The NO-cGMP signaling pathway and depression: mechanisms and therapeutic prospects

Depression is a highly prevalent and serious mental disorder affecting populations worldwide. However, the traditional monoamine hypothesis does not fully account for its pathogenesis. In recent years, considerable attention has been directed toward the role of the NO-cGMP signaling pathway in the pathophysiology and treatment of depression.Nitric oxide (NO), a gaseous neurotransmitter, activates soluble guanylate cyclase (sGC), thereby increasing the level of the second messenger cyclic guanosine monophosphate (cGMP). In turn, this regulation modulates protein kinase G (PKG) and its downstream signaling cascades. This pathway has been implicated in synaptic plasticity, neurogenesis, and inflammatory responses.Substantial evidence indicates that abnormalities in the NO-cGMP pathway-observed both in patients with depression and in animal models-manifest as elevated NO levels, decreased cGMP content, and altered activities of related enzymes. These changes are thought to interact with multiple other signaling systems to jointly contribute to depressive pathophysiology.A variety of antidepressant drugs and natural products (e.g., vitamin C, pyridoxine, curcumin) have been shown to exert antidepressant effects through modulation of this pathway. Therapeutic strategies targeting this pathway-including NO donors, sGC activators, and phosphodiesterase (PDE) inhibitors-exhibit therapeutic potential.The present review comprehensively summarizes the molecular mechanisms of the NO-cGMP signaling pathway, its role in the pathogenesis of depression, and targeted treatment strategies, with the aim of providing a theoretical foundation for the development of novel antidepressants.