Protective Effects Of Ciwujia Injection On Heart Toxicity And Cerebral Ischemia Injury And It's Mechanism

Objective:In this study,the protective effect of Ciwujia Injection?CI?on the decrease of cardiac contractile function was studied by using the chemotherapy drug doxorubicin hydrochloride to induce rat cardiotoxicity model,as well as providing experimental basis for its clinical application.The pharmacological effects and related mechanisms of CI against cerebral ischemia injury was studied by Middle cerebral artery occlusion?MCAO?induced by Fecl₃,as well as providing experimental basis for its clinical application of cerebral ischemia.Methods:1)The cardiotoxicity model in rats was established by ip injection of doxorubicin hydrochloride with a dose of 2.5 mg/kg every week for 6 weeks,and the total cumulative dose is 15 mg/kg.Rats were equally divided into five groups with 10rats in each group?e.g.model group,three test groups of CI,positive group?.In addition,a normal control group of 10 rats was injected intraperitoneally with normal saline?NS?once a week for 6 weeks.Normal control and model group were given NS intravenously.The test groups were given CI and the positive group was given ShenqiFuzheng Injection.The CI and ShenqiFuzheng Injection were infused by tail vein for 1 h when doxorubicin hydrochloride administrated.The parameters of left ventricular systolic function including ejection fraction?EF?,shortening fraction?FS?,the maximal rate of rise of left ventricular pressure(+LVdp/dt_max),and heart geometric shape were measured.Cardiomyocyte apoptosis was measured with immunohistochemistry,apoptosis-related protein and oxidative stress factors such asSOD,MDA,and LPO were measured with enzyme-linked immune sorbent assay,or chemical method.The ultrastructural changes of myocardium under electron microscope were observed.2)The MCAO model in rats was established by FeCl₃solution.The neurological deficit score was performed after the rats awake.Thirty rats were equally divided into five groups with 6 rats in each group?e.g.model group,three test groups of CI:11.25,22.5 and 45 mg/kg,positive group:4.5mg/kg?.The corresponding drug solution was infused into the tail vein for 2 hours for 3 times.Neurologic defective scores were measured by blinding before and after administration.Cerebral infarction size,cerebral edema,platelet aggregation and coagulation parameters?PT,TT,APTT and FIB?were measured after administration,oxidative stress factors?SOD,MDA,GSH and GSH-Px?,inflammatory factors?ICAM-1,VCAM-1,IL-1?,IL-6 and TNF??,TXB2,6-k-PGF1?and NO were measured with enzyme–linked sorbent assay,or chemical measurd.Results:1)Compared with model group,after CI treatment?50,100 and 200mg/kg?,thr cardiac systolic function was improved;the declined EF,FS,and+LVdp/dt_maxax increased?P<0.05,0.01?.The heart geometric shape was improved significantly with CI treatment,the expanded LVIDs and LVVs decreased?P<0.05,0.01?.CI can inhibit myocardial cell apoptosis?P<0.01?.The myocardial apoptosis rate decreased?P<0.01?,and the Bax/Bcl-2 decreased?P<0.01?.In addition,CI?100 and 200 mg/kg?can decline the generation of LPO,MDA and increase the activity of SOD.2)Compared with model group,after CI treatment?11.25,22.5 and 45mg/kg?,the detection indexes were improved.CI?45mg/kg?can significantly improve the neurological deficit?P<0.001?,inhibitplatelet aggregation?P<0.001?,decline the generation of MDA?P<0.05?,increase the activity of GSH-PX?P<0.05?and decline the ratio of MDA/SOD and TXB2/6-k-PGF1??T/P?.At the high dose of 45 mg/kg,the range of cerebral infarction and the degree of edema was significantly reduced?P<0.01,0.05?.After CI treatment?22.5 and 45mg/kg?,the inflammatory factor IL-1?was decreased?P<0.05⁰.01?.After CI treatment?45mg/kg?,IL-6?TNF?were decreased.Conclusion:CI can effectively relieve cardiotoxicity induced by doxorubicin hydrochloride in rats,increase cardiac function,improve the cardiac configuration,and reduce the damage of myocardial ultrastructure.The mechanism may be related to decreasing oxidative stress,and inhibition of apoptosis in impaired myocardial cells.CI has therapeutic effect on focal cerebral infarction injury caused by Fecl₃ of middle cerebral artery occlusion,which can improve neurological deficit,decrease the range of cerebral infarction and the degree of edema and inhibit platelet aggregating.The mechanism may be related to decreasing oxidative stress,inflammatory damage,the balance of T/P and regulation of platelet function.