Opposite in vivo effects of agents that stimulate or inhibit the glutamate/cysteine exchanger system [Formulaomitted] on the inhibition of hippocampal LTP by As

• Published in: Hippocampus 2016-12, Vol.26 (12), p.1655-1665
• Main Authors: Zhang, Dainan, Jin, Baozhe, Ondrejcak, Tomas, Rowan, Michael J
• Format: Article
• Language: English
• ISSN: 1050-9631; 1098-1063
• DOI: 10.1002/hipo.22667

Aggregated amyloid s-protein (As) is pathognomonic of Alzheimer's disease and certain assemblies of As are synaptotoxic. Excess glutamate or diminished glutathione reserve are both implicated in mediating or modulating As-induced disruption of synaptic plasticity. The system [Formulaomitted] antiporter promotes Na super(+)-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 [Formulaomitted], the inhibitor sulfasalazine and facilitator N-acetylcysteine, to modulate the ability of As1-42 to inhibit long-term potentiation (LTP) in the CA1 area of the anaesthetized rat. Whereas acute systemic treatment with sulfasalazine lowered the threshold for As to interfere with synaptic plasticity, N-acetylcysteine prevented the inhibition of LTP by As alone or in combination with sulfasalazine. Moreover acute N-acetylcysteine also prevented the inhibition of LTP by TNF alpha , a putative mediator of As actions, and repeated systemic N-acetylcysteine treatment for 7 days reversed the delayed deleterious effect of As 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.