Cognitive deficits in rats after forebrain cholinergic depletion are reversed by a novel NO mimetic nitrate ester

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
B M BennettGregory R J Thatcher

Abstract

Many conditions adversely affecting learning, memory, and cognition are associated with reductions in forebrain acetylcholine (ACh), most notably aging and Alzheimer's disease. In the current study, we demonstrate that bilateral depletion of neocortical and hippocampal ACh in rats produces deficits in a spatial learning task and in a recently described, delayed visual matching-to-sample task. Oral administration of the novel nitrate, GT1061 (4-methyl-5-(2-nitroxyethyl) thiazole HCl), and the acetylcholinesterase inhibitor, donepezil, reversed the cognitive deficits in both memory tasks in a dose-dependent manner. GT1061 was superior in the delayed matching-to-sample task. GT1061 was absorbed rapidly after oral administration, crossed the blood brain barrier, and achieved brain concentrations that were slightly higher than those found in plasma. The activity of GT1061 was NO mimetic: soluble guanylyl cyclase (sGC) was activated, but selectivity was observed for sGC in the hippocampus relative to the vasculature; and hippocampal levels of phosphorylated ERK1/2, which is a postulated intermediary in the formation of long-term memory, were increased. The beneficial effect on visual and spatial memory task performance supports the c...Continue Reading

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Citations

Dec 30, 2008·ACS Chemical Biology·Timothy W CorsonCraig M Crews
Oct 5, 2013·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Robert E McCullumsmithJames H Meador-Woodruff
Jan 6, 2009·BMC Neuroscience·Nicholas J G Webster, Michael C Pirrung
Aug 8, 2013·Future Medicinal Chemistry·Qin Zhihui
Jan 6, 2016·Drugs·Lidia Bakota, Roland Brandt
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Feb 2, 2011·The International Journal of Neuropsychopharmacology·Andreas ReifAnn-Christine Ehlis
Sep 20, 2011·ACS Medicinal Chemistry Letters·Samer Abdul-HayGregory R J Thatcher
Jul 25, 2018·CNS Neuroscience & Therapeutics·Xiao-Mei JiangXiao-Liang Wang
Oct 1, 2006·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Dale SchenkJohn Q Trojanowski

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