The Effects Of Leptin On Focal Cerebral Ischemia In Rats Via The Mitochondrial Signal Transducer And Activator Of Transcription 3(STAT3) Pathway

Background: Ischemic cerebral infarction is the most common type of cerebrovascular disease,which is caused by various causes of brain blood supply disorder,leading to brain tissue ischemia,hypoxia necrosis and the corresponding neurological deficit.The lesions of acute ischemic cerebral infarction were composed of the core infarct area and the ischemic penumbra.The cells located in the center of ischemic cerebral infarction can be rapidly and irreversibly necrosis under the condition of ischemia and hypoxia.However,there are still a lot of nerve cells in the ischemic penumbra around the core infarct area due to collateral circulation.There are a large number of dormant or semi dormant brain cells in the ischemic penumbra.Due to the lack of energy supply,these cells can only maintain the integrity of their own morphology,which can not exercise the original normal function.Reversibility of brain cell injury in ischemic penumbra is one of the pathological basis of emergency treatment in patients with ischemic cerebral infarction.If the cells in theischemic penumbra can be saved in time,the function and activity of the cells will be improved.It is very important for the survival of brain cells to maintain the integrity of mitochondrial function in low perfusion environment.The recent research results show that leptin may play a positive protective effect on brain nerve cells in the stroke,which can significantly reduce the cerebral ischemia hypoxia induced cell death,reduce infarct area and provide a new direction for the treatment of cerebrovascular disease.STAT3 is one of the major intracellular signaling pathways after leptin and receptor binding.STAT3 located in the nucleus as a transcription factor affecting the expression of specific genes in the nucleus;in addition,STAT3 turn in mitochondria can improve mitochondrial hypoxia tolerance.Based on the research of MCAO rat model shows that leptin can promote the phosphorylation of STAT3 in the nucleus.However,it has not been reported in the literature that leptin activates the mitochondrial STAT3 signaling pathway in cerebral ischemia.Objective To investigate the effects of leptin on the ischemic core and penumbral regions via mitochondrial STAT3 signal pathway,the results will make complete exposition of effects mechanism of leptin-induced mitochondrial STAT3 phosphorylation on mitochondrial oxidative stress for the first time at the level of molecular signal transduction.The completion of this project will be beneficial to provide a strong evidence for the neuroprotective effect of leptin on acute ischemic cerebral infarction,and to provide a new way for the treatment of acute ischemic cerebral infarction.Methods Ischemia was induced in the brain by occluding the middle cerebral artery(MCA)in SD rat.The experiments were divided into three groups:the sham operation group(Sham),the vehicle group(Vehicle)and the leptin group(Leptin)to study how leptin affects mitochondrial oxidative stress via the mitochondria-targeted STAT3 pathway in the cerebral ischemic core and the penumbra.The weight,the degree of brain edema,the area of cerebral infarction and neurological deficits were measured and scored.The mitochondrial respiratory chain enzymatic activities,the content of reactive oxygen species,and the level of mitochondrial STAT3 protein phosphorylation were measured in the ischemic core and the penumbra.Result1.Leptin reduced the neurological deficits in rats,but did not affect the weight change.2.Leptin reduced the infarct area and the degree of edema in rats.3.Leptin induced STAT3 phosphorylation in rat with the ischemic core and the penumbra.4.Leptin reduced the formation of reactive oxygen species(ROS)in rat with the ischemic core and the penumbra.5.Leptin increased the enzymatic activities of mitochondrial respiratory chain I and II in rat with ischemic core and the penumbra.Conclusions Leptin pretreatment could promote the phosphorylation of mitochondrial STAT3 in the ischemic core and the penumbra,thus protecting the mitochondrial respiratory chain complex I and II enzymatic activities from ischemic injury.These effects decreased the formation of ROS,reduced brain edema,improved neurological defects,reduced the infarct size,and eventually decreased experimental ischemic injury induced by permanent MCAO in rats.