Methylglyoxal Accumulation is Associated with Brain Inflammation after Myocardial Infarction with Sex and Regional Differences

ABSTRACT Patients with myocardial infarction (MI) have an increased risk of developing neurological disease and cognitive impairment, but the mechanisms underlying the heart‐brain interaction remain to be better elucidated. Methylglyoxal (MG), a highly reactive dicarbonyl, is a shared causative factor associated with cardiovascular and neurological diseases. MG‐derived advanced glycation end products (MG‐AGEs) accumulate in the heart and circulation post‐MI, making it a promising target in studying the heart‐brain axis. Here, we report that MG‐AGEs accumulate in the mouse brain at 6 h and 7 days post‐MI, with the highest expression observed in the brainstem, followed by the cortex. Notably, males had higher MG‐AGE expression compared to females in most brain regions. The accumulation of MG‐AGEs in the brain was correlated with increased neuroinflammation, including a greater number of activated microglia and macrophages, and increased expression of AGE receptors. Greater inflammatory factor expression (NF‐κB and TNF‐α) and a reduction in tight junction proteins of the blood brain barrier were also observed. Taken together, this study reveals a novel MG‐mediated mechanism with sex‐based differences that may contribute significantly to heart‐brain interactions after MI and identifies a promising therapeutic target for treating the neurological impairment associated with heart disease.