CZL-80,a novel caspase-1 inhibitor,pro⁃motes functional recovery after progressive ischemic stroke

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.

Risk factors for progressive ischemic stroke: A retrospective analysis

BACKGROUND： Progressive ischemic stroke has higher fatality rate and disability rate than common cerebral infarction, thus it is very significant to investigate the early predicting factors related to the occurrence of progressive ischemic stroke, the potential pathological mechanism and the risk factors of early intervention for preventing the occurrence of progressive ischemic stroke and ameliorating its outcome. OBJECTIVE： To analyze the possible related risk factors in patients with progressive ishcemic stroke, so as to provide reference for the prevention and treatment of progressive ishcemic stroke. DESIGN： A retrospective analysis. SETTING： Department of Neurology, General Hospital of Beijing Coal Mining Group. PARTICIPANTS： Totally 280 patients with progressive ischemic stroke were selected from the Department of Neurology, General Hospital of Beijing Coal Mining Group from March 2002 to June 2006, including 192 males and 88 females, with a mean age of （62±7） years old. They were all accorded with the diagnostic standards for cerebral infarction set by the Fourth National Academic Meeting for Cerebrovascular Disease in 1995, and confired by CT or MRI, admitted within 24 hours after attack, and the neurological defect progressed gradually or aggravated in gradients within 72 hours after attack, and the aggravation of neurological defect was defined as the neurological deficit score decreased by more than 2 points. Meanwhile, 200 inpatients with non-progressive ischemic stroke （135 males and 65 females） were selected as the control group. METHODS： After admission, a univariate analysis of variance was conducted using the factors of blood pressure, history of diabetes mellitus, fever, leukocytosis, levels of blood lipids, fibrinogen, blood glucose and plasma homocysteine, cerebral arterial stenosis, and CT symptoms of early infarction, and the significant factors were involved in the multivariate non-conditional Logistic regression analysis. MAIN OUTCOME MEASURES： Results of the univariate analysis of variance of the factors related to progressive ischemic stroke; Results of the multivariate regression analysis. RESULTS： All the 480 patients were involved in the analysis of results. ① Results of the univariate analysis variance： There were significantly more patients with fever, leukocytosis, history of diabetes mellitus, cerebral arterial stenosis and CT symptoms of early infarction in the progressive ischemic stroke group than in the control group （P 〈 0.01）; The levels of blood glucose and fibrinogen in the progressive ischemic stroke group were significantly higher than those in the control group, while the level of blood pressure was significantly lower than that in the control group （P 〈 0.05 - 0.01）. ② Results of the multivariate Logistic regression analysis： The independent predicting factors for progressive ischemic stroke were history of diabetes mellitus, fever, leukocytosis, cerebral arterial stenosis, CT symptoms of early infarction, blood glucose and blood pressure （OR =2.61,2.96, 3.79, 1.03, 3.57, 2.68, 95% CI 0.92 - 3.59, P 〈 0.05 - 0.01）. CONCLUSION： History of diabetes mellitus, fever, leukocytosis, levels of blood pressure, blood glucose, cerebral arterial stenosis and CT symptoms of early infarction are the risk factors for progress ischemic stroke