Improvement by nefiracetam of β‐amyloid‐(1‐42)‐induced learning and memory impairments in rats

Abstract

1 We have previously demonstrated that continuous i.c.v. infusion of amyloid b-peptide (Ab), the major constituent of senile plaques in the brains of patients with Alzheimer's disease, results in learning and memory de®cits in rats. 2 In the present study, we investigated the e ects of ne®racetam [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384] on Ab-(1-42)-induced learning and memory de®cits in rats. 3 In the Ab-(1-42)-infused rats, spontaneous alternation behaviour in a Y-maze task, spatial reference and working memory in a water maze task, and retention of passive avoidance learning were signi®cantly impaired as compared with Ab-(40-1)-infused control rats. 4 Ne®racetam, at a dose range of 1 ± 10 mg kg 71 , improved learning and memory de®cits in the Ab-(1-42)-infused rats when it was administered p.o. 1 h before the behavioural tests. 5 Ne®racetam at a dose of 3 mg kg 71 p.o. increased the activity of choline acetyltransferase in the hippocampus of Ab-(1-42)-infused rats. 6 Ne®racetam increased dopamine turnover in the cerebral cortex and striatum of Ab-(1-42)-infused rats, but failed to a ect the noradrenaline, serotonin and 5-hydroxyindoleacetic acid content. 7 These results suggest that ne®racetam may be useful for the treatment of patients with Alzheimer's disease. Keywords: Alzheimer's disease; amyloid b-peptide; ne®racetam (DM-9384); reference memory; voltage-sensitive calcium channels; working memoryAbbreviations: 5-HIAA, 5-hydroxyindoleacetic acid; Ab, amyloid b-peptide; ACh, acetylcholine; AD, Alzheimer's disease; ANOVA, one-way analysis of variance; APP, b-amyloid precursor protein; ChAT, choline acetyltransferase; DOPAC, 3,4-dihydroxyphenylacetic acid; GABA, g-aminobutyric acid; HVA, homovanillic acid; VSCC, voltagesensitive calcium channels IntroductionAlzheimer's disease (AD) is the most common cause of progressive decline of cognitive function in aged humans. The disease is characterized neuropathologically by the presence of numerous senile plaques and neuro®brillary tangles accompanied by neuronal loss. The senile plaques are composed of amyloid b-peptide (Ab), a 40 ± 42 amino acid peptide fragment of the b-amyloid precursor protein (APP) (Kang et al., 1987). Transgenic mice, which overexpress human APP containing the mutations associated with familial AD, develop many of the pathological characterizations associated with AD (Games et al., 1995;Johnson-Wood et al., 1997; Sturchler-Pierrat et al., 1997). Furthermore, Ab is cytotoxic to neurons (Yankner et al., 1990) and renders neurons vulnerable to various insults including excitotoxicity (Koh et al., 1990;Mattson et al., 1992). These previous ®ndings suggest that Ab has a central role in the pathogenesis of AD. We have previously demonstrated that continuous infusion of Ab-(1-40) into the cerebral ventricle of rats results in learning and memory de®cits, suggesting that accumulation of Ab in the brain is related to cognitive impairments in AD . Continuous Ab-(1-40) infusion causes a decrease in choline acetyltransferase ...

Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

“…CLN treatment attenuated contextual memory impairment caused by Ab detected in PA as well as Ab-induced spatial working memory impairment in YM. As reported in earlier studies (Yamada et al, 1999, i.c.v. injection of Ab downregulates the expression level of ChAT in neurons of the medial septum.…”

“…Intracerebroventricular injection of toxic Ab peptides has been reported to impair spatial working memory in rodents (Maurice et al, 1996;Yamada et al, 1999Yamada et al, , 2005. We have recently established a toxic Ab-induced mouse model of AD by using repetitive i.c.v.…”

Development of a Femtomolar-Acting Humanin Derivative Named Colivelin by Attaching Activity-Dependent Neurotrophic Factor to Its N Terminus: Characterization of Colivelin-Mediated Neuroprotection against Alzheimer's Disease-Relevant InsultsIn VitroandIn Vivo

“…Intracerebroventricular injection of toxic A␤ peptides has been reported to impair spatial working memory in rodents (Flood et al, 1991;Delobette et al, 1997;Yamada et al, 1999;Yamaguchi and Kawashima, 2001;Stepanichev et al, 2003b). Although administration of A␤ into cerebral ventricles has usually been performed by a one-shot or bolus intracerebroventricular injection of a large dose of A␤, rats with dementia have been constructed successfully by continuous infusion of A␤ via an osmotic pump connected to the cerebral ventricle (Nitta et al, 1997; Yamada et …”

Effects of Pre-Germinated Brown Rice on .BETA.-Amyloid Protein-Induced Learning and Memory Deficits in Mice

“…The bamyloid (Ab) peptide that comprises senile plaques induces brain dysfunction, as evidenced by neurodegeneration and learning and memory impairment in rodents. [1][2][3][4][5][6] Several reports have demonstrated that Ab 1-40 , Ab and Ab [25][26][27][28][29][30][31][32][33][34][35] proteins impaired learning and memory to the same extent. 1,4,5) Similarly, Terranova et al have shown that those three proteins induce the cognitive dysfunction in rats.…”