Neuroprotective effect of heparin Trisulfated disaccharide on ischemic stroke

GLYCOCONJUGATE JOURNAL(2021)

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摘要
Cells undergoing hypoxia experience intense cytoplasmic calcium (Ca 2+ ) overload. High concentrations of intracellular calcium ([Ca 2+ ] i ) can trigger cell death in the neural tissue, a hallmark of stroke. Neural Ca 2+ homeostasis involves regulation by the Na + /Ca 2+ exchanger (NCX). Previous data published by our group showed that a product of the enzymatic depolymerization of heparin by heparinase, the unsaturated trisulfated disaccharide (TD; ΔU, 2S-GlcNS, 6S), can accelerate Na + /Ca 2+ exchange via NCX, in hepatocytes and aorta vascular smooth muscle cells. Thus, the objective of this work was to verify whether TD could act as a neuroprotective agent able to prevent neuronal cell death by reducing [Ca 2+ ] i . Pretreatment of N2a cells with TD reduced [Ca 2+] i rise induced by thapsigargin and increased cell viability under [Ca 2+] I overload conditions and in hypoxia. Using a murine model of stroke, we observed that pretreatment with TD decreased cerebral infarct volume and cell death. However, when mice received KB-R7943, an NCX blocker, the neuroprotective effect of TD was abolished, strongly suggesting that this neuroprotection requires a functional NCX to happen. Thus, we propose TD-NCX as a new therapeutic axis for the prevention of neuronal death induced by [Ca 2+ ] i overload.
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关键词
Hypoxia,Stroke,Calcium overload,Trisulfated disaccharide,Neuroprotection
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