1βafter subarachnoid hemorrhage.In conclusion,our findings suggest that caspase-8 inhibition alleviates subarachnoid hemorrhage-induced brain injuries by suppressing inflammation.The study was approved by the Institutional Animal Ethics Committee of the First Affiliated Hospital,School of Medicine,Zhejiang University,China(approval No.2016-193)on February 25,2016.
基金supported by the grants from Hebei Province Science and Technology Ministry,No.20276102DKey Project of Hebei Province Education Ministry,No.ZD2010106
文摘Dl-3n-butylphthalide can effectively treat cerebral ischemia;however,the mechanisms underlying the effects of dl-3n-butylphthalide on microcirculation disorders following diffuse brain injury remain unclear.In this study,models of diffuse brain injury were established in Sprague-Dawley rats with the vertical impact method.Dl-3n-butylphthalide at 80 and 160 mg/kg was given via intraperitoneal injection immediately after diffuse brain injury.Ultrastructural changes in the cerebral cortex were observed using electron microscopy.Cerebral blood flow was measured by laser Doppler flowmetry,vascular density was marked by tannic acid-ferric chloride staining,vascular permeability was estimated by the Evans blue method,brain water content was measured using the dry-wet method,and rat behavior was measured by motor function and sensory function tests.At 6,24,48,and 72hours after administration of dl-3n-butylphthalide,reduced cerebral ultrastructure damage,increased vascular density and cerebral blood flow,and improved motor and sensory functions were observed.Our findings demonstrate that dl-3n-butylphthalide may have protective effects against diffuse brain injury by ameliorating microcirculation disorder and reducing blood-brain barrier damage and cerebral edema.
