Cognitive Deficits in Rats after Forebrain Cholinergic Depletion are Reversed by a Novel NO Mimetic Nitrate Ester

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-tosample 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 concept that stimulating the NO/sGC/cGMP signal transduction system can provide new, effective treatments for cognitive disorders. This approach may be superior to that of current drugs that attempt only to salvage the residual function of damaged cholinergic neurons. Neuropsychopharmacology (2007) 32, 505-513.

Phosphodiesterase 5 Inhibition Improves Synaptic Function, Memory, and Amyloid- Load in an Alzheimer's Disease Mouse Model

“…These results are in agreement with the observation that NO-mimetic molecules may reverse the cognitive impairment caused by scopolamine (Thatcher et al, 2004), or by forebrain cholinergic depletion (Bennett et al, 2007), suggesting that stimulating the NO/cGMP signal transduction system can provide new, effective treatments for cognitive disorders. With regard to the beneficial effect on memory, it is interesting to note that inhibition of PDE5 activity during a time window starting immediately after training for fear learning or after acquisition of the spatial task and ending at no more than 4 h after them improves learning in the transgenic animals.…”

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

“…Medication effects have been assessed in several ways. Rodent animal models are typically used for these studies and the medication administered for up to 4 weeks (Bennett et al, 2007;Delfs et al, 1995;Toyooka et al, 2002a, b;Uezato et al, 2009). As such a short duration of treatment does not model a lifetime of treatment, longer treatment intervals (such as 6 months) would be more analogous to the treatment course in human subjects (Tamminga et al, 1990;Tamminga et al, 1994).…”

Nitric Oxide Mimetic Molecules as Therapeutic Agents in Alzheimers Disease

“…A reliable rat model of visual recognition memory deficit has been reported [210]. In this model a lesion induced by intracerebroventricular infusion of 192 IgG-saporin induced a deficit in visual recognition memory that was completely reversed in a dose dependent manner by oral administration of GT 1061, which proved superior to donepezil: moreover, drug administration was observed to elevate levels of phosphorylated ERK in the hippocampus [212].…”