Abstract 10766: Sovateltide Induces Neuroprotection in a Neonatal Rat Model of Hypoxic Ischemic Encephalopathy

Abstract

Introduction: Hypoxic-ischemic encephalopathy(HIE) is a major cause of morbidity, mortality, and severe neurodevelopmental disability in term neonates. The development of a treatment strategy that could provide neuroprotection is still required. We have shown that agonism of endothelin B(ETB) receptors mediated through sovateltide provides neuroprotection and enhances neurovascular remodeling in several neuropathological conditions. Hypothesis: We hypothesize that administering sovateltide alone or as an adjuvant therapy with hypothermia could provide neuroprotection by reducing oxidative stress and promoting cell survival post-HIE brain injury. Methods: Sprague-Dawley male and female rat pups were grouped separately and were divided into 5 different subgroups (1) Control; (2) HIE+Vehicle; (3) HIE+Hypothermia; (4) HIE+sovateltide; and (5) HIE+sovateltide+hypothermia. HIE was induced by ligating the right carotid artery on a postnatal day (PND) 7, followed by hypoxia for 120 min and hypothermia (32-34°C) for 5 h. On PND 7, sovateltide (5 μg/kg, ICV) was injected after hypoxic-ischemic injury. Pups were euthanized on PND 10. Brains were isolated, and ETB receptors, VEGF, NGF, cell death and oxidative stress makers - malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were assessed. Results: Animals receiving sovateltide showed a significant (p<0.0001) upregulation of ETB receptor (135%), VEGF (110%), and NGF (183%) expression in the brain compared to vehicle. Vehicle-treated animals had high oxidative stress levels, as indicated by increased lipid peroxidation, MDA, and decreased antioxidants, SOD, and GSH compared to control. These effects were reversed (p<0.001) in sovateltide alone or in combination with the hypothermia, indicating reduced oxidative stress in these animals. Additionally, sovateltide alone or in combination with hypothermia reduced (p<0.001) cell death compared to vehicle or hypothermia alone. Similar findings were obtained in both male and female rats. Conclusion: Sovateltide alone or as an adjunct to hypothermia exerts neuroprotective effects in HIE-induced brain injury in rat pups, suggesting sovateltide could be a potential therapeutic agent for neonatal HIE.