The Alzheimer's disease drug memantine increases the number of radial glia-like progenitor cells in adult hippocampus.
New neurons are continuously generated in the hippocampus of the adult mammalian brain, and N-methyl-D-aspartate receptor (NMDA-R) antagonists have been found to increase the number of newly generated neurons in the dentate gyrus (DG) of the adult hippocampus. In this study, we examined the effect of memantine, an NMDA-R antagonist that is clinically used for the treatment of Alzheimer's disease, on primary progenitor cells exhibiting a radial glia-like (RGL) morphology in the DG. We injected 3-month-old mice with memantine (50 mg/kg body weight, intraperitoneally [i.p.]); 3 days later, we injected the mice with 5-bromo-2-deoxyuridine (BrdU; 75 mg/kg body weight, i.p.). We then counted the number of BrdU-labeled RGL progenitor cells in the DG 1 or 7 days after the BrdU-injection. The number of BrdU-labeled RGL progenitor cells had increased significantly by 5.1-fold on day 1 and by 13.7-fold on day 7 after BrdU-injection. Immunohistochemical staining revealed that the BrdU-labeled RGL progenitor cells expressed two primary progenitor cell marker proteins, nestin and Sox2. These results clearly demonstrated that memantine promotes the proliferation of RGL progenitor cells. We also found that memantine increased the ratio of horizontally aligned RGL progenitor cells, which are probably produced by symmetric division. These findings suggest that memantine increases the proliferation of primary progenitor cells and expands the primary progenitor cell pool in the adult hippocampus by stimulating symmetric division.
Namba
Takashi
T
Department of Neurochemistry, National Institute of Neuroscience, Kodaira, Tokyo, Japan.
Maekawa
Motoko
M
Yuasa
Shigeki
S
Kohsaka
Shinichi
S
Uchino
Shigeo
S
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000032:analysis / Q000378:metabolism; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D064231:Nestin; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000032:analysis / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D015415:Biomarkers; D018691:Excitatory Amino Acid Antagonists; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D016194:Receptors, N-Methyl-D-Aspartate; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D001973:Bromodeoxyuridine; D008559:Memantine