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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Acknowledgements
We are grateful to Aeromics, Inc. for providing us with AER-271. We thank Lee Ann New for providing technical assistance in NDS assessment. The study was supported by grants from the Laerdal Foundation (JSW); NIH NICHD T32 HD040686 (JSW), R01HD069620 (AEK), and 5R01HD075760 (MDM); and NIH NINDS 1K23NS101036 (RMJ), R01NS084967 (AEK), R21NS098057 (TCJ), R01NS084604 (RSBC), and 1R01NS087978 (PMK).
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J.S.W., P.M.K., and M.D.M. were involved in study conception and design, as well as statistical analysis. J.S.W., K.J-.F., and H.A. contributed to acquisition of animal data. G.W.F., P.R.McG., and M.F.P. contributed to acquisition of drug level analysis. J.S.W., R.M.J., A.E.K., T.C.J., R.S.B.C., P.M.K., and M.D.M. were involved with interpretation of data. J.S.W. drafted the article and all authors revised it critically for important intellectual content and approved the final version for publication.
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G.W.F., P.R.McG., and M.F.P. are employees of Aeromics, Inc., which provided AER-271 and performed drug level analysis but had no influence on study design, outcome assessment, statistical analysis, writing of the manuscript, or decision to submit for publication.
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Wallisch, J.S., Janesko-Feldman, K., Alexander, H. et al. The aquaporin-4 inhibitor AER-271 blocks acute cerebral edema and improves early outcome in a pediatric model of asphyxial cardiac arrest. Pediatr Res 85, 511–517 (2019). https://doi.org/10.1038/s41390-018-0215-5
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DOI: https://doi.org/10.1038/s41390-018-0215-5
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