Cannabinoid Receptor Agonist WIN55,212-2 Attenuates Injury In The Hippocampus Of Rats After Deep Hypothermic Circulatory Arrest

Objectives:Deep Hypothermic Circulatory Arrest(DHCA)has been widely applicated in aortic and complex congenital heart disease surgery.It not only provides a bloodless field for the operators but also decreases the metabolism of neurons under hypothermia,which increases the tolerance of the neurological system to ischemia and hypoxia.Due to the ischemia and hypoxia during DHCA and systematic inflammation caused by cardiopulmonary bypass(CPB),postoperative neurological deficits,such as delirium,postoperative cognitive dysfunction,and paraplegia,remain a challenge in cardiac surgery.In recent years,numerous studies have demonstrated that the endogenous cannabinoid system is involved in the process of neurological damage in stroke,which has a significant neuroprotective value.This study aimed to investigate the effect of WIN55,212-2,a cannabinoid agonist,on brain injury in a rat model of DHCA.Methods:Twenty-four Male Sprague Dawley rats were randomly divided into three groups:Control group(underwent CPB only),DHCA group(CPB with DHCA),and WIN group(WIN55,212-2 pretreatment before CPB with DHCA).Histopathological changes in the brain were evaluated by hematoxylin-eosin staining.Plasma levels of superoxide dismutase(SOD)and proinflammatory cytokines,including interleukin(IL)-1β,IL-6,and tumor necrosis factor-alpha(TNF-α),were determined by enzyme-linked immunosorbent assay(ELISA).Expression of SOD in the hippocampus was detected by western blot and immunofluorescence staining.Levels of apoptotic-related protein caspase-3 and type 1 cannabinoid receptor(CB1R)in the hippocampus were evaluated by western blot.Results:WIN55,212-2 administration attenuated histopathological injury of the hippocampus in rats underwent DHCA,associated with lowered levels of IL-1 p,IL-6,and TNF-α(P<0.05,P<0.001,P<0.01,vs.DHCA respectively)and increased level of SOD(P<0.05 vs.DHCA).WIN55,212-2 treatment also increased the content of SOD in the hippocampus.The protein expression of caspase-3 was downregulated and the expression of CB1R was upregulated in the hippocampus by WIN55,212-2.Conclusions:Administration of WIN55,212-2 alleviates hippocampal injury induced by DHCA in rats by regulating intrinsic inflammatory and oxidative stress responses through a CB1R-dependent mechanism.