Methylgloxal and anxiety disorder

methylglyoxal, aka pryuvaldehyde

A recent paper in The Journal of Clinical Investigation by researchers from the University of Chicago, working together with Assistant Research Professor of Biochemistry Leigh Plant from Brandeis, reveals a new mechanism for anxiety disorders involving the metabolite methylglyoxal (MG) (right).  The researchers investigated the effect of Glyoxalase 1 (Glo1) expression in mice. Increasing Glo1 copy number, and hence expression, in mice increased anxiety-like behavior. Since Glo1 metabolizes MG, they looked for a direct effect by administering MG, and found it had an anxiolytic effect in the mouse model (n.b.. MG is toxic, so don’t take it to treat anxiety). Inhibitors of Glo1 might therefore have anxiolytic effects, which they showed for the inhibitor S-bromobenzylglutathione cyclopentyl diester

Electrophysiology experiments were conducted to elucidate the mechanism of action of MG, suggesting that it had a GABAergic effect in vivo, and specifically that it is an agonist of the GABAA receptor in multiple neuron types.

So why is a relatively reactive small molecule, normally considered a by-product of glycolysis in animals, acting at neuronal receptors? Can this be exploited with pharmacological methods? What other functions does methylglyoxal have in the nervous system?  It may have many — another very recent paper in Nature Medicine suggests a role for MG in pain sensitivity and diabetic neuropathy, so there may be many interesting parts to this story.

Pre-med undergraduates should take note — keeping track of all those metabolites in glycolysis that you learn about in introductory biochemistry is far from irrelevant to modern medicine!



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