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

Authors

Jessica S. Wallisch, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Keri Janesko-Feldman, Safar Center for Resuscitation Research, Pittsburgh, PA, USA.
Henry Alexander, Safar Center for Resuscitation Research, Pittsburgh, PA, USA.
Ruchira M. Jha, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.Follow
George W. Farr, Aeromics, Inc, Cleveland, OH, USA.
Paul R. McGuirk, Aeromics, Inc, Cleveland, OH, USA.
Anthony E. Kline, Safar Center for Resuscitation Research, Pittsburgh, PA, USA.
Travis C. Jackson, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Marc F. Pelletier, Aeromics, Inc, Cleveland, OH, USA.
Robert S. Clark, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Patrick M. Kochanek, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
Mioara D. Manole, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA. mioara.manole@chp.edu.

Document Type

Article

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Medical Subject Headings

Animals; Aquaporin 4 (antagonists & inhibitors); Asphyxia (complications); Brain Edema (prevention & control); CA1 Region, Hippocampal (pathology); Chlorophenols; Disease Models, Animal; Female; Fluorine Compounds (pharmacology, therapeutic use); Heart Arrest (etiology, physiopathology); Humans; Male; Rats; Rats, Sprague-Dawley; Treatment Outcome

Publication Date

3-1-2019

Publication Title

Pediatric research

E-ISSN

1530-0447

Volume

85

Issue

4

First Page

511

Last Page

517

PubMed ID

30367162

Digital Object Identifier (DOI)

10.1038/s41390-018-0215-5

Recommended Citation

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.; Kochanek, Patrick M.; and Manole, Mioara D., "The aquaporin-4 inhibitor AER-271 blocks acute cerebral edema and improves early outcome in a pediatric model of asphyxial cardiac arrest" (2019). Neurology. 1366.
https://scholar.barrowneuro.org/neurology/1366