"Calcium bombs" as harbingers of synaptic pathology and their mitigation by magnesium at murine neuromuscular junctions.

Autor:	Dissanayake KN; Euan MacDonald Centre for Motor Neurone Disease Research, The University of Edinburgh, Edinburgh, United Kingdom.; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom., Redman RR; Euan MacDonald Centre for Motor Neurone Disease Research, The University of Edinburgh, Edinburgh, United Kingdom.; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom., Mackenzie H; Euan MacDonald Centre for Motor Neurone Disease Research, The University of Edinburgh, Edinburgh, United Kingdom.; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom., Eddleston M; Clinical Pharmacology, Toxicology and Therapeutics, Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom., Ribchester RR; Euan MacDonald Centre for Motor Neurone Disease Research, The University of Edinburgh, Edinburgh, United Kingdom.; Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, United Kingdom.
Jazyk:	angličtina
Zdroj:	Frontiers in molecular neuroscience [Front Mol Neurosci] 2022 Jul 26; Vol. 15, pp. 937974. Date of Electronic Publication: 2022 Jul 26 (Print Publication: 2022).
DOI:	10.3389/fnmol.2022.937974
Abstrakt:	Excitotoxicity is thought to be an important factor in the onset and progression of amyotrophic lateral sclerosis (ALS). Evidence from human and animal studies also indicates that early signs of ALS include degeneration of motor nerve terminals at neuromuscular junctions (NMJs), before degeneration of motor neuron cell bodies. Here we used a model of excitotoxicity at NMJs in isolated mouse muscle, utilizing the organophosphorus (OP) compound omethoate, which inhibits acetylcholinesterase activity. Acute exposure to omethoate (100 μM) induced prolonged motor endplate contractures in response to brief tetanic nerve stimulation at 20-50 Hz. In some muscle fibers, Fluo-4 fluorescence showed association of these contractures with explosive increases in Ca 2+ ("calcium bombs") localized to motor endplates. Calcium bombs were strongly and selectively mitigated by increasing Mg 2+ concentration in the bathing medium from 1 to 5 mM. Overnight culture of nerve-muscle preparations from Wld S mice in omethoate or other OP insecticide components and their metabolites (dimethoate, cyclohexanone, and cyclohexanol) induced degeneration of NMJs. This degeneration was also strongly mitigated by increasing [Mg 2+ ] from 1 to 5 mM. Thus, equivalent increases in extracellular [Mg 2+ ] mitigated both post-synaptic calcium bombs and degeneration of NMJs. The data support a link between Ca 2+ and excitotoxicity at NMJs and suggest that elevating extracellular [Mg 2+ ] could be an effective intervention in treatment of synaptic pathology induced by excitotoxic triggers. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Dissanayake, Redman, Mackenzie, Eddleston and Ribchester.)
Databáze:	MEDLINE
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