Differential effects of ziprasidone and haloperidol on immobilization-stress-induced CRF mRNA expression in the hypothalamic paraventricular nucleus of rats.

OBJECTIVES: Corticotropin-releasing factor (CRF) plays a prominent role in mediating the effect of stressors on the hypothalamic-pituitary-adrenal axis. In this study, we examined the effects of chronic administration of second-generation antipsychotic drug ziprasidone on CRF mRNA expression in the hypothalamic paraventricular nucleus (PVN) of rats with or without immobilization stress. METHODS: The rats were subjected to immobilization stress 2 h/day for 3 weeks. The effect of ziprasidone (2.5 mg/kg, 21 days) on CRF mRNA expression was determined using in situ hybridization of tissue sections from the rat hypothalamic PVN. Haloperidol (1.0 mg/kg, 21 days) was used for comparison. RESULTS: Haloperidol increased the expression of CRF mRNA in the PVN under basal conditions, whereas ziprasidone had no effect. Chronic immobilization stress increased CRF expression. The chronic administration of ziprasidone prevented the increase in CRF mRNA expression caused by immobilization stress. CONCLUSIONS: These results suggest that ziprasidone may have a regulatory effect on the stress-induced CRF mRNA expression and a role in the treatment of depressive mood symptom.

Effects of olanzapine on brain-derived neurotrophic factor gene promoter activity in SH-SY5Y neuroblastoma cells.

PURPOSE: Atypical antipsychotics have neuroprotective effects, which may be one of the mechanisms for their success in the treatment of schizophrenia. Growing evidence suggest that brain-derived neurotrophic factor (BDNF) is abnormally regulated in patients with schizophrenia, and its expression can be up-regulated by atypical antipsychotics. Atypical antipsychotic drugs may positively regulate transcription of the BDNF gene, but the molecular mechanism of atypical antipsychotic drug action on BDNF gene activity has not been investigated. The aim of the present study was to explore the possible involvement of some intracellular signaling pathways in olanzapine action on BDNF promoter activity. METHODS: We examined the effects of olanzapine on BDNF gene promoter activity in SH-SY5Y cells transfected with a rat BDNF promoter fragment (-108 to +340) linked to the luciferase reporter gene. The changes in glycogen synthase kinase-3beta (GSK-3beta) and cAMP response element (CRE) binding protein (CREB) phosphorylation were measured by Western blot analysis. RESULTS: Olanzapine treatment (10-100 microM) increased basal BDNF gene promoter activity in a dose-dependent manner and increased protein levels at high dose, and inhibitors of protein kinase A (PKA), H-89 (10 microM), phosphatidylinositol 3-kinase (PI3K), wortmannin (0.01 microM), PKC (protein kinase C), GF109203 (10 microM), calcium/calmodulin kinase II (CaMKII), and KN-93 (20 microM) partially attenuated the stimulatory effect of olanzapine on BDNF promoter activity. In line with these results, a Western blot study showed that olanzapine (100 microM) increased phosphorylated levels of GSK-3beta and CREB, which are notable downstream effectors of the PKA, PI3K, PKC, and CaMKII signaling pathways. CONCLUSIONS: These results demonstrate that the up-regulation of olanzapine on BDNF gene transcription is linked with enhancement of CREB-mediated transcription via PKA, PI3K, PKC, and CaMKII signaling pathways, and olanzapine may exert neuroprotective effects through these signaling pathways in neuronal cells.

Clinical effectiveness of the Kampo medicine kamishoyosan for adjunctive treatment of tardive dyskinesia in patients with schizophrenia: a 16-week open trial.

The purpose of the present study was to evaluate the clinical effectiveness of kamishoyosan for antipsychotic-induced tardive dyskinesia, and to investigate the relationship between tardive dyskinesia and serum brain-derived neurotrophic factor (BDNF) levels. Sixty-nine schizophrenia patients were enrolled; of these, 49 presented with tardive dyskinesia while the remaining 20 patients showed no tardive dyskinesia. The tardive dyskinesia group was treated for 16 weeks with kamishoyosan and assessed using the abnormal involuntary movement scale. The abnormal involuntary movement scale scores in the tardive dyskinesia group were evaluated at baseline and after 4, 8, and 16 weeks of treatment. The BDNF levels of all subjects were measured at baseline in order to compare differences in serum BDNF levels between the tardive dyskinesia group and the non-tardive dyskinesia group, and to correlate the severity of tardive dyskinesia and serum BDNF in the tardive dyskinesia group. A meaningful reduction in total abnormal involuntary movement scale scores was observed in the tardive dyskinesia group treated with kamishoyosan at 4, 8, and 16 weeks of treatment (P < 0.01). No significant differences in serum BDNF levels were detected between the tardive dyskinesia group and the non-tardive dyskinesia group at baseline. Furthermore, no significant correlation was seen between the severity of tardive dyskinesia and serum BDNF levels. The present study suggests that kamishoyosan might be a promising adjunctive treatment for antipsychotic-induced tardive dyskinesia.

Antidepressant-like effects of the traditional Chinese medicine kami-shoyo-san in rats.

Kami-shoyo-san (KSS), a traditional Chinese medicine, has been used to treat patients with neuropsychiatric disorders. The aim of the present paper was to investigate whether KSS has antidepressant-like effects, and to assess its mechanism of action, using male Sprague-Dawley rats given 10-fold (KSS 10X) or 20-fold (KSS 20X) the typical human daily dosage. Immobility time was measured by the forced swimming test, and hippocampal neurogenesis was quantified under immobilization stress. Rats given KSS 20X, but not those given KSS 10X, had a significantly lower immobility time and improved neurogenesis in the hippocampus. These results suggest that KSS possesses an antidepressant-like effect at a behavioral and molecular level.