Methylglyoxal modification of TrkB enhances synaptic plasticity in prefrontal cortex and promotes resilience to chronic stress

Major depressive disorder (MDD) is a severe psychiatric illness that affects about 16 percent of the global population. Despite massive efforts, unravelling the pathophysiology of MDD and developing effective treatments is still a huge challenge. Here, we report a novel therapeutic axis of methylglyoxal (MGO)/tropomyosin receptor kinase B (TrkB) for treating MDD. As an endogenous metabolite, MGO was demonstrated directly binding to the extracellular domain of TrkB, provoking its dimerization and autophosphorylation. This rapidly enhances the expression of brain-derived neurotrophic factor (BDNF) and forms a BDNF-positive feedback loop. Low-dose treatment of MGO effectively promotes the hippocampal neurogenesis and exhibits sustained antidepressant effects in chronic unpredictable mild stress rat models. In addition, the modulation on MGO concentration by overexpression or inhibition of Glyoxalase 1 (GLO1) has been demonstrated associated with depression behaviors in rats. Furthermore, we also identified a natural product luteolin and its derivative lutD as potent inhibitors of GLO1 and explored their precise binding modes. Our findings reveal a novel regulatory mechanism underlying MDD and depict principles for the rational design of new antidepressants targeting GLO1. Adult Sprague-Dawley (SD) male rats (180 - 200 g) were group-housed with standard laboratory bedding and conditions (12-h light/dark cycle, 22 ± 1°C, ad libitum access to food and water) for 1 week prior to the experiments. All rats were randomly assigned to three experimental groups, i.e., non-stress control + saline (SAL); stress (CMS) + SAL; stress (CMS) + drugs (5 mM/kg/day of MGO or 10 mg/kg/day of luteolin). To avoid the possible bias induced by the behavioral tests, the rats in each group were divided into two sets (n = 10 per set). The first set provided tissue samples used for morphological analysis, western blotting and qRT-PCR analyses, while the second one was adopted for behavioral assessments. During the last 3 weeks of the CMS protocol, rats were injected ip daily with drugs.