NAKANE Hideyuki Nagasaki University, Graduate School of Biomedical Sciences, Lecturer, 大学院・医歯薬学総合研究科, 講師 (90274795)
FUJIMARU Kosuke Nagasaki University, Hospital of Medicine and Dentistry, Lecturer, 医学部・歯学部附属病院, 講師 (70284685)
IMAMURA Akira Nagasaki University, Graduate School of Biomedical Sciences, Lecturer, 大学院・医歯薬学総合研究科, 講師 (40325642)
齋藤 利和 札幌医科大学, 医学部, 教授 (50128518)
|Budget Amount *help
¥3,500,000 (Direct Cost : ¥3,500,000)
Fiscal Year 2004 : ¥1,700,000 (Direct Cost : ¥1,700,000)
Fiscal Year 2003 : ¥1,800,000 (Direct Cost : ¥1,800,000)
Previously, we have reported that decreased activity of cAMP signaling was found in mood disorder's brain samples, and antidepressants activate cAMP signaling by changing the G protein functions. It is reported that activation of cAMP-PKA system regulates MAP kinase and PI 3-kinase pathway, which known to the major signaling cascades of trophic factors (IGF-1.BDNF), in the surviving process of mature neurons. Recently, the p-CREB expression in immature neurons was reported, and upregulation of cAMP induced increase the proliferation of newborn cells in adult rat hippocampus. However, the role and mechanisms of cAMP signals in the neural stem cell(NSC) differentiation have not yet been elucidated.
In the present study, we developed a quantitative and stable in vitro assay system to evaluate the neural stem cell differentiation using MAP2-ELISA. Here, we evaluated the effects of moodstabilizers in promoting neuronal differentiation in vitro.
In our experiment system, the differentiation of
NSCs to the neurons were dose-dependently enhanced by the treatments of trophic factors, BDNF and IGF-1. These actions were the same as reported byArsenijevic Y.(1998) and other past.
The SSRIs, fluoxethine and paroxethine promoted the differentiation of neural stem cells in almost clinicaly effective doses. Lithium tested here promoted the differentiation of NSCs. These suggest that the enhancing effect of the differentiation of NSCs in common to the antidepressants and mood stabilizer may contributes to their clinical efficacies for mood disorders. Since it is well suggested that cAMP and PLC signaling pathway is a common target for antidepressants and moodstabilizers, the detailed examination of the changes of cAMP-CREB/PLC-CREB system and trophic factor signaling in NSCs by the treatment of moodstabilizers, is required.
It becomes a subject of future research how the action of antidepressants and moodstabilizers on NSC differentiation change under existence of neurons and/or glias.
Additionaly, neurotoxic effects of antipsychotics have been demonstrated in relation to extrapyramidal side effects(EPS), including tardive dyskinesia(TD). Recent morphological and neuroimaging studies demonstrate cytoarchitectural changes in schizophrenic brains. It is still controversial whether they are caused by illness itself or neurotoxicity by antipsychotic agents. Haloperidol induced apoptotic cell death is reported in cultured neurons, which is mediated by reactive oxygen species(ROS), mitogen-activated protein kinases p38 and c-jun-NH2-terminal protein kinase(JNK). Current studies report the role of neuronal toxicity induced by neuroleptics in the development of TD. In this study, we examined the effects of long-term treatment with antipsychotic agents in cultured cortical neurons and implications of caspase-3 in apoptotic cascade induced by haloperidol. Less