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Hypochlorous acid induces apoptosis of cultured cortical neurons through activation of calpains and rupture of lysosomes

journal contribution
posted on 2023-05-17, 01:43 authored by Yap, YW, Whiteman, M, Bay, BH, Li, Y, Sheu, FS, Qi, RZ, Tan, CH, Cheung, NS
3-Chlorotyrosine, a bio-marker of hypochlorous acid (HOCl) in vivo, was reported to be substantially elevated in the Alzheimer's disease (AD) brains. Thus, HOCl might be implicated in the development of AD. However, its effect and mechanism on neuronal cell death have not been investigated. Here, we report for the first time that HOCl treatment induces an apoptotic-necrotic continuum of concentration-dependent cell death in cultured cortical neurons. Neurotoxicity caused by an intermediate concentration of HOCl (250 ìm) exhibited several biochemical markers of apoptosis in the absence of caspase activation. However, the involvement of calpains was demonstrated by data showing that calpain inhibitors protect cortical neurons from apoptosis and the formation of 145/150 kDa á-fodrin fragments. Moreover, an increase in cytosolic Ca2+ concentration was associated with HOCl neurotoxicity and Ca2+ channel antagonists, and Ca2+ chelators prevented cleavage of á-fodrin and the induction of apoptosis. Finally, we found that calpain activation ruptured lysosomes. Stabilization of lysosomes by calpain inhibitors or imidazoline drugs, as well as inhibition of cathepsin protease activities, rescued cells from HOCl-induced neurotoxicity. Our results showed for the first time that HOCl induces apoptosis in cortical neurons, and that the cell death process involves calpain activation and rupture of lysosomes.

History

Publication title

Journal of Neurochemistry

Volume

98

Issue

5

Pagination

1597-1609

ISSN

0022-3042

Department/School

Menzies Institute for Medical Research

Publisher

Blackwell Publishing Ltd

Place of publication

9600 Garsington Rd, Oxford, England, Oxon, Ox4 2Dg

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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