AUTHOR=Cifuentes Enrique G. , Hornick Mary G. , Havalad Suresh , Donovan Ramona L. , Gulati Anil 

TITLE=Neuroprotective Effect of IRL-1620, an Endothelin B Receptor Agonist, on a Pediatric Rat Model of Middle Cerebral Artery Occlusion

JOURNAL=Frontiers in Pediatrics

VOLUME=6

YEAR=2018

URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2018.00310

DOI=10.3389/fped.2018.00310

ISSN=2296-2360

ABSTRACT=<p><bold>Objective:</bold> The purpose of this study was to determine the potential neuroprotective effect of endothelin B (ET<sub>B</sub>) receptor agonist IRL-1620 treatment in a pediatric model of ischemic stroke.</p><p><bold>Design:</bold> A prospective, animal model study.</p><p><bold>Setting:</bold> An experimental laboratory.</p><p><bold>Subjects:</bold> Three-month-old male Wistar Han rats.</p><p><bold>Interventions:</bold> The rats underwent permanent middle cerebral artery occlusion (MCAO). At 2, 4, and 6 h post MCAO, they were treated with saline, IRL-1620 (5 μg/kg, IV), and/or ET<sub>B</sub> antagonist BQ788 (1 mg/kg, IV).</p><p><bold>Measurements and Main Results:</bold> The rats were evaluated over the course of 7 days for neurological and motor deficit, cerebral blood flow (CBF), and infarct volume. Young rats treated with IRL-1620 following MCAO improved significantly in neurological and motor assessments as compared to the vehicle-treated group, as measured by neurological score (<italic>P</italic> = 0.00188), grip test (<italic>P</italic> &lt; 0.0001), and foot-fault error (<italic>P</italic> = 0.0075). CBF in the infarcted hemisphere decreased by 45–50% in all groups immediately following MCAO. After 7 days, CBF in the infarcted hemisphere of the IRL-1620 group increased significantly (<italic>P</italic> = 0.0007) when compared to the vehicle-treated group (+2.3 ± 23.3 vs. −45.4 ± 10.2%). Additionally, infarct volume was significantly reduced in IRL-1620-treated rats as compared to vehicle-treated rats (<italic>P</italic> = 0.0035, 41.4 ± 35.4 vs. 115.4 ± 40.9 mm<sup>3</sup>). Treatment with BQ788 blocked the effects of IRL-1620.</p><p><bold>Conclusions:</bold> IRL-1620 significantly reduced neurological and motor deficit as well as infarct volume while increasing CBF in a pediatric rat model of cerebral ischemia. These results indicate that selective ET<sub>B</sub> receptor stimulation may provide a novel therapeutic strategy in the treatment of pediatric ischemic stroke as has been demonstrated in adult ischemic stroke.</p>