24S-hydroxycholesterol and 25-hydroxycholesterol differentially impact hippocampal neuronal survival following oxygen-glucose deprivation

• Published in: PloS one 2017-03, Vol.12 (3), p.e0174416-e0174416
• Main Authors: Sun, Min-Yu, Taylor, Amanda, Zorumski, Charles F, Mennerick, Steven
• Format: Article
• Language: English
• Subjects: Aging; Aging (artificial); Aging (natural); Allosteric properties; Alzheimer's disease; Alzheimers disease; Animals; Apolipoprotein E; Apoptosis; Assaying; Astrocytes; Binding energy; Biology and Life Sciences; Biotechnology; Brain; Brain research; Brain slice preparation; Calcium; Cancer; Carbon dioxide; Care and treatment; Cell culture; Cell death; Cell Hypoxia - drug effects; Cell Survival - drug effects; Cells, Cultured; Central nervous system; Cerebrospinal fluid; Cholesterol; Cholesterol metabolism; Dementia disorders; Excitotoxicity; Exposure; Female; Glucose - deficiency; Hippocampus; Hippocampus (Brain); Hippocampus - drug effects; Hippocampus - pathology; Hydrogen Peroxide - pharmacology; Hydroxycholesterols - pharmacology; Hypoxia; Inhibition; Injuries; Ischemia; Kinases; Male; Medicine; Medicine and Health Sciences; Metabolism; Metabolites; Mice; Modulation; Modulators; Movement disorders; N-methyl-D-aspartate; Nervous system; Neurodegenerative diseases; Neurons; Neurons - drug effects; Neurons - pathology; Neurosciences; Nitrogen; Oxidation; Oxygen; Parkinson's disease; Pharmacology; Physical Sciences; Physiological aspects; Proteins; Psychiatry; Rats; Risk factors; Rodents; Specifications; Stains; Stroke; Survival; Toxicity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0174416

N-methyl-D-aspartate receptors (NMDARs), a major subtype of glutamate receptor mediating excitatory transmission throughout the CNS, participate in ischemia-induced neuronal death. Unfortunately, undesired side effects have limited the strategy of inhibiting/blocking NMDARs as therapy. Targeting endogenous positive allosteric modulators of NMDAR function may offer a strategy with fewer downsides. Here, we explored whether 24S-hydroxycholesterol (24S-HC), an endogenous positive NMDAR modulator characterized recently by our group, participates in NMDAR-mediated excitotoxicity following oxygen-glucose deprivation (OGD) in primary neuron cultures. 24S-HC is the major brain cholesterol metabolite produced exclusively in neurons near sites of glutamate transmission. By selectively potentiating NMDAR current, 24S-HC may participate in NMDAR-mediated excitotoxicity following energy failure, thus impacting recovery after stroke. In support of this hypothesis, our findings indicate that exogenous application of 24S-HC exacerbates NMDAR-dependent excitotoxicity in primary neuron culture following OGD, an ischemic-like challenge. Similarly, enhancement of endogenous 24S-HC synthesis reduced survival rate. On the other hand, reducing endogenous 24S-HC synthesis alleviated OGD-induced cell death. We found that 25-HC, another oxysterol that antagonizes 24S-HC potentiation, partially rescued OGD-mediated cell death in the presence or absence of exogenous 24S-HC application, and 25-HC exhibited NMDAR-dependent/24S-HC-dependent neuroprotection, as well as NMDAR-independent neuroprotection in rat tissue but not mouse tissue. Our findings suggest that both endogenous and exogenous 24S-HC exacerbate OGD-induced damage via NMDAR activation, while 25-HC exhibits species dependent neuroprotection through both NMDAR-dependent and independent mechanisms.