Antidepressant Effects of L-Arginine and Its Role in Brain Energy Metabolism.

BACKGROUND

Mitochondrial dysfunction and impaired cellular energy metabolism are increasingly recognized as key contributing factors in depression. This study evaluated the amino acid L-arginine as a potential agent for behavioral rescue and bioenergetic restoration using a corticosterone-induced rat model of depression.

METHODS

Male rats were randomly assigned to four groups (n = 10): control (DMSO intraperitoneally [i.p.] + water oral gavage), corticosterone-induced depression (20 mg/kg, i.p. for 14 days), L-arginine treatment (150 mg/kg, oral gavage for 14 days), and fluoxetine (10 mg/kg, oral gavage for 14 days). To ensure handling equivalence, all oral administrations were performed via gavage (1.0 mL/100 g). Behavioral rescue was assessed via open field, forced swim (FST), and tail suspension (TST) tests. Hippocampal energy metabolism and PI3K/Akt/mTOR pathway activation were analyzed.

RESULTS

L-arginine significantly improved the hippocampal bioenergetic profile, demonstrating efficacy comparable to the positive control fluoxetine. It led to a significant reduction in immobility time during FST and TST, alongside restoring glycolysis, the tricarboxylic acid cycle, and mitochondrial respiratory chain activities. Concurrently, L-arginine enhanced the activation state of the PI3K/Akt/mTOR signaling pathway (phosphorylated Akt/Akt and p-mTOR/mTOR ratios) and improved the functional state of the mitochondrial permeability transition pore. These metabolic and signaling improvements strongly correlated with the rescue of depressive-like behaviors.

CONCLUDION: Our findings demonstrate that L-arginine possesses potent antidepressant-like potential, mediated through bioenergetic restoration and signaling pathway modulation. By activating key metabolic processes in the hippocampus, L-arginine effectively restores impaired cellular energy homeostasis, suggesting its promise as a metabolic modulator for alleviating neurobiological disturbances associated with depressive conditions.