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Neuroprotective effect of heparin Trisulfated disaccharide on ischemic stroke

Abstract

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; ΔU, 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 [Ca2+]i rise induced by thapsigargin and increased cell viability under [Ca2+]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 [Ca2+]i overload.

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Acknowledgments

This work was supported by Fundação de Amparo à Pesquisa de São Paulo - FAPESP (2011/00526-7; 2015/03964-6; 2017/18765-4), Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq (402391/2013-3; 465656/2014-5) and National Institute of General Medical Sciences (GM23244), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES (Finance Code 001).

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Correspondence to Ivarne L. S. Tersariol or Marimélia Porcionatto.

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Chiarantin, G.M.D., Delgado-Garcia, L.M., Zamproni, L.N. et al. Neuroprotective effect of heparin Trisulfated disaccharide on ischemic stroke. Glycoconj J 38, 35–43 (2021). https://doi.org/10.1007/s10719-020-09966-4

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  • DOI: https://doi.org/10.1007/s10719-020-09966-4

Keywords

  • Hypoxia
  • Stroke
  • Calcium overload
  • Trisulfated disaccharide
  • Neuroprotection