| Objectives(1)The purpose of this research is to study the pharmacodynamic effects of Carnosic acid and Acetyl carnosic acid on cardiovascular and cerebrovascular diseases.(2)The purpose of this research is to investigate the protective effect of Carnosic acid preconditioning on cerebral ischemia-reperfusion injury in rats and its possible molecular mechanism.Methods(1)The protective effects of carnosic acid and acetyl carnosic acid on cardiovascular and cerebrovascular in mouse were evaluated by acute cerebral ischemia and hypoxia,thrombus in vivo and chloroform-induced arrhythmia models.(2)Middle cerebral artery occlusion(MCAO)model was established.About 7 days prior to set up model,rats were given the drug by gavage once a day.After the last administration,the MCAO model was established by the improved suture method.The coagulation function,platelet aggregation and blood cell count were detected.At the same time,TTC staining was used to detect the range of cerebral infarction.The protective effects of carnosic acid and acetylcarnosic acid on cerebral ischemia in rats were investigated.(3)The models of cerebral ischemia reperfusion injury were established in rats.SD male rats were randomly divided into high dose group of carnosic acid,medium dose group of carnosic acid,low dose group of carnosic acid,model group and sham group.Mode of processing was same as(2).After 2h of ischemia,the rats were perfused.Zea-longa score was used to evaluate the neural function of rats.TTC staining was used to detect the infarct area.The expression of LDH,GSH-PX and MDA were detected by spectrophotometry.The expression of TNF-?,TNF-?,IL-1,IL-1? was detected by ELISA Kit.Q-PCR and Western Blot were used to detect the expression of proteins that related to oxidative stress pathway.TUNEL was used to detect neuronal apoptosis.The coagulation function,platelet aggregation and blood cell count were detected.Results(1)Carnosic acid and acetyl carnosic acid have protective effects on mice with cardiovascular and cerebrovascular diseases.Acetyl carnosic acid can significantly prolonged the wheezing time in the model of acute cerebral ischemia and hypoxia.In the arrhythmia model,the incidence of ventricular fibrillation in the acetyl carnosic acid and carnosic acid were similar to that in the compound salvia miltiorrhiza,breviscapine and the propranolol Hydrochloride group.In the mouse model of thrombosis in vivo,the death time was significantly prolonged in the acetylcarnosic acid group.(2)Carnosic acid and acetyl carnosic acid have protective effects on cerebral ischemia in rats.In the model of MCAO,the symptoms of nerve injury in rats were improved by pretreating with carnosic acid.TTC results showed that the infarct range had decreased.Blood coagulation function test showed that Activated partial thromboplastin time was prolonged,the content of Fibrinogen was decreased and the platelet aggregation was inhibited.Blood routine shows that some physiological indicators have a certain change.By pretreating with acetyl carnosic acid,the ATPP was prolonged,the FIB content was decreased and some blood routine physiological indicators also changed.(3)Carnosic acid has a protective effect on cerebral ischemia reperfusion injury in rats and the mechanism is diverse.Zea-Longa score showed that carnosic acid could alleviate the symptoms of nerve injury in rats at 24h after reperfusion.The results of TTC staining showed that the cerebral infarct size of the rats with pretreatment carnosic acid was significantly reduced.At the same time,the FIB content decreased and the platelet aggregation rate decreased.Blood cell test results showed a decrease in white blood cell count.The content of malondialdehyde in the low dose group of carnosic acid was significantly down-regulated,and the activity of glutathione(GSH)peroxidase in the high dose and middle dose group of carnosic acid was significantly up-regulated.ELISA Kit results showed that the expression of TNF-?,TNF-P,IL-1 and IL-11? was increased by carnosic acid pretreatment.Q-PCR results showed that carnosic acid pretreatment could increase the mRNA expression of AKT,eNOS,ERK5,HOX-1,Keap1,MEK5,Nrf2 and TRPV4 in the cortex.On the contrary,the expression levels of these factors in the hippocampus were decreased.Western blotting showed that the expression of MEK5 and AKT was up-regulated in the cortex after administration of carnosic acid,the level of Keapl was down-regulated and other protein expressions were also changed.TUNEL staining showed that the apoptotic rate of the high dose and medium dose groups of carnosic acid was significantly reduced.Conclusions(1)In the model of acute cerebral ischemia and hypoxia,thrombosis in vivo and arrhythmia in mouse and MCAO in rats,carnosic acid and acetylcarnosic acid have certain changes on some indicators.It has protective effects on cardiovascular and cerebrovascular diseases.It shows different biological activities which may be related to the changes of polarity,electronegativity and the pH of the compounds.(2)In the model of cerebral ischemia-reperfusion injury,camosic acid can reduce the infarct size of rat cortex and improve the neurological function of rats.It has a protective effect.Studies have shown that it has an effect on the expression of proteins that related to the oxidative stress pathway from brain tissue,inflammatory factors,oxygen free radicals,apoptosis and coagulation.Its mechanism may be related to anti-oxidative stress pathway,anti-apoptosis and anti-inflammation. |
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