The role of neural stem cells for in vitro models of schizophrenia: neuroprotection via Akt/ERK signal regulation.
Recent neuroimaging studies have revealed progressive morphological brain changes during the course of schizophrenia, and the neurotrophic and neurogenetic effects of atypical antipsychotics are believed to prevent or retard these brain volume reductions. In addition to drug-induced neural stem cell (NSC) activation, transplantation of exogenous NSCs has been proposed as a possible approach to repair the damaged brain in psychiatric disease. NSC transplantation embraces not only neuron replacement but also enhanced neuroprotection of existing neurons with the goal of restoring the impaired brain. However, little is known about the cell-cell interactions of exogenous NSCs with existing neurons, or about their neuroprotective actions especially in psychiatric diseases. In the present study, we used cortical neuron cultures to examine the neurotrophism and neuroprotection of exogenous NSCs against the neuronal damage induced by exposure to the NMDA receptor antagonist, MK-801. We also investigated their role in serum/nutrient deprivation stress. The exogenous NSCs exerted neuroprotective effects against both types of apoptotic injuries considered as in vitro schizophrenic disease models. Exogenous NSCs also altered cellular survival signaling in injured neurons by indirect cell-cell contact in an injury-dependent manner. In MK-801 exposure, NSCs increased phosphorylated Akt (p-Akt) and ERK (p-ERK), both of which were reduced by this stress. While, in serum/nutrient deprivation, NSCs increased p-Akt, but decreased p-ERK which was increased by this damage. Our results demonstrate that exogenous NSCs have anti-apoptotic activities and can rescue cortical neurons by directing cellular survival signaling of neurons into the proper direction, without cell contact.
Ono
Takafumi
T
Department of Neuropsychiatry, School of Medicine, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo 0608543, Japan. tono@sapmed.ac.jp
Hashimoto
Eri
E
Ukai
Wataru
W
Ishii
Takao
T
Saito
Toshikazu
T
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D058953:Neural Stem Cells / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D000077152:Olanzapine; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018709:Statistics, Nonparametric
D014150:Antipsychotic Agents; D002070:Butadienes; D002867:Chromones; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D018696:Neuroprotective Agents; D009570:Nitriles; C113580:U 0126; D001569:Benzodiazepines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016291:Dizocilpine Maleate; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000077152:Olanzapine