Neuroprotective effect of heparin Trisulfated disaccharide on ischemic stroke

Cells undergoing hypoxia experience intense cytoplasmic calcium (Ca2+) overload. High concentrations of intracellular calcium ([Ca2+](i)) can trigger cell death in the neural tissue, a hallmark of stroke. Neural Ca2+ homeostasis involves regulation by the Na+/Ca2+ 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; Delta U, 2S-GlcNS, 6S), can accelerate Na+/Ca2+ 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 [Ca2+](i). Pretreatment of N2a cells with TD reduced [Ca-i(2+]) rise induced by thapsigargin and increased cell viability under [Ca-I(2+]) 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 [Ca2+](i) overload.

Automated summary

Cells experiencing hypoxia can undergo Ca2+ overload, leading to neural cell death. The compound TD may act as a neuroprotective agent by accelerating Na+/Ca2+ exchange to reduce [Ca2+] (i). Experimental evidence from N2a cells and a murine stroke model supports the effectiveness of TD in neuroprotection.