Stroke is one of the leading causes of disability and death globally.It occurs when a major artery is occluded in the brain and leads to death of cells within the injured tissue.（＋）-Borneol,a simple bicyclic monote...Stroke is one of the leading causes of disability and death globally.It occurs when a major artery is occluded in the brain and leads to death of cells within the injured tissue.（＋）-Borneol,a simple bicyclic monoterpene extracted from traditional Chinese medicine,is widely used in various types of diseases.However,no study has proved the effects of（＋）-borneol on functional recovery from permanent ischemic stroke and the mechanism is still unknown.Here,we report that in the rat model of permanent cerebral ischemia,we found that（＋）-borneol（1.0 mg/kg） significantly ameliorated infarct size and neurological scores via reducing the expression of inducible nitric oxide synthase（iNOS）and tumor necrosis factor-alpha（TNF-α） in a dose dependent manner.Notably,（＋）-borneol showed long-term effects on the improvement of sensorimotor functions in the photothrombotic model of stroke,which decreased the number of foot faults in the grid-walking task and forelimb asymmetry scores in the cylinder task,at least in part through reducing loss of dendritic spines in the length,brunch number and density.These findings suggest that（＋）-borneol could serve as a therapeutic target for ischemic stroke.展开更多
OBJECTIVE To investigate the effects of IMM-H004 on permanent focal cerebral ischemia injury and associated cardiopulmonary complications,further elucidating the molecular mechanisms.METHODS The effects of IMM-H004 we...OBJECTIVE To investigate the effects of IMM-H004 on permanent focal cerebral ischemia injury and associated cardiopulmonary complications,further elucidating the molecular mechanisms.METHODS The effects of IMM-H004 were investigated in wild-type(WT) and CKLF1-/-rats.The effects of IMM-H004 on ischemic stroke injury and its cardiopulmonary complications were determined using 2,3,5-triphenyltetrazolium chloride(TTC) staining,behavior tests,magnetic resonance imaging(MRI)scans,enzyme-linked immunosorbent assay(ELISA),Nissl staining,and histo-pathological examination.Multiple molecular experiments including immunohistological staining,immunofluorescence staining,quantitative RT-PCR,Western blotting,and co-immunoprecipitation assays were used to elucidate the underlying mechanisms.RESULTS IMM-H004 treatment provided significant protection against ischemic stroke-induced brain injury and associated cardiopulmonary complications,through CKLF1-depedent-anti-inflammation pathway in rats.IMM-H004 downregulated the amount of CKLF1 and disturbed the combination between CKLF1 and C-C chemokine receptor type 4,suppressing the inflammatory response and protecting the damaged organs in ischemic setting.CONCLUSION This preclinical study established efficacy of IMM-H004 as a potential therapeutic medicine for ischemic stroke and associated cardiopulmonary complications.The protective effects of IMM-H004 may due to its specific mechanism through CKLF1.These results support further efforts to develop IMM-H004 for human clinical trials in acute cerebral ischemia,especially for patients who are not suitable for reperfusion therapy.展开更多
基金supported by grants from National Natural Science Foundation of China(91232304, 31530091,81571188 and 81222016)the Natural Science Foundation of Jiangsu Province(BK2011029)Distinguished Young Scientists Fund(BK20130040)
文摘Stroke is one of the leading causes of disability and death globally.It occurs when a major artery is occluded in the brain and leads to death of cells within the injured tissue.（＋）-Borneol,a simple bicyclic monoterpene extracted from traditional Chinese medicine,is widely used in various types of diseases.However,no study has proved the effects of（＋）-borneol on functional recovery from permanent ischemic stroke and the mechanism is still unknown.Here,we report that in the rat model of permanent cerebral ischemia,we found that（＋）-borneol（1.0 mg/kg） significantly ameliorated infarct size and neurological scores via reducing the expression of inducible nitric oxide synthase（iNOS）and tumor necrosis factor-alpha（TNF-α） in a dose dependent manner.Notably,（＋）-borneol showed long-term effects on the improvement of sensorimotor functions in the photothrombotic model of stroke,which decreased the number of foot faults in the grid-walking task and forelimb asymmetry scores in the cylinder task,at least in part through reducing loss of dendritic spines in the length,brunch number and density.These findings suggest that（＋）-borneol could serve as a therapeutic target for ischemic stroke.
基金The project supported by ZYBZH-Y-HUN-24National Natural Science Foundation of China(81730096+6 种基金U1402221)National Mega-project for Innovative Drugs(2018ZX09711001-002-0072018ZX09711001-003-0052018ZX09711001-009-013)CAMS Innovation Fund for Medical Sciences(2016-I2M-1-004)Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150)PUMC Graduate Educationand Teaching Reform Project(10023201600801)
文摘OBJECTIVE To investigate the effects of IMM-H004 on permanent focal cerebral ischemia injury and associated cardiopulmonary complications,further elucidating the molecular mechanisms.METHODS The effects of IMM-H004 were investigated in wild-type(WT) and CKLF1-/-rats.The effects of IMM-H004 on ischemic stroke injury and its cardiopulmonary complications were determined using 2,3,5-triphenyltetrazolium chloride(TTC) staining,behavior tests,magnetic resonance imaging(MRI)scans,enzyme-linked immunosorbent assay(ELISA),Nissl staining,and histo-pathological examination.Multiple molecular experiments including immunohistological staining,immunofluorescence staining,quantitative RT-PCR,Western blotting,and co-immunoprecipitation assays were used to elucidate the underlying mechanisms.RESULTS IMM-H004 treatment provided significant protection against ischemic stroke-induced brain injury and associated cardiopulmonary complications,through CKLF1-depedent-anti-inflammation pathway in rats.IMM-H004 downregulated the amount of CKLF1 and disturbed the combination between CKLF1 and C-C chemokine receptor type 4,suppressing the inflammatory response and protecting the damaged organs in ischemic setting.CONCLUSION This preclinical study established efficacy of IMM-H004 as a potential therapeutic medicine for ischemic stroke and associated cardiopulmonary complications.The protective effects of IMM-H004 may due to its specific mechanism through CKLF1.These results support further efforts to develop IMM-H004 for human clinical trials in acute cerebral ischemia,especially for patients who are not suitable for reperfusion therapy.
