Endogenous Molecules as Candidate Neuroprotectants in Neonatal Hypoxic–Ischemic Encephalopathy: Mechanistic Insights and Therapeutic Potential

Neonatal hypoxic–ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term neurological disability. Although therapeutic hypothermia (TH) improves outcomes in eligible infants with moderate-to-severe HIE, its efficacy is incomplete, highlighting the need for additional neuroprotective strategies. Endogenous neuroprotective compounds are particularly attractive candidates because they participate in intrinsic cellular defense mechanisms and can modulate components of the hypoxic–ischemic injury cascade. This review focuses on five endogenous molecules—carnosine, citicoline, kynurenic acid (KYNA), lactoferrin, and N-acetylaspartylglutamate (NAAG)—whose neuroprotective effects have been demonstrated in experimental models of neonatal hypoxia-ischemia (HI). These molecules act through distinct but partly overlapping mechanisms involving modulation of glutamatergic neurotransmission, antioxidant defense, mitochondrial protection, anti-inflammatory signaling, and inhibition of regulated cell death. Their complementary actions suggest that they may represent components of a broader endogenous neuroprotective network rather than independent protective mechanisms. However, differences in blood–brain barrier accessibility, pharmacokinetics, therapeutic windows, and the predominantly preclinical nature of the available evidence remain important limitations to translation. Future studies should define optimal dosing, establish safety in the developing brain, and determine whether rational combinations of these compounds, particularly as adjuncts to TH, can provide more effective protection against neonatal hypoxic–ischemic brain injury.