Nitric Oxide Modulation in Schizophrenia Pathophysiology

Schizophrenia is a multifactorial disorder marked by disruptions in neurotransmitter systems and neurodevelopmental trajectories. Emerging evidence implicates nitric oxide (NO) as a pivotal neuromodulator in this condition. NO is synthesised by nitric oxide synthases (NOS), of which neuronal, endothelial and inducible isoforms regulate synaptic plasticity, neurotransmitter release and vascular function. Dysregulation of NO production can drive nitrosative stress, leading to oxidative damage and altered glutamatergic and dopaminergic signalling. Aberrant NO levels during critical periods of brain development may contribute to synaptic pruning deficits and cognitive impairments. Conversely, modulation of NO pathways by exogenous donors or NOS inhibitors holds promise for restoring neurotransmitter balance, attenuating inflammatory cascades and alleviating negative and cognitive symptoms that are poorly addressed by conventional antipsychotics. Integrative analyses of protein–protein interactions have further identified nitrergic targets amenable to pharmacological repurposing. Together, these lines of research underscore the global significance of NO modulation as both a window into schizophrenia pathophysiology and a platform for innovative therapeutic strategies.

Research from Nature Portfolio

A computational mapping of the schizophrenia protein–protein interaction network has revealed a subset of drug candidates whose expression signatures are anti-correlated with disease-associated gene profiles. By integrating these data with drug-target relationships, researchers have pinpointed small molecules that modulate key nitrergic nodes within the interactome. Several of these repurposable compounds, although originally developed for other indications, converge on NO-related proteins and pathways, suggesting novel avenues for therapeutic intervention that could complement or enhance existing treatments.

Nitric Oxide Modulation in Schizophrenia Pathophysiology publication trend

The graph below shows the total number of articles in nitric oxide modulation in schizophrenia pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Nitric oxide (NO): A gaseous signalling molecule involved in neurotransmission, vascular regulation and synaptic plasticity.

Nitrosative stress: Cellular damage caused by excessive reactive nitrogen species, including NO-derived radicals.

Nitric oxide synthases (NOS): Enzymes that catalyse NO production, comprising neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) isoforms.

NMDA receptor: An ionotropic glutamate receptor critical for synaptic plasticity and cognitive function.

Protein–protein interactome: The complete network of physical interactions between proteins within a biological system.

NO donor: A compound that releases nitric oxide in vivo, used to augment nitrergic signalling.

References

1. Role of nitric oxide and related molecules in schizophrenia pathogenesis: biochemical, genetic and clinical aspects. Frontiers in Physiology (2015).
2. Potentially repurposable drugs for schizophrenia identified from its interactome. Scientific Reports (2019).
3. The Effect of Clozapine and Novel Glutamate Modulator JNJ-46356479 on Nitrosative Stress in a Postnatal Murine Ketamine Model of Schizophrenia. International Journal of Molecular Sciences (2023).
4. The Nitric Oxide (NO) Donor Molsidomine Attenuates Memory Impairments Induced by the D1/D2 Dopaminergic Receptor Agonist Apomorphine in the Rat. Molecules (2023).
5. An Investigation of the Sodium Nitroprusside Effects on Serum Lipids in an Animal Model of Schizophrenia by the Magnetic Resonance Study. ACS Omega (2024).