A Primeval Mechanism of Tolerance to Desiccation Based on Glycolic Acid Saves Neurons from Ischemia in Mammals by Reducing Intracellular Calcium-Mediated Excitotoxicity

Abstract

Stroke is the second leading cause of death and disability worldwide. Current treatments, like pharmacological thrombolysis or mechanical thrombectomy, re-open occluded arteries but do not protect against ischemia-induced damage caused before reperfusion or ischemia/reperfusion-induced neuronal damage. It has been shown that knocking out djr-1.1 and djr-1.2 or glod-4 results in a decreased tolerance to anhydrobiosis in C elegans dauer larva and that Glycolic Acid (GA) can rescue this phenotype. During the process of desiccation/rehydration, a metabolic stop/start similar to the one observed during ischemia/reperfusion occurs. In this study we tested the protective effect of GA against ischemia in three different models (oxygen-glucose deprivation in vitro and Global cerebral ischemia as well as Middle Cerebral Artery Occlusion in vivo). Our results show that GA, given during reperfusion, strongly protects against ischemia-induced neuronal death, reduces the mortality in mice with large infarcts, significantly reduces the ischemic area in the brain and improves the functional outcome. The effect of GA is stronger when the substance is applied near the damaged tissue (i.e. directly to the neurons in vitro or intra-arterially via the internal carotid artery in vivo). These results suggest that GA treatment has the potential to dramatically reduce the mortality and disability caused by stroke in patients.

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“…Despite the inability to regulate this genes, our results show that high concentrations of GA and DL still have neuroprotective properties in mammals. In a recently published study, we showed that GA protects against ischemia in several stroke models: in an oxygen glucose deprivation (OGD) model in vitro , in a global cerebral ischemia mouse model and in a middle cerebral artery occlusion mouse model 34 . We have also been able to reproduce the in vitro results in dopaminergic neurons in a mouse model of PD generated by exposing WT and DJ-1 KO mice to PQ.…”