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.

Abstract

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.

Citation

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. https://doi.org/10.14814/phy2.14007

• 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
• DOI: https://doi.org/10.14814/phy2.14007
• Keywords: Aglycemia; Glucose; Hypothermia; Neuroprotection
• Public URL: https://nottingham-repository.worktribe.com/output/1570464
• Publisher URL: https://physoc.onlinelibrary.wiley.com/doi/full/10.14814/phy2.14007
• Contract Date: Feb 20, 2019