Mitochondrial dynamic modulators improve cognitive function in rats with myocardial infarction

Abstract

AbstractBackgroundCognitive impairment is the most frequent mental health problem among people with heart failure (HF). Brain pathologies in HF‐induced cognitive impairment are possibly associated with the imbalance of brain mitochondrial dynamics. Therefore, therapeutic interventions targeting mitochondrial dynamics by mitochondrial fission inhibition or mitochondrial fusion enhancement would provide beneficial outcomes to the brain of HF subjects. This study aimed to test whether modulating mitochondrial dynamic improves cognitive function in HF rats via reduced brain mitochondrial dysfunction, and dendritic spine loss.MethodRats underwent either sham surgery or permanent left anterior descending coronary artery ligation‐induced myocardial infarction (MI). MI rats developed HF with reduced ejection fraction (%LVEF <50%) at 1‐week post‐operation. Then, MI rats were assigned to receive one of four following interventions: (1) DMSO as a vehicle, (2) enalapril (a positive control, 10 mg/kg/day, orally), (3) mitochondrial division Inhibitor (Mdivi‐1, 1.2 mg/kg/day, intraperitoneal (IP) injection), (4) mitochondrial fusion promotor (M1, 2 mg/kg/day, IP injection). All rats were received the intervention for 4 weeks, then, the cognitive function via NOL was assessed, and were sacrificed. Brain mitochondrial function and dendritic spine density were determined.ResultHF rats developed cognitive impairment, when compared to the sham group, and it was associated with increased brain mitochondrial oxidative stress, and dendritic spine loss in hippocampus (Figure). Treatment with Mdivi‐1 and M1 improved cognitive function similar to enalapril, as indicated by increasing %preference of NOL. Furthermore, all treatments effectively reduced brain mitochondrial ROS levels and hippocampal dendritic spine loss in HF rats (Figure).ConclusionMitochondrial fusion inhibitor and mitochondrial fusion improved cognitive function in HF rats through a reduction of mitochondrial ROS levels and preserved dendritic spine density.