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

  • Pediatr Res. 2019 Mar;85(4):511-517. doi: 10.1038/s41390-018-0215-5.
Jessica S Wallisch  1  2  3 ,  Keri Janesko-Feldman  3 ,  Henry Alexander  3 ,  Ruchira M Jha  1  3 ,  George W Farr  4 ,  Paul R McGuirk  4 ,  Anthony E Kline  3  5 ,  Travis C Jackson  1  3 ,  Marc F Pelletier  4 ,  Robert S B Clark  1  2  3  6 ,  Patrick M Kochanek  1  2  3  6 ,  Mioara D Manole  7  8  9
Affiliations
  • 1. Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 2. Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
  • 3. Safar Center for Resuscitation Research, Pittsburgh, PA, USA.
  • 4. Aeromics, Inc, Cleveland, OH, USA.
  • 5. Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA.
  • 6. Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
  • 7. Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA. [email protected].
  • 8. Safar Center for Resuscitation Research, Pittsburgh, PA, USA. [email protected].
  • 9. Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
PMID: 30367162 DOI: 10.1038/s41390-018-0215-5
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.

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