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Opposite in vivo effects of agents that stimulate or inhibit the glutamate/cysteine exchanger system x c − on the inhibition of hippocampal LTP by Aß
Author(s) -
Zhang Dainan,
Jin Baozhe,
Ondrejcak Tomas,
Rowan Michael J.
Publication year - 2016
Publication title -
hippocampus
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.767
H-Index - 155
eISSN - 1098-1063
pISSN - 1050-9631
DOI - 10.1002/hipo.22667
Subject(s) - long term potentiation , glutamate receptor , chemistry , synaptic plasticity , pharmacology , acetylcysteine , ltp induction , sulfasalazine , neuroscience , nmda receptor , glutathione , excitotoxicity , biochemistry , medicine , biology , antioxidant , enzyme , receptor , disease , ulcerative colitis
ABSTRACT Aggregated amyloid ß‐protein (Aß) is pathognomonic of Alzheimer's disease and certain assemblies of Aß are synaptotoxic. Excess glutamate or diminished glutathione reserve are both implicated in mediating or modulating Aß‐induced disruption of synaptic plasticity. The systemx c −antiporter promotes Na + ‐independent exchange of cystine with glutamate thereby providing a major source of extracellular glutamate and intracellular glutathione concentrations. Here we probed the ability of two drugs with opposite effects on systemx c −, the inhibitor sulfasalazine and facilitator N‐acetylcysteine, to modulate the ability of Aß1‐42 to inhibit long‐term potentiation (LTP) in the CA1 area of the anaesthetized rat. Whereas acute systemic treatment with sulfasalazine lowered the threshold for Aß to interfere with synaptic plasticity, N‐acetylcysteine prevented the inhibition of LTP by Aß alone or in combination with sulfasalazine. Moreover acute N‐acetylcysteine also prevented the inhibition of LTP by TNFα, a putative mediator of Aß actions, and repeated systemic N‐acetylcysteine treatment for 7 days reversed the delayed deleterious effect of Aß on LTP. Since both of these drugs are widely used clinically, further evaluation of their potential beneficial and deleterious actions in early Alzheimer's disease seems warranted. © 2016 Wiley Periodicals, Inc.