Nitric oxide and traumatic brain injury

Dysregulation of the nitric oxide/nitric oxide synthase system is consistently observed in the aftermath of traumatic brain injury. It plays a pivotal yet paradoxical role in traumatic brain injury progression. Moreover, the modulation of the altered nitric oxide/nitric oxide synthase homeostasis via inhaled nitric oxide, nitric oxide donors, nitric oxide synthase inhibitors, and indirect methods such as mild hypothermia and medical gases in the brain, both during and after traumatic brain injury, can exert a significant impact on the clinical outcome. This review integrates current findings from preclinical studies and clinical trials to elucidate the dynamic contributions of nitric oxide to traumatic brain injury pathophysiology and to highlight emerging interventions targeting nitric oxide-related pathways. While physiological nitric oxide levels support cerebral blood flow and neuroprotection, excessive production via nitric oxide synthase isoforms (especially inducible nitric oxide synthase) drives secondary injury through cytotoxicity, edema, and blood-brain barrier disruption. Therapeutic strategies targeting nitric oxide pathways, including inhaled nitric oxide, nitric oxide donors, and specific nitric oxide synthase inhibitors like VAS203, show significant neuroprotective potential in preclinical models, though clinical translation remains limited.