Cardioprotective Effect Of Different Regimens Of Huperzine A In Cerebral-Cardiac Syndrome After Ischemic Stroke

Background:Stroke is the leading cause of death and disability in the Chinese population,of which ischemic stroke accounts for about 69.9%.Ischemic stroke-induced serious adverse cardiac complications refer to cerebral-cardiac syndrome(CCS),which mainly manifests as arrhythmia,cardiac dysfunction,acute myocardial infarction and so on.Of note,ischemic stroke-induced overactive systemic and cardiac inflammatory response is chief pathogenesis of CCS.Macrophages play an important role in cardiac inflammatory injury.Monocyte chemotactic factor-1(MCP-1)is key chemokine by directing macrophage recruitment and activation.Huperzine A(Hup A)is a cholinesterase inhibitor,which exerts anti-inflammatory function by regulating macrophage recruitment and function,also called the ’cholinergic anti-inflammatory pathway’.However,the role of Hup A in CCS is still unclear.The stated goal of this study was to evaluate the effect and potential mechanism of Hup A in CCS.Methods:Firstly,we established the middle cerebral artery occlusion(MCAO)mouse model to mimic ischemic stroke.Secondly,five treatment schemes were designed from three aspects:long-term administration,short-term administration and single administration,including long-term continuous administration,short-term continuous administration,single administration at 10 min before MCAO,single administration on the first day after MCAO and single administration on the third day after MCAO.Echocardiography and electrocardiogram were used to evaluate cardiac function before and at different time points after MCAO.The number of cardiac macrophages and MCP-1 expression were used to evaluate cardiac inflammation.Results:We found that the QT interval and QTc interval were significantly prolonged,accompanied by decreased left ventricular ejection fraction and shortening fraction in MCAO mice,suggesting that CCS occurred after ischemic stroke.Different Hup A treatment schemes had different effects on cardiac function in MCAO mice.Single Hup A administration on the third day after MCAO preformed obvious cardioprotective effect,since the left ventricular ejection fraction and shortening fraction were significantly enhanced.Single Hup A administration on the third day after MCAO did not alleviate the cerebral damage,suggesting that it had no central neuroprotective effect on ischemic stroke.Moreover,we found the number of macrophages and MCP-1 expression are increased in the heart after MCAO.Single Hup A administration on the third day after MCAO inhibits the MCP-1 expression and reduces the number of cardiac macrophages,resulting in reducing the cardiac inflammatory injury after ischemic stroke.Conclusion:Single Hup A treatment on the third day after MCAO is an effective treatment for CCS.Furthermore,Hup A reduces the number of cardiac macrophages by reducing the expression of MCP-1 in the heart after ischemic stroke,thereby reducing the cardiac inflammatory damage,and ultimately playing a protective role in the CCS.