Abstract
In this study, we monitored gene expression profiles using cDNA microarrays after an acute systemic administration of the high affinity N-methyl-D-aspartate (NMDA) uncompetitive antagonist MK-801 (1 mg/kg; 4 h), and the clinically used moderate affinity antagonist memantine (25 mg/kg; 4 h) in adult rat brains. From a microarray containing 1090 known genes, 13 genes were regulated by both treatments of which 12 were upregulated and one was downregulated. In addition, 28 and 34 genes were regulated (⩾1.5- or ⩽0.67-fold change) by either memantine or MK-801, respectively. Genes commonly regulated by both treatments and not previously reported were confirmed by in situ hybridization (ISH) and include regenerating liver inhibitory factor-1 (RL/IF-1), GDP-dissociation inhibitor 1 (GDI-1), neural visinin Ca2+-binding protein 2 (NVP-2), neuromedin B receptor, and Na+/K+ transporting ATPase 2β. ISH with memantine (5–50 mg/kg) revealed regulation of these genes in other cortical and hippocampal regions. RL/IF-1 induction occurred at 1 h and returned to basal levels by 8 h, consistent with the profile of an immediate early gene. Western blot analysis showed increases (∼30–65%) in GDI-1 protein present in both cytosolic and membrane fractions that were significant in the 84-kDa Rab bound form, suggesting that memantine influences Ras-like GTPase function. Genes regulated by a 5 mg/kg dose of memantine might be important in its therapeutic effects. These findings increase the number of known, differentially altered genes after treatment of uncompetitive NMDA receptor antagonists and suggest broader actions of these agents than previously realized.
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Acknowledgements
We thank Drs Antero Salminen and Outi Kontkanen for helpful discussions and critical comments. We are also grateful to Markus Storvik for his support in animal experiments. We are indebted to Dr Jarno Laitinen for providing GTP, and Dr G Quack at Merz+Pharmaceuticals, Frankfurt/Main, Germany for endowment of Memantine × HCl. This study has been supported by the Academy of Finland.
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Marvanová, M., Lakso, M. & Wong, G. Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis. Neuropsychopharmacol 29, 1070–1079 (2004). https://doi.org/10.1038/sj.npp.1300398
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DOI: https://doi.org/10.1038/sj.npp.1300398
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