Abstract
Objective: The purpose of this study was to determine the potential neuroprotective effect of endothelin B (ETB) receptor agonist IRL-1620 treatment in a pediatric model of ischemic stroke.Design: A prospective, animal model study.Setting: An experimental laboratory.Subjects: Three-month-old male Wistar Han rats.Interventions: 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 ETB antagonist BQ788 (1 mg/kg, IV).Measurements and Main Results: 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 (P = 0.00188), grip test (P < 0.0001), and foot-fault error (P = 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 (P = 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 (P = 0.0035, 41.4 ± 35.4 vs. 115.4 ± 40.9 mm3). Treatment with BQ788 blocked the effects of IRL-1620.Conclusions: 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 ETB receptor stimulation may provide a novel therapeutic strategy in the treatment of pediatric ischemic stroke as has been demonstrated in adult ischemic stroke.
Highlights
Stroke is an increasingly recognized cause of morbidity and mortality in children, with an estimated annual incidence of 2.4 to 11 per 100,000 [1]
Since the discovery of increased endothelin (ET) concentration in both plasma and cerebrospinal fluid after cerebral ischemia, ET and its possible role in the pathophysiology of ischemic stroke has been the focus of much discussion
Day 7 post mid-cerebral artery occlusion (MCAO) reflected the maximum impact of IRL-1620 on recovery
Summary
Stroke is an increasingly recognized cause of morbidity and mortality in children, with an estimated annual incidence of 2.4 to 11 per 100,000 [1]. Acute ischemic stroke accounts for 50% of strokes in children. Hospitalizations for acute ischemic stroke in children have risen partly as a result of increased risk factors, such as longer survival of children with cardiac anomalies, diabetes, hypertension, obesity, infection, trauma, sickle cell disease, cancer, hypercoagulable states, and metabolic disorders [2, 3]. Restoring cerebral blood flow (CBF) and saving dying neurons are goals for ischemic brain injury therapy. The human brain contains a high density of ET receptors, located throughout neurons, astrocytes, and cerebrovasculature [6]. These centrally located receptors regulate various functions, including CBF and cellular migration, proliferation, and apoptosis [7,8,9]
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