The Anti-inflammatory Peptide RLS-0071 Reduces Immune Cell Recruitment and Oxidative Damage in a Neonatal Rat Model of Hypoxic-Ischemic Encephalopathy.

Abstract

Perinatal hypoxic-ischemic encephalopathy (HIE) is a major contributor to infant death and neurological injury worldwide. Both neuroglia and infiltrating peripheral immune cells contribute to inflammation and oxidative stress, which leads to neuronal loss and cerebral tissue necrosis in neonates with HIE. To date, there are no approved pharmacological interventions to treat inflammatory responses in infants affected by HIE. Therapeutic hypothermia (TH) remains the only effective treatment option. Therefore, novel pharmacotherapeutics that interrupt immune-mediated brain inflammation in HIE represent a promising target for intervention. To meet this unmet need, this study tested the hypothesis that a novel anti-inflammatory peptide, RLS-0071 (pegtarazimod), could modulate neuroinflammation in a neonatal rat model of HIE.RLS-0071 was evaluated in the acute stages of hypoxic-ischemic injury utilizing the well-established Vannucci rat pup model of HIE. Rat pups subject to hypoxia-ischemic brain insult received three interventions: normothermia, hypothermia, and RLS-0071. Histopathological effects were assessed via fluorescence microscopy of the hypoxic-ischemic induced cerebral infarct in the cortex at 24 and 48 hours after controlled oxygen deprivation.Increased surviving neurons were seen at 48 hours for RLS-0071 treatment compared with hypothermia treatment as assessed by neuronal nuclear protein (NeuN) staining. Ionized calcium-binding adaptor molecule 1 (Iba1)-positive microglial recruitment was reduced by fourfold in RLS-0071 treatment or hypothermia-treated rats between 24 and 48 hours, compared to normothermia controls. Likewise, myeloperoxidase (MPO) staining showed a twofold decrease in RLS-0071 or hypothermia-treated rats between 24 and 48 hours compared to normothermia controls.Our findings suggest that RLS-0071 decreases immune cell recruitment and oxidative damage to levels comparable to TH in an animal model of HIE. · No pharmacologic interventions for HIE currently exist.. · TH is the current standard of care.. · RLS-0071 increases neuron survival and lowers microglial cell influx in a HIE rat model.. · RLS-0071 limits oxidative damage in a HIE rat model.. · RLS-0071 may provide an orthogonal treatment for HIE..