Caspase‐dependent Apoptosis Inhibition Improves Cognitive Function in Myocardial Infarction Rats

Abstract

AbstractBackgroundCognitive impairment was frequently found following myocardial infarction (MI). Apoptosis, particularly in the hippocampal area, has been proposed as a mechanism involving in the cognitive impairment through the initiation of brain cell death and subsequently dendritic spine loss. The hypothesis of this study is that the inhibition of apoptosis using a pan‐caspase inhibitor (Z‐VAD‐FMK) improves hippocampal dependent cognitive function in MI rats via attenuating brain apoptosis and dendritic spine lossMethodMale Wistar rats were divided into sham operation or permanent left anterior descending coronary artery ligation‐induced MI. After one week, MI rats with LVEF less than 50% were randomly assigned to one of three interventions: (1) MI‐vehicle (DMSO), (2) Enalapril as a positive control (10 mg/kg/day, PO), and (3) A pan‐caspase inhibitor (Z‐VAD‐FMK, 1 mg/kg/day, IP). All rats received the intervention for 4 weeks, then cardiac function and hippocampal‐dependent cognitive function were assessed before they were sacrificed. Hippocampal dendritic spine density and apoptotic protein expression were determined.ResultMI‐vehicle rats exhibited cardiac dysfunction (as shown by a decrease in %LVEF), cognitive impairment (as shown by decreased %preference of novel object recognition), and hippocampal dendritic spine loss. Furthermore, our data showed that apoptosis was significantly increased (as shown by increased cleaved‐caspase 3/Pro‐caspase 3 levels) in MI‐vehicle rats, compared with the sham rats (as shown in Figure). Treatment with Z‐VAD‐FMK and enalapril equally improved cardiac function, cognitive function, and increased hippocampal dendritic spine density, compared with the MI‐vehicle rats. Z‐VAD‐FMK demonstrated a greater benefit in reducing apoptosis than enalapril in the brain of MI rats.ConclusionApoptosis inhibitor shared similar efficacy with enalapril in improving cognitive function through suppressing brain apoptosis and restoring hippocampal dendritic spine density in MI rats.