Endothelin Receptor-A (ETa) Inhibition Fails to Improve Neonatal Hypoxic-Ischemic Brain Injury in Rats
Cerebral hypoxia-ischemia (HI) is an important cause of mortality and disability in newborns. It is a result of insufficient oxygen and glucose circulation to the brain, initiating long-term cerebral damage and cell death. Emerging evidence suggests that
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Abstract Cerebral hypoxia-ischemia (HI) is an important cause of mortality and disability in newborns. It is a result of insufficient oxygen and glucose circulation to the brain, initiating long-term cerebral damage and cell death. Emerging evidence suggests that endothelin receptor-A (ETA) activation can play an important role in mediating brain damage. In this study, we investigated the role of ETA receptor inhibition using ABT-627 in neonatal HI injured rats. Postnatal day 10 Sprague-Dawley rat pups (n = 91) were assigned to the following groups: sham (n = 28), HI (vehicle, n = 32), and HI with ABT-627 at 3 mg/kg (n = 31). The Rice-Vannucci model was used to induce ischemia by ligating the right common carotid artery, followed by a 2 h hypoxic episode using 8% oxygen in a 37°C chamber. Postoperative assessment was conducted at 48 h after injury and again at 4 weeks. At the acute time point, investigative markers included cerebral edema, infarction volume, and body weight change. Neurobehavioral testing was measured at 4 weeks post-injury. Our findings indicated that ABT-627 had no effect on the measured parameters. This study suggests that ETA receptor blockade using ABT-627 post-treatment fails to improve neurological outcomes in neonatal HI injured rats.
N.H. Khatibi, L.K. Lee, Y. Zhou, R. Martin, R. Applegate, and G. Stier Department of Anesthesiology, Loma Linda Medical Center, Loma Linda, CA, USA W. Chen, W. Rolland, and N. Fathali Department of Physiology and Pharmacology, Loma Linda University, School of Medicine, Loma Linda, CA, USA J.H. Zhang (*) Department of Anesthesiology, Loma Linda Medical Center, Loma Linda, CA, USA and Department of Physiology and Pharmacology, Loma Linda University, School of Medicine, Loma Linda, CA, USA and Department of Neurosurgery, Loma Linda Medical Center, Loma Linda, CA, USA and Department of Neurosurgery, Loma Linda Medical Center, 11234 Anderson Street, Room 2562B, Loma Linda, CA 9235, USA e-mail: [email protected]
Keywords ABT-627 · Endothelin receptor-A (ETA) · Hypoxic-ischemic (HI) · Endothelins · Brain injury
Introduction Cerebral hypoxia-ischemia (HI) is a fatal, life-threatening event during the perinatal period responsible for a large number of mortalities and disabilities in newborns [1, 2]. With a reported incidence of 2–9 per 1,000 births, HI can be caused by a number of events, including a reduction in uterine circulation from uterine contractions, umbilical cord compression, and placental abruption to name a few [3]. The concern with HI is the mounting inflammatory response produced by a reduction in cerebral blood flow. To date, adequate therapeutic interventions aimed at treating the short- and long-term consequences of HI are limited. Although multiple studies have shown mild improvements with various treatment modalities, including erythropoietin and hypothermia, there continue to be significant limitations in their ability to improve neurobehavioral deficits or reduce mortality [4]. Therefore, development of a new treatment intervention t
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