Methylglyoxal is the main culprit to impairing neuronal function: mediated through tryptophan depletion

Depression is a common and prevalent illness and the exact cause of major depressive disorder is not known. Here, we investigated how methylglyoxal (MGO) stress induces depression and unveiled the potential molecular mechanism. Our in vivo results suggested that MGO caused depression in mice, confirmed by several behavioral tests. Interestingly, it halted the mice’s brain’s tryptophan levels and its related neurotransmitters. In addition, MGO induced a reduction in the number of cells in different hippocampal regions. Moreover, it decreased tryptophan hydroxylase 1 (TPH1) and tryptophan hydroxylase 1 (TPH2) levels in the brain and large intestine. Surprisingly, MGO showed the highest affinity and trapping ability toward tryptophan. Most importantly, combined treatment with MGO-tryptophan displayed similar effects as those exhibited by the tryptophan-null treatment in neuronal cells, which included neuronal apoptosis, decrease TPH1 and TPH2 levels, and inhibition of neuronal outgrowth. However, tryptophan treatment improved MGO induced depression-like behavior of mice and recovered the loss of neuronal and hippocampal cells. Subsequently, it also induced MGO detoxifying factors, tryptophan levels, and reduces inflammation in the intestine. Collectively, our data revealed that MGO induced depression facilitated by neuronal and synaptic dysfunction is mediated through the disturbance of tryptophan metabolism in the brain and intestine. ### Competing Interest Statement The authors have declared no competing interest. * DM : Diabetes mellitus MGO : Methylglyoxal GO : Glyoxal TPH1 : Tryptophan hydroxylase 1 TPH2 : Tryptophan hydroxylase 2 CEL : Carboxymethyl-lysine MGH1 : Methylglyoxal-derived hydroimidazolones 5-HT : 5-hydroxytryptamine 5-HTTP : 5-hydroxytryptophan DA : Dopamine EP : Epinephrine NE : Norepinephrine DG : Dentate gyrus CA3 : Cornu ammonis 3 CA1 : Cornu ammonis 3 Bax : BCL-2 Associated X protein BcL-2 : B-cell lymphoma 2 GLO-I : Glyoxalase-I GLO-II : Glyoxalase-II PTPRT : Protein tyrosine phosphatase receptor type T Padi2 : Protein-arginine deiminase type-2