A Comparative Study of the Impact of NO-Related Agents on MK-801- or Scopolamine-Induced Cognitive Impairments in the Morris Water Maze

Abstract

Learning and memory deficits accompany numerous brain dysfunctions, including schizophrenia and Alzheimer’s disease (AD), and many studies point to the role of nitric oxide (NO) in these processes. The present investigations constitute the follow-up of our previous research, in which we investigated the activity of NO releasers and a selective inhibitor of neuronal NO synthase (nNOS) to prevent short-term memory deficits in novel object recognition and T-maze. Here, the ability of the compounds to prevent the induction of long-term memory deficits by MK-801 or scopolamine administration was investigated. The Morris Water Maze test, a reliable and valid test of spatial learning and memory, was used, in which escape latency in the acquisition phase and nine different parameters in the retention phase were measured. A fast NO releaser (spermine NONOate), a slow NO releaser (DETA NONOate), and a nNOS inhibitor, N(ω)-propyl-L-arginine (NPLA), were used. The compounds were administered i.p. at a dose range of 0.05–0.5 mg/kg. All compounds prevented learning deficits in the acquisition phase and reversed reference memory deficits in the retention phase of the scopolamine-treated mice. Spermine NONOate was the least effective. In contrast, the drugs poorly antagonised MK-801-induced deficits, and only the administration of DETA NONOate induced some improvements in the retention trial.

The Impact of LY487379 or CDPPB on eNOS Expression in the Mouse Brain and the Effect of Joint Administration of Compounds with NO• Releasers on MK-801- or Scopolamine-Driven Cognitive Dysfunction in Mice

“…A significant amount of research to date has indicated that NO donors induce an antiamnesic effect when administered alone [35,36,[58][59][60][61]. The most commonly known NO donor, sodium nitroprusside, reversed MK-801-or ketamine-induced cognitive deficits in animal models [61,62] and effectively improved cognition in randomized double-blind placebo-controlled studies in schizophrenic patients [63].…”

“…Studies concerning the activity of NONOates in animal models of brain disorders have indicated the potency of the compounds to decrease infarct size and prevent vasospasms caused by stroke in rodent models of ischemia [66,67]. Our recent studies on NONOates proved that the compounds are potent antiamnesic agents as well [35,36]. The potency of the compounds to prevent not only amnesia but also other symptoms accompanying brain disorders would constitute a great benefit.…”

“…In the present studies, the influence of positive allosteric modulators of mGlu 5 (CDPPB) and mGlu 2 (LY487379) receptors on eNOS expression in pharmacologically driven models of cognitive decline were examined. Similar to previous research, MK-801 was used to induce schizophrenia-related cognitive symptoms and scopolamine was used to induce Alzheimer's-type dementia [35,36]. Subsequently, the efficacy of the simultaneous activation of mGlu receptors and NO release in novel object recognition (NOR) were examined.…”

“…Selective and noncompetitive NMDA antagonist; K i = 37.2 nM 0.9% NaCl [38] Scopolamine hydrobromide (Abcam, Cambridge, UK) (α,S)-α-(Hydroxymethyl) benzeneacetic acid (1α,2β,4β,5α,7β)-9-methyl-3-oxa-9-azatricyclo and 20 nM for human and rat, respectively 10% Tween 80 [40] In all our experiments, MK-801 was administered at a dose of 0.3 mg/kg and scopolamine at 1 mg/kg [35,36,[41][42][43]. The doses of spermineNONOate and DETANONOate were established in our previous investigations [35,36]. The doses of CDPPB and LY487379 on MK-801-induced deficits were adjusted from [41][42][43].…”

Psychopharmacology and Biological Studies of Psychosis

“…Cieślik et al investigated the activity of NO releasers and a selective inhibitor of neuronal NO synthase (nNOS) in preventing the occurrence of short-term memory deficits. The results indicate that scopolamine-induced dysfunctions in hippocampal-dependent spatial learning and memory can be alleviated via treatment with NO-related agents [ 5 ].…”