The aquaporin-4 inhibitor AER-271 blocks acute cerebral edema and improves early outcome in a pediatric model of asphyxial cardiac arrest

• Published in: Pediatric research Vol. 85; no. 4; pp. 511 - 517
• Main Authors: Wallisch, Jessica S, Janesko-Feldman, Keri, Alexander, Henry, Jha, Ruchira M, Farr, George W, McGuirk, Paul R, Kline, Anthony E, Jackson, Travis C, Pelletier, Marc F, Clark, Robert S B, Kochanek, Patrick M, Manole, Mioara D
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.03.2019
• Subjects: Animals; Aquaporin 4 - antagonists & inhibitors; Aquaporins; Asphyxia - complications; Brain Edema - prevention & control; CA1 Region, Hippocampal - pathology; Cardiac arrest; Chlorophenols; Disease Models, Animal; Edema; Female; Fluorine Compounds - pharmacology; Fluorine Compounds - therapeutic use; Heart Arrest - etiology; Heart Arrest - physiopathology; Humans; Male; Rats; Rats, Sprague-Dawley; Rodents; Treatment Outcome
• ISSN: 0031-3998; 1530-0447
• DOI: 10.1038/s41390-018-0215-5

Cerebral edema after cardiac arrest (CA) is associated with increased mortality and unfavorable outcome in children and adults. Aquaporin-4 mediates cerebral water movement and its absence in models of ischemia improves outcome. We investigated early and selective pharmacologic inhibition of aquaporin-4 in a clinically relevant asphyxial CA model in immature rats in a threshold CA insult that produces primarily cytotoxic edema in the absence of blood-brain barrier permeability. Postnatal day 16-18 Sprague-Dawley rats were studied in our established 9-min asphyxial CA model. Rats were randomized to aquaporin-4 inhibitor (AER-271) vs vehicle treatment, initiated at return of spontaneous circulation. Cerebral edema (% brain water) was the primary outcome with secondary assessments of the Neurologic Deficit Score (NDS), hippocampal neuronal death, and neuroinflammation. Treatment with AER-271 ameliorated early cerebral edema measured at 3 h after CA vs vehicle treated rats. This treatment also attenuated early NDS. In contrast to rats treated with vehicle after CA, rats treated with AER-271 did not develop significant neuronal death or neuroinflammation as compared to sham. Early post-resuscitation aquaporin-4 inhibition blocks the development of early cerebral edema, reduces early neurologic deficit, and blunts neuronal death and neuroinflammation post-CA.