AbstractBackgroundObesity is widely acknowledged as a major risk factor for brain and heart complications. Brain inflammation and microglial activation can be induced by either cardiac ischemia/reperfusion (I/R) injury or obese condition. While mitochondrial fission inhibitor (Mdivi‐1) and fusion promoter (M1) have already been reported as potential cardioprotective therapies, their protective effects in the brain suffered from cardiac I/R injury under obese condition have not been investigated.MethodThirty male Wistar rats were fed with a high‐fat diet (HFD) for 12 weeks to induce obese‐insulin resistance, and then were randomly divided into the sham (HFS, n=6) and the cardiac I/R (n=24) groups. Cardiac I/R rats were intravenously injected with either vehicle (HFV, n=6), Mdivi‐1 (HFMD, n=6), M1 (HFM1, n=6), or Mdivi‐1+M1 (HFMD+M1, n=6) 15 min prior to a 30‐min ischemia by left anterior descending coronary artery ligation, followed by 120‐min reperfusion. At the end of the protocol, the brain was rapidly removed to determine the protein expression of brain inflammation, microglial markers, and brain pathological conditions.ResultCardiac I/R markedly induced brain pathology via increasing inflammation, microglial activation, and brain pathologies, as shown by increased levels of tumor necrosis factor alpha (TNF‐α), ionized calcium binding adaptor molecule 1 (IBA1), and beta‐amyloid (Aβ) per amyloid‐beta precursor protein (APP) ratio in the HFV group, compared with those of HFS group (p<0.05, Figure 1). In HFD‐fed rats with cardiac I/R injury, either Mdivi‐1, M1, or combined therapies provided neuroprotection by restoring TNF‐α, IBA1, and Aβ/APP protein levels (p<0.05, Figure 1), as well as improved left ventricular ejection fraction [58±5% HFMD; 53±3% HFM1; 55±6% HFMD+M1 vs 42±2% HFV].ConclusionRebalancing brain mitochondrial dynamics rescued brain inflammation and brain pathologies induced by cardiac I/R injury of obese rats. These findings suggest that the modulators of mitochondrial dynamics may act as a novel therapeutic approach for combating brain damage caused by cardiac I/R in an obese subject.