Higher Circulating Trimethylamine N-oxide Sensitizes Sevoflurane-Induced Cognitive Dysfunction in Aged Rats Probably by Downregulating Hippocampal Methionine Sulfoxide Reductase A.

Abstract

Gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) has recently been shown to promote oxidative stress and inflammation in the peripheral tissues, contributing to the pathogenesis of many diseases. Here we examined whether pre-existing higher circulating TMAO would influence cognitive function in aged rats after anesthetic sevoflurane exposure. Aged rats received vehicle or TMAO treatment for 3weeks. After 2weeks of treatment, these animals were exposed to either control or 2.6% sevoflurane for 4h. Oneweek after exposure, freezing as measured by fear conditioning test, microglia activity, proinflammatory cytokine expression and NADPH oxidase-dependent reactive oxygen species (ROS) production in the hippocampus (a key brain structure involved in learning and memory) were comparable between vehicle-treated rats exposed to control and vehicle-treated rats exposed to sevoflurane. TMAO treatment, which increased plasma TMAO before and 1week after control or sevoflurane exposure, significantly reduced freezing to contextual fear conditioning, which was associated with increases in microglia activity, proinflammatory cytokine expression and NADPH oxidase-dependent ROS production in the hippocampus in rats exposed to sevoflurane but not in rats exposed to control. Moreover, hippocampal expression of antioxidant enzyme methionine sulfoxide reductase A (MsrA) was reduced by TMAO treatment in both groups, and TMAO-induced reduction in MsrA expression was negatively correlated with increased proinflammatory cytokine expression in rats exposed to SEV. These findings suggest that pre-existing higher circulating TMAO downregulates antioxidant enzyme MsrA in the hippocampus, which may sensitize the hippocampus to oxidative stress, resulting in microglia-mediated neuroinflammation and cognitive impairment in aged rats after sevoflurane exposure.