l-Arginine Attenuates Brain Dysfunction in Heat-stress Rat Model via Modulating Nitric Oxide-dependent Pathway

Background: Heat stress (HS) is the body’s inability to manage internal heat efficiently. It impairs endothelial function, causes oxidative stress, and disrupts nitric oxide (NO) signaling, highlighting the downstream effects of endothelial dysfunction, including impaired vascular integrity, systemic inflammation, multiple-organ injury, and specifically, brain injury. As a NO modulator, l-arginine shows neuroprotective efficacy by restoring NO bioavailability and reducing HS-induced cerebrovascular and neuronal damage. Objectives: The study aims to elucidate the neuroprotective role of l-arginine on HS-induced brain dysfunction via modulating the NO pathway. Materials and Methods: HS was induced by placing rats in a heated plexiglass chamber (42–45°C) for 75 min daily over 28 days. Body weight and rectal temperature were measured weekly. Various neurobehavioral parameters were assessed to evaluate anxiety, depression, memory, and pain sensitivity. Oxidative stress was measured using biochemical parameters, whereas heat shock proteins (HSPs) and molecular estimations, along with neuroinflammatory and pro-apoptotic assessments, were performed using reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Results: Heat-stressed rats exhibited significant degradation of brain health, characterized by upregulation of stress proteins (HSP70/HSP90), responsible for neuronal injury. We observed a significant, dose-dependent response with l-arginine (100 and 500 mg/kg p.o.) on body weight and temperature with relevant gene expression. Additionally, l-arginine reduces oxidative stress and inflammation in the brain. Overall, l-arginine alleviates neuronal deficits by reducing anxiety, depression, and pain sensitivity while improving memory. Conclusion: Heat exposure for 28 consecutive days in rats’ brains elevates the HSPs expression, oxidative stress, inflammation, and apoptosis; ultimately impairs the endothelial nitric oxide synthase (eNOS) pathway. l-Arginine significantly provides neuroprotection by restoring these molecular disturbances and re-establishing neurovascular integrity by targeting the eNOS-dependent NO pathway.