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

Abstract

Stroke is the second leading cause of death and disability worldwide. Current treatments, such as pharmacological thrombolysis or mechanical thrombectomy, reopen occluded arteries but do not protect against ischemia‐induced damage that occurs before reperfusion or neuronal damage induced by ischemia/reperfusion. It has been shown that disrupting the conversion of glyoxal to glycolic acid (GA) results in a decreased tolerance to anhydrobiosis in Caenorhabditis elegans dauer larva and that GA itself 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, the protective effect of GA is tested in different ischemia models, i.e., in commonly used stroke models in mice and swine. The results show that GA, given during reperfusion, strongly protects against ischemic damage and improves functional outcome. Evidence that GA exerts its effect by counteracting the glutamate‐dependent increase in intracellular calcium during excitotoxicity is provided. These results suggest that GA treatment has the potential to reduce mortality and disability in stroke patients.

DJ-1 products glycolic acid and D-lactate restore deficient axonal trafficking and DNA damage response in FUS and SOD1-associated amyotrophic lateral sclerosis

“…GA and DL can help to maintain calcium homeostasis (Chovsepian, Berchtold et al, 2022). ER-mitochondria associations have become of increasing interest in neurodegenerative diseases, since these specialized tight structural associations between a closely apposed ER surface and outer mitochondria membrane were reported to regulate a variety of essential physiological functions including calcium signaling, phospholipid synthesis/exchange and mitochondrial biogenesis and dynamics and cell death (Grossmann, Berenguer-Escuder et al, 2019, Grossmann, Malburg et al, 2023, Liu et al, 2019, Pereira, Grossmann et al, 2023).…”

Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective

“…24 Conversely, glycolic acid has been described as neuroprotective, preventing ischemiainduced neuronal death in in vitro and in vivo models of stroke. 25 Despite the less distinct increases, all three metabolites could be of interest for our understanding of SSADHD pathophysiology.…”

“…Glutaric acid is known to be neurotoxic, albeit in the context of glutaric aciduria type I with a more pronounced accumulation of this metabolite 24 . Conversely, glycolic acid has been described as neuroprotective, preventing ischemia‐induced neuronal death in in vitro and in vivo models of stroke 25 . Despite the less distinct increases, all three metabolites could be of interest for our understanding of SSADHD pathophysiology.…”

Enhanced brain delivery of hypoxia-sensitive liposomes by hydroxyurea for rescue therapy of hyperacute ischemic stroke

“…9,10 Therefore, the main purpose of treatment in the hyperacute stage of ischemic stroke is to rescue the neurons in the penumbra as soon as possible and avoid expansion of the infarction area. 11…”

“…9,10 Therefore, the main purpose of treatment in the hyperacute stage of ischemic stroke is to rescue the neurons in the penumbra as soon as possible and avoid expansion of the infarction area. 11 To save the ischemic penumbra, our research has focused on regulation of the blood-brain barrier permeability and the recovery of blood flow. For one thing, due to the presence of the blood-brain barrier, most drugs and nanoparticles are prevented from entering the brain parenchyma, which seriously hinders the efficacy of drugs and the prognosis for patients.…”