Neuroprotective effect of heparin Trisulfated disaccharide on ischemic stroke

Chiarantin, Gabrielly M. D.; Delgado-Garcia, Lina M.; Zamproni, Laura N.; Lima, Marcelo A.; Nader, Helena B.; Tersariol, Ivarne L. S.; Porcionatto, Marimélia

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.

Citation

Chiarantin, G. M. D., Delgado-Garcia, L. M., Zamproni, L. N., Lima, M. A., Nader, H. B., Tersariol, I. L. S., & Porcionatto, M. (2021). Neuroprotective effect of heparin Trisulfated disaccharide on ischemic stroke. Glycoconjugate Journal, 38(1), 35--43. https://doi.org/10.1007/s10719-020-09966-4

• Journal Article Type: Article
• Acceptance Date: Nov 26, 2020
• Online Publication Date: Jan 7, 2021
• Publication Date: 2021-02
• Deposit Date: May 30, 2023
• Journal: Glycoconjugate Journal
• Print ISSN: 0282-0080
• Electronic ISSN: 1573-4986
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 38
• Issue: 1
• Pages: 35--43
• DOI: https://doi.org/10.1007/s10719-020-09966-4
• Keywords: Cell Biology; Molecular Biology; Biochemistry
• Publisher URL: https://link.springer.com/article/10.1007\%2Fs10719-020-09966-4
• Additional Information: Received: 5 August 2020; Revised: 15 November 2020; Accepted: 26 November 2020; First Online: 7 January 2021; : ; : The authors declare that they have no conflicts of interest.; : This article does not contain any studies with human participants or animals performed by any of the authors.