Neuroprotective Effect of Sovateltide (IRL 1620, PMZ 1620) in a Neonatal Rat Model of Hypoxic-Ischemic Encephalopathy

Therapeutic hypothermia with modest results is the only treatment currently available for neonatal hypoxic ischemic encephalopathy (HIE). Endothelin B (ETB) receptors in the brain are shown to have neural restorative capacity. ETB receptors agonist sovateltide alone or as an adjuvant therapy may enhance neurovascular remodeling in HIE. Sprague-Dawley rat pups were grouped based on treatments into (1) Control; (2) HIE + Vehicle; (3) HIE + Hypothermia; (4) HIE + sovateltide; and (5) HIE + sovateltide + hypothermia. HIE was induced on postnatal day (PND) 7, followed by sovateltide (5 µg/kg) intracerebroventricular injection and/or hypothermia. On PND 10, brains were analyzed for the expression of vascular endothelial growth factor (VEGF), nerve growth factor (NGF), ETB receptors, oxidative stress and cellular damage markers. Vehicle-treated animals had high oxidative stress level as indicated by an increase in lipid peroxidation factor, malondialdehyde, and decreased antioxidants, reduced glutathione and superoxide dismutase, compared to control. These effects were reversed in sovateltide alone (p < 0.001) or in combination with the therapeutic hypothermia (p < 0.001), indicating that ETB receptor activation reduces oxidative stress injury following HIE. Animals receiving sovateltide demonstrated a significant (p < 0.0001) upregulation of ETB receptor, VEGF, and NGF expression in the brain compared to vehicle-treated animals. Additionally, sovateltide alone or in combination with therapeutic hypothermia significantly (p < 0.001) reduced cell death when compared to vehicle or therapeutic hypothermia alone, demonstrating that sovateltide is neuroprotective and attenuates neural damage following HIE. These findings are important and merit additional studies for development of new interventions for improving neurodevelopmental outcomes after HIE.