title: Opposite in vivo effects of agents that stimulate or inhibit the glutamate/cysteine exchanger system xc- on the inhibition of hippocampal LTP by Aß.
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 system xc- 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 system xc-, 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.
authors.affiliation: Department of Pharmacology and Therapeutics, and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.|Department of Neurosurgery, the First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China.
authors.forename: Dainan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, the First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, China.
authors.forename: Baozhe
authors.initials: B
authors.lastname: Jin
authors.affiliation: Department of Pharmacology and Therapeutics, and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Tomas
authors.initials: T
authors.lastname: Ondrejcak
authors.affiliation: Department of Pharmacology and Therapeutics, and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D026922:Amino Acid Transport Systems, Acidic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002408:Catheters, Indwelling; D002491:Central Nervous System Agents / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008298:Maleates / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*; D017208:Rats, Wistar; D012460:Sulfasalazine / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D027182:Amino Acid Transport System y+
chemical_list: D000111:Acetylcysteine; D026922:Amino Acid Transport Systems, Acidic; D016229:Amyloid beta-Peptides; D002491:Central Nervous System Agents; D005978:Glutathione; D008298:Maleates; D010446:Peptide Fragments; D012460:Sulfasalazine; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); C014476:diethyl maleate; C000723960:Slc7a11 protein, rat; D027182:Amino Acid Transport System y+
keywords: CA1; N-acetylcysteine; TNFα; sulfasalazine; synaptic plasticity