Identification of Genes Regulated by Memantine and MK-801 in Adult Rat Brain by cDNA Microarray Analysis

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 (X1.5-or p0.67-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 Ca 2 þ -binding protein 2 (NVP-2), neuromedin B receptor, and Na þ /K þ transporting ATPase 2b. 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 (B30-65%) 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.

Memantine Upregulates BDNF and Prevents Dopamine Deficits in SIV-Infected Macaques: A Novel Pharmacological Action of Memantine

“…Therefore, it is reasonable to think that the amelioration of dopamine deficits by memantine in our study might rather be due to the observed BDNF upregulation than to the generally known NMDA antagonist action of memantine. In this line, a recent report on administration of memantine in adult rats, led to upregulation of several genes independent of the glutamatergic blockade, suggesting broader actions than previously realized (Marvanova et al, 2004). The trophic quality of memantine shown in this manuscript is supported by a paper published during the revision of our manuscript on the effects of a short-term treatment of HIV patients with memantine.…”

Abnormalities of neurotransmitter and neuropeptide systems in human neuroepithelioma cells infected by three Toxoplasma strains

“…A two way analysis of variance (ANOVA) was used to detect genes with statistically significant expression levels between each Toxoplasma strain and their corresponding set of mock-infected cells. Due to the exploratory nature of the study and the fact that the brain normally shows small changes in gene expression (Marvanová et al 2004; Guiry et al 2010), genes were judged to be differentially expressed if their transcripts differed from that of controls with an ANOVA p < 0.01 and a fold change > 1.2 fold in either direction. Based on the differentially expressed gene list, a further group of genes coding for NNS was selected according to the KEGG PATHWAY database (hsa04080,!Neuroactive ligand-receptor interaction-Homo sapiens: http://www.genome.jp/kegg-bin/show_pathway?hsa04080).…”

Differential Effects of Three CanonicalToxoplasmaStrains on Gene Expression in Human Neuroepithelial Cells

“…A two-way analysis of variance (ANOVA) was used to detect genes with statistically significant expression levels between Toxoplasma strains and their corresponding sets of mock-infected cells. Due to the exploratory nature of the study and the fact that the brain normally shows small changes in gene expression (18,37), genes whose transcripts were judged to be differentially expressed, meaning they had to have an ANOVA P value of Յ0.01 and a change in expression of at least 1.2-fold in either direction, were selected as candidates for further functional analyses (54,58).…”