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

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

doi:10.14814/phy2.14007

Angus M Brown, Bruce R Ransom + Show 3 more

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

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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 mmol/L 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.

Highlights

It is widely accepted that hypothermia affords protection during ischemia, that is, combined anoxia and hypoglycemia, in the central nervous system with the optimal degree of protection occurring with hypothermia of 5 to 8°C (Wassink et al 2018); hyperthermia augmenting injury (Greer et al 2008; Campos et al 2013)
We have previously shown that exposure to aglycemia caused delayed failure of the stimulus evoked compound action potential (CAP) in Mouse optic nerves (MONs) with partial recovery of the CAP possible, but dependent upon duration of aglycemia exposure (Baltan Tekko€k et al 2003; Yang et al 2014)
In MONs exposed to 45 min of aglycemia the CAP fell to zero where it remained for about 10 min before reperfusion partially rescued the CAP, suggesting the injury process commences after the CAP has completely failed, rather than at the onset of CAP failure

Summary

Introduction

It is widely accepted that hypothermia affords protection during ischemia, that is, combined anoxia and hypoglycemia, in the central nervous system with the optimal degree of protection occurring with hypothermia of 5 to 8°C (Wassink et al 2018); hyperthermia augmenting injury (Greer et al 2008; Campos et al 2013). The majority of available information regarding hypothermic neuroprotection in the CNS concerns ischemic injury to gray matter regions, notably the hippocampus and the cortex (Greiner et al 1998; Colbourne et al 1999). The majority of the hypoglycemia induced injury is attributable to activation of NADPH oxidase during reperfusion (Suh et al 2007), suggesting a potentially viable therapeutic strategy is to impose hypothermia during reperfusion, whereas the mitochondrial permeability transition pore contributes to reperfusion injury in cardiac myocytes (Morciano et al 2017). Prior data from rodent central white matter revealed there is no advantage in imposing hypothermia following exposure to anoxia (Stys et al 1992a), but no equivalent information is available for aglycemic injury

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