Elucidating the Pivotal Neuroprotective Mechanisms and Therapeutic Variants of Erythropoietin in Neonatal Brain Injury

Neonatal brain injury (NBI) encompasses a variety of neurological acquired conditions affecting newborns. These conditions include hypoxia-ischemia, hyperoxic, periventricular leukomalacia, intrauterine infection, as well as perinatal cerebral hemorrhage. Each year, thousands of babies are born with signs of brain injury. It is estimated that two-thirds of these newborn infants with brain injury would either die or survive with mild to severe neurologic sequelae, largely due to the absence of no widely accepted treatment methods. Erythropoietin (Epo) is a humoral intermediary associated with the maturation as well as the proliferation of erythroid progenitor cells. Systematic administration of Epo triggers the elevation of Epo levels in cerebrospinal fluid (CSF) extracts, which means that Epo is capable of crossing the blood-brain barrier into the CSF. It has been reported that Epo treatment enhances the brain's network connectivity, improving local information transmission and promoting a shift toward a more integrated and consistent network architecture. This, in turn, augments both local and global connectivity efficiency. Exogenous Epo was found to be capable of regulating neurogenesis. Moreover, Epo was also reported to be associated with the inhibition of demyelination of axons, as well as the production of myelin-derived inhibitory proteins, which are inhibitory factors involved in axonal extension. Administration of recombinant human erythropoietin in neonatal rats provided neuroprotection against hyperoxiainduced oxidative stress. Furthermore, Epo administration during the neonatal period was shown to reverse molecular alterations associated with impaired development of the potassium-chloride cotransporter isoform 2 (KCC2), as well as deficits related to preterm birth during the postnatal period. Moreover, Epo was capable of blocking microglial stimulation, decreasing phagocytosis in vitro, as well as inhibiting the generation of inflammatory cytokines in vitro as well as in vivo. Thus, Epo via EpoR is able to influence brain connectivity, synaptogenesis, neurite repair, oxygeninduced brain injury, potassium chloride co-transporters, and inflammation via key signaling pathways to induce therapeutic as well as neuroprotection in NBI. Thus, Epo is a very promising neuroprotective as well as a therapeutic agent in the treatment of NBI. This review aimed to explore the neuroprotective and therapeutic mechanisms of Epo in NBI, as well as the potential of Epo variants.