title: Beneficial effect of cilostazol-mediated neuronal repair following trimethyltin-induced neuronal loss in the dentate gyrus.
abstract: Cilostazol acts as an antiplatelet agent and has other pleiotropic effects based on phosphodiesterase-3-dependent mechanisms. We evaluated whether cilostazol would have a beneficial effect on neuronal repair following hippocampal neuronal damage by using a mouse model of trimethyltin (TMT)-induced neuronal loss/self-repair in the hippocampal dentate gyrus [Ogita et al. (2005) J Neurosci Res 82:609-621]; these mice will hereafter be referred to as impaired animals. A single treatment with cilostazol (10 mg/kg, i.p.) produced no significant change in the number of 5-bromo-2'-deoxyuridine (BrdU)-incorporating cells in the dentate granule cell layer (GCL) or subgranular zone on day 3 after TMT treatment. However, chronic treatment with cilostazol on days 3-15 posttreatment resulted in an increase in the number of BrdU-incorporating cells in the dentate GCL of the impaired animals, and these cells were positive for neuronal nuclear antigen or doublecortin. Cilostazol was effective in elevating the level of phosphorylated cyclic adrenosine monophosphate response element-binding protein (pCREB) in the dentate gyrus of impaired animals. The results of a forced swimming test revealed that the chronic treatment with cilostazol improved the depression-like behavior seen in the impaired animals. In the cultures of hippocampal neural stem/progenitor cells, exposure to cilostazol produced not only enhancement of proliferation activity but also elevation of pCREB levels. Taken together, our data suggest that cilostazol has a beneficial effect on neuronal repair following neuronal loss in the dentate gyrus through promotion of proliferation and/or neuronal differentiation of neural progenitor cells in the subgranular zone.
authors.affiliation: Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoneyama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hasebe
authors.forename: Taro
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shiba
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Ogita
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000077407:Cilostazol; D018891:Dentate Gyrus / Q000166:cytology*; D066298:In Vitro Techniques; D008124:Locomotion; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D013550:Swimming; D013777:Tetrazoles / Q000494:pharmacology*; D014298:Trimethyltin Compounds / Q000633:toxicity*
chemical_list: D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D013777:Tetrazoles; D014298:Trimethyltin Compounds; C046488:trimethyltin; D050882:CREB-Binding Protein; D001973:Bromodeoxyuridine; D000077407:Cilostazol
keywords: cilostazol; dentate gyrus; depression; neural progenitor cell; neuronal loss; neuronal regeneration; trimethyltin