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Hypothermic neuroprotection during reperfusion following exposure to aglycemia in central white matter is mediated by acidification

Brown, Angus M.; Evans, Richard D.; Smith, Paul A.; Rich, Laura R.; Ransom, Bruce R.


Richard D. Evans

Laura R. Rich

Bruce R. Ransom


Hypoglycemia is a common iatrogenic consequence of type 1 diabetes therapy that can lead to central nervous system injury and even death if untreated. In the absence of clinically effective neuroprotective drugs we sought to quantify the putative neuroprotective effects of imposing hypothermia during the reperfusion phase following aglycemic exposure to central white matter. Mouse optic nerves (MONs), central white matter tracts, were superfused with oxygenated artificial cerebrospinal fluid (aCSF) containing 10 mM glucose at 37°C. The supramaximal compound action potential (CAP) was evoked and axon conduction was assessed as the CAP area. Extracellular lactate was measured using an enzyme biosensor. Exposure to aglycemia, simulated by omitting glucose from the aCSF, resulted in axon injury, quantified by electrophysiological recordings, electron microscopic analysis confirming axon damage, the extent of which was determined by the duration of aglycemia exposure. Hypothermia attenuated injury. Exposing MONs to hypothermia during reperfusion resulted in improved CAP recovery compared with control recovery measured at 37°C, an effect attenuated in alkaline aCSF. Hypothermia decreases pH implying that the hypothermic neuroprotection derives from interstitial acidification. These results have important clinical implications demonstrating that hypothermic intervention during reperfusion can improve recovery in central white matter following aglycemia.


Brown, A. M., Evans, R. D., Smith, P. A., Rich, L. R., & Ransom, B. R. (2019). Hypothermic neuroprotection during reperfusion following exposure to aglycemia in central white matter is mediated by acidification. Physiological Reports, 7(5), 1-13.

Journal Article Type Article
Acceptance Date Jan 30, 2019
Online Publication Date Mar 4, 2019
Publication Date Mar 4, 2019
Deposit Date Feb 20, 2019
Publicly Available Date Feb 20, 2019
Journal Physiological Reports
Electronic ISSN 2051-817X
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 7
Issue 5
Article Number e14007
Pages 1-13
Keywords Aglycemia; Glucose; Hypothermia; Neuroprotection
Public URL
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