Neuroimmune-endocrine interactions in perinatal asphyxia: from brain injury to neuroprotection

Perinatal asphyxia (PA) remains a major cause of neonatal mortality and long-term neurodevelopmental disability worldwide. Although hypoxic–ischemic brain injury has traditionally been attributed to oxygen deprivation, excitotoxicity, and oxidative stress, accumulating evidence indicates that neurological outcomes are determined by complex interactions among metabolic, mitochondrial, neuroimmune, and neuroendocrine mechanisms. Following hypoxic–ischemic injury, primary energy failure rapidly triggers excitotoxicity, mitochondrial dysfunction, calcium dysregulation, and oxidative damage, leading to activation of microglia and astrocytes, release of pro-inflammatory cytokines, disruption of blood–brain barrier integrity, and recruitment of peripheral immune cells. These events contribute to the development of secondary energy failure and persistent neuroinflammation. Simultaneously, activation of hypoxia-responsive pathways, including hypoxia-inducible factor-1 (HIF-1), heat shock protein 70 (HSP70), glutathione-dependent antioxidant defenses, and neuroendocrine stress responses involving the hypothalamic–pituitary–adrenal axis, promote endogenous adaptation and neuroprotection. Nitric oxide signaling further links mitochondrial dysfunction, oxidative and nitrosative stress, inflammatory activation, and neuronal injury. Together, these mechanisms form an integrated neuroimmune-endocrine network that influences both injury progression and tissue repair. In this review, we propose Brain Energy Failure as a unifying conceptual framework linking mitochondrial dysfunction, oxidative and nitrosative stress, neuroinflammation, endocrine adaptation, and endogenous neuroprotective responses following perinatal hypoxia. We further discuss the role of biomarkers associated with neuro-immuno-endocrine dysfunction, including inflammatory mediators, oxidative stress markers, endocrine factors, and indicators of neuronal and glial injury. Recent evidence has highlighted the therapeutic potential of multimodal neuroprotective approaches, including endogenous lipid mediators such as palmitoylethanolamide (PEA), which exert anti-inflammatory, antioxidant, and mitoprotective effects. We also review current and emerging neuroprotective strategies targeting mitochondrial dysfunction, oxidative stress, inflammatory signaling, and bioenergetic instability, and discuss their translational implications. Understanding the interactions among these interconnected pathways may facilitate biomarker-guided diagnosis, personalized neuroprotection, and the development of more effective therapies aimed at improving long-term neurological outcomes following perinatal asphyxia.