Hypoxic-ischemic encephalopathy (HIE) is a major cause of neurologic disabilities and mortality in term neonates, which is mainly caused due to intrapartum complications. Its clinical outcomes are devastating and include neurological disabilities such as cerebral palsy, seizures, and neurodevelopmental disorders in neonates. The incidence of HIE is estimated to be ranged from 1 to 8 per 1000 live births in developed countries and about 26 per 1000 live births in underdeveloped countries
[74], constitutes the second cause of mortality in neonates and the third cause of mortality in children < 5 years old
[75][76]. The pathophysiology of HIE involves a decrease in placental perfusion or disruption of the delivery of oxygen and glucose in the umbilical cord because of a variety of conditions, including placental abruption, prolapse of the umbilical cord, and uterine rupture. The inadequate placental perfusion causes hypoxia and disrupts the homeostasis in the fetus. Hypoxia leads to a decrease in cardiac output and reduces cerebral blood flow in the fetus. In a moderate decrease, the cerebral blood flow is shunted from the anterior circulation to the posterior circulation, and perfusion in the brainstem, cerebellum, and basal ganglia is maintained. Consequently, the damage is restricted mainly to the cerebral cortex and watershed areas of the cerebral hemispheres. While on the other hand, an acute hypoxia condition invokes an abrupt decrease in cerebral blood flow and produces injury also in the basal ganglia and thalami
[77]. The acute hypoxic damage in HIE has been categorized in different phases based on the temporal sequence of the injury. The reduced delivery of oxygen and glucose leads to anaerobic metabolism in the brain, which causes decreased ATP and increased lactic acid production. Due to ATP shortage, transcellular transport is reduced, which causes intracellular accumulation of sodium, water, and calcium. Moreover, upon membrane depolarization, cells release the excitatory amino acid glutamate, and more calcium flows into the cell via N-methyl-D-aspartate–gated channels. The high calcium level in cytosol induces an array of deleterious effects, including necrosis or calpain activation followed by apoptosis, also known as excitotoxicity. Production of free radicals is known to be increased in the hypoxic condition, which causes peroxidation of free fatty acids, which causes more cellular damage. In trauma, neural cells are also known to produce several-fold higher levels of NO, which causes further cellular damage. In summary, the culmination of energy failure, acidosis, glutamate release, lipid peroxidation, and the toxic effect of nitric oxide leads to cell death via necrosis and activates apoptotic cascades in the spinal cord after injury. Depending on the timing of the injury and the available medical intervention, partial recovery may occur during the first 30 to 60 min after the insult. This partial recovery provides a latent phase of injury, which could last from 1 to 6 h and is characterized by recovery of oxidative metabolism, inflammation, and continuation of the activated apoptotic cascades
[78]. The secondary phase of injury commonly follows the latent phase within approximately 6 to 15 h after the acute insult. Events in this phase include cytotoxic edema, excitotoxicity, and severe mitochondrial activity failure, leading to cell death and clinical deterioration. The occurrence of seizures is very common in this phase of injury. In some months after the acute insult, a tertiary phase occurs, which involves late cell death, remodeling of the injured brain, and astrogliosis
[79]. Neonates with suspected HIE are classified according to the Sarnat staging system
[80], which evaluates the level of consciousness, muscle tone, tendon reflexes, complex reflexes, and autonomic function. The Sarnat stage classifies neonatal HIE into the following three categories: stage I (mild), stage II (moderate), and stage III (severe). The pathophysiology of HIE is highly complex, which makes the discovery of effective drugs and interventions very difficult, as evidenced by the failure of several drug trials
[81]. At present, there is only one therapy for HIE; therapeutic hypothermia, which has been accepted in its clinical management. The effectiveness of hypothermia in reducing neurological injury caused by HIE has been demonstrated through several clinical trials, including the ICE study
[82], Cool Cap study
[83], NICHD study
[84], and TOBY study
[79]. Although the procedure of therapeutic hypothermia is effective, it suffers various limitations, such as the unavailability of trained personnel, equipment, and pediatric neurology support at most of the NICUs (newborn ICUs). Furthermore, its efficacy in preventing neurological disorders in HIE neonates is poor as more than 40% of neonates undergoing hypothermia still develop adverse neurological outcomes
[85]. Moreover, the long-term (>2 years) impact of this therapy on neurodevelopment in children remains unclear
[86]. Presently, it is a matter of the most concern that a significant number of HIE-affected infants still die or suffer from neurological disabilities whether they receive the hypothermia treatment or not
[83][87][88][89]. A decade ago, to address these concerns, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) had invited a panel of experts to review the available evidence, identify knowledge gaps, and suggest research priorities. The panel recommended the development of adjuvant therapies to hypothermia, the use of biomarkers, as well as further refinements in therapeutic hypothermia
[88]. Hence, HIE has been an area of global health concern, and the development of new drugs/interventions or adjuvants to therapeutic hypothermia is urgently required. Nonetheless, several adjuvant therapies to hypothermia are undergoing and evaluating the improved survival and neurodevelopmental outcomes in newborns with HIE; more research aiming the treatment optimization and prevention and/or eventually reversal of the HIE damage will be useful. One such potential adjuvant or alternative therapy for neonatal HIE could be a selective agonist of ETBRs such as sovateltide. As previously mentioned, the research group has demonstrated the role of sovateltide in both neuroprotection and neuroregeneration in adult rat models of cerebral ischemia
[29][30]. Additionally, it was found to reduce oxidative stress, increase pro-angiogenic, pro-survival, and anti-apoptotic markers, and increase the number of proliferating cells in rodent brains
[28][29][30][31]. Importantly, the researchers' recent studies have shown the role of sovateltide mediated ETBRs stimulation on regulating the mitochondria-mediated apoptotic pathway in rat brains after ischemic stroke damage and its correlation with improved neurological and motor functions in these rats
[31]. Furthermore, the researchers observed that it improved mitochondrial fusion, decreased fission, increased size, and biogenesis in sovateltide treated rat brains with ischemic stroke
[33]. The researchers also demonstrated a novel role of sovateltide in NPCs-mediated regeneration and repair in the rat brain tissues
[34]. Therapeutic hypothermia is known to preserve mitochondrial function; it is conceivable that its future adjuvants targeting mitochondria would ensure further efficacy. Hence, it would therefore be of interest to determine the efficacy of sovateltide (which has shown its roles in mitochondrial fate determination as well as in regeneration and repair of neural tissues) in an animal model of neonatal HIE.