Diminishing glutathione availability and age-associated decline in neuronal excitability

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• 作者：Shawn N. Watson ; Jonathon R. Lee ; Tara E. Risling ; Petra M. Hermann ; Willem C. Wildering
• 关键词：Aging ; Oxidative stress ; Lipid peroxidation ; Neuronal excitability ; Electrophysiology ; Glutathione imaging ; Lymnaea stagnalis ; Redox balance ; Identified neuron ; 纬-Glutamylcysteine synthetase inhibition ; Mollusk ; Pyroglutamate
• 刊名：Neurobiology of Aging
• 出版年：May, 2014
• 年：2014
• 卷：35
• 期：5
• 页码：1074-1085
• 全文大小：1627 K

文摘

Oxidative stress is frequently implicated in diminished electrical excitability of aging neurons yet the foundations of this phenomenon are poorly understood. This study explored links between alterations in cellular thiol-redox state and age-associated decline in electrical excitability in identified neurons (right pedal dorsal 1 [RPeD1]) of the gastropod Lymnaea stagnalis. Intracellular thiol redox state was modulated with either dithiothreitol or membrane permeable ethyl ester of the antioxidant glutathione (et-GSH). Neuronal antioxidant demand was manipulated through induction of lipid peroxidation with 2,2鈥?azobis-2-methyl-propanimidamide-dihydrochloride (AAPH). Glutathione synthesis was manipulated with buthionine sulfoximine (BSO). We show that; glutathione content of snail brains declines with age, whereas pyroglutamate content increases; treatment with AAPH and BSO alone aggravated the natural low excitability state of old RPeD1, but only the combination of AAPH聽+ BSO affected electrical excitability of young RPeD1; et-GSH reversed this effect in young RPeD1; et-GSH and dithiothreitol treatment reversed age-associated low excitability of old RPeD1. Together, these data argue for a tight association between glutathione availability and the regulation of neuronal electrical excitability and indicate perturbation of cellular thiol-redox metabolism as a key factor in neuronal functional decline in this gastropod model of biological aging.