Targeting the mitochondrial thermogenesis pathway for neuroprotection in neonatal hypoxic-ischemic encephalopathy by curcumin.

Neonatal hypoxic-ischemic (HI) brain injury remains a major cause of death and long-term neuro-disability leading to hypoxic-ischemic encephalopathy (HIE), and current hypothermia therapy is only partially effective. Curcumin is a polyphenolic compound with antipyretic and neuroprotective activities, but its role in thermos-metabolic control after neonatal HI has not been defined. Using the Rice-Vannucci model in postnatal day-7 mice, we found that curcumin administered either before HI (100-300 µg/g, i.p.) or after HI (200 µg/g within 3 h) significantly reduced infarct volume, improved survival and body-weight recovery, and accelerated restoration of sensorimotor and cognitive functions. Infrared thermography and rectal monitoring showed that HI induced focal, lesion-side brain hyperthermia, accompanied by a rise in core temperature, whereas curcumin lowered both parameters during the acute post-insult phase. Text-mining, protein-protein interaction, and GO enrichment analyses of 191 HI-related genes identified a thermometabolic-centered mitochondrial signature, with glutaminase 2 (GLS2) and nicotinamide phosphoribosyltransferase (NAMPT) ranked as central nodes. Docking analyses demonstrated favorable binding of curcumin to GLS2 and NAMPT, consistent with curcumin-mediated restraint of mitochondrial energy/heat production and with the observed reductions in microglial activation, caspase-dependent apoptosis, and neuronal loss. These findings define mitochondrial thermos-metabolic regulation as a druggable target in neonatal HI and support the further development of curcumin-based pharmacological interventions within this pathway. Targeting the mitochondrial thermogenesis pathway for neuroprotection in neonatal HIE by curcumin.