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NEUROPHARMACOLOGY

Effect of Subchronic Treatment of Memantine, Galantamine, and Nicotine in the Brain of Tg2576 (APPswe) Transgenic Mice

Karolinska Institutet, Neurotec Department, Division of Molecular Neuropharmacology, Karolinska University Hospital Huddinge, Stockholm, Sweden

An increasing number of studies suggest that the present clinical therapy used in Alzheimer's disease (AD), in addition to having a symptomatic effect, also may interact with the ongoing neuropathological processes in the brain. The aim of this study was to investigate the effect of the cholinesterase inhibitor galantamine and the N-methyl-D-aspartate (NMDA) antagonist memantine in comparison to nicotine on the neuropathology of Tg2576 transgenic mice (APPswe). Nontransgenic and APPswe mice at 10 months of age were treated subcutaneously with saline, memantine, galantamine, or nicotine for 10 days. Nicotine reduced the guanidinium-soluble amyloid- peptide (A) levels by 46 to 66%, whereas the intracellular A levels remained unchanged. Treatment with nicotine also resulted in less glial fibrillary acidic protein immunoreactive astrocytes around the plaques, increased levels of synaptophysin, and increased number of 7 nicotinic acetylcholine receptors (nAChRs) in the cortex of APPswe transgenic mice. Galantamine treatment caused an increase in the cortical levels of synaptophysin in the APPswe mice. Memantine treatment reduced the total cortical levels of membrane-bound amyloid precursor protein (45–55%) in both transgenic and nontransgenic mice, which eventually may decrease the level of A. In conclusion, galantamine, memantine, and nicotine have different interactions with A processes, 7 nAChRs, and NMDA receptors in APPswe mice. These different effects might have therapeutic relevance, and this knowledge might be applicable to the development of new effective therapeutic strategies for AD.

Address correspondence to: Professor Agneta Nordberg, Karolinska Institutet, Neurotec Department, Division of Molecular Neuropharmacology, Karolinska University Hospital Huddinge, Novum 5th floor, 141 86 Stockholm, Sweden. E-mail: agneta.nordberg{at}neurotec.ki.se