Activation of glutamine synthetase (GS) as a new strategy for the treatment of major depressive disorder and other GS-related diseases.

Glutamine synthetase (GS) plays a crucial role in the homeostasis of the glutamate-glutamine cycle in the brain. Hypoactive GS causes depressive behaviors. Under chronic stress, GS has no change in expression, but its activity is decreased due to nitration of tyrosine (Tyr). Thus, we speculate that agents that prevent nitration or facilitate denitration of GS would be candidates for new antidepressants. Using human recombinant GS and mouse lysate from the medial prefrontal cortex, we demonstrated that Tyr (0.0313-0.5 µM) dose-dependently protected GS activity against peroxynitrite-induced Tyr-nitration of GS. Diet supplementation with Tyr exerted significant antidepressant effects in a chronic immobilization stress depression mouse model. We further found that dipeptides, such as tyrosyl-glutamine (YQ), that had appropriate chemical properties for medication also increased GS activity both in vitro and in vivo and exerted antidepressant effects. Because reduced GS activity also occurs in epilepsy and hyperammonemia, we evaluated whether Tyr and YQ had therapeutic effects. Interestingly, Tyr or YQ administration significantly attenuated kainic acid-induced seizures in mice and reduced blood ammonia levels in azoxymethane- or bile duct ligation-induced hyperammonemia mouse models, which was accompanied by an increment in GS activity. The activation of GS was accomplished by a decrement in Tyr-nitration, so-called Tyr-denitration. Therefore, this study demonstrates that the activation of GS could be a new strategy to treat depression and other GS-related diseases.