Memantine combined with environmental enrichment improves spatial memory and alleviates Alzheimer's disease-like pathology in senescence-accelerated prone-8 (SAMP8) mice

Jingde Dong,Mi Zhou,Xiaoqiang Wu,Mingyang Du,Xiaoshan Wang

doi:10.7555/jbr.26.20120053

Abstract

Memantine is a N-methyl-D-aspartate (NMDA) receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease (AD). Environmental enrichment (EE) has shown significant beneficial effects on functional improvement in AD. In this study, we sought to determine whether combining these two distinct therapies would yield greater benefit than either drug used alone. We investigated the effect of memantine combined with EE on spatial learning and memory and AD-like pathology in a widely used AD model, the senescence-accelerated prone mice (SAMP8). The SAMP8 mice were randomly assigned to enriched housing (EH) or standard housing (SH), where either memantine (20 mg/kg) or saline was given by gastric lavage once daily continuously for eight weeks. Our results showed that, when provided separately, memantine and EE significantly improved spatial learning and memory by shortening escape latencies and increasing the frequency of entrance into the target quadrant. When combined, memantine and EE showed additive effect on learning and memory as evidenced by significant shorter escape latencies and higher frequency of target entrance than either drug alone. Consistent with the behavior results, pathological studies showed that both memantine and EE significantly reduced hippocampal CA1 neurofibrilliary tangles (NFTs) as well as amyloid beta precursor protein (APP) levels. Combining both therapies synergistically lessened NFTs and APP expression compared to either drug alone in SAMP8 mice, indicating that the combination of memantine with EE could offer a novel and efficient therapeutic strategy for the treatment of AD.

Highlights

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive impairments in memory, language, visuospatial cognition and behavior[1]
Forty male SAMP8 mice were divided in four groups and held in standard housing (SH), while another 40 male SAMP8 mice were housed in composed groups in enriched housing (EH)
To determine the effect of memantine combined with enriched environment on SAMP8 mice, we treated 20 of the mice within either the SH or EH group with memantine [20 mg/(kg·d)] through gastric lavage for continuous 8 weeks while the remaining 20 mice within either the SH or EH group were treated with the same doses of saline in the same way

Summary

Introduction

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive impairments in memory, language, visuospatial cognition and behavior[1]. These clinical manifestations are caused by neuron degeneration with deposition of amyloid plaques and formation of neurofibrillary tangles (NFTs), which lead to progressive and irreversible loss of neurons and cognitive decline[2]. Dong J et al / Journal of Biomedical Research, 2012, 26(6): 439-447 plaques consist of fibrils that are formed from the amyloid-β (Aβ) peptide. Aβ peptides, which primarily consist of a short peptide of 40 amino acids in length Aβ (1-40) and a longer peptide of 42 residues Aβ (1-42). are the proteolytic cleavage products of a transmembrane protein, amyloid β precursor protein (APP)[3,4].

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