| 1 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Dec 35: 1950-6 |
|---|
| PMID | 21839137 |
| Title | Olanzapine stimulates proliferation but inhibits differentiation in rat oligodendrocyte precursor cell cultures. |
| Abstract | In the developing brain, oligodendrocyte progenitor cells (OPCs) proliferate, migrate, and differentiate into mature oligodendrocytes (OLs) capable of myelinating axons. Recently, OPCs have been identified as an abundant and widespread population in the adult as well as in the developing animal. Current research indicates that these OPCs in the adult brain can proliferate and differentiate into myelinating OLs, albeit with different potentialities from those in developing animals. Multiple lines of evidence, from neuroimaging, postmortem, and genetic association studies, have implicated OL and myelin dysfunction in the pathogenesis of schizophrenia. If altered OL function is involved in pathogenesis, OPCs may thus respond to antipsychotic drugs during the recovery process. In the present study, we used primary OPC cultures from optic nerve of newborn Wistar rat pups to investigate the direct effects of haloperidol (HPD; a typical antipsychotic) and olanzapine (OLZ; an atypical antipsychotic) on the proliferation and differentiation of OPCs. Our results showed that 1) OLZ treatment significantly increased the number of viable OPCs when compared to HPD treatment at relatively high concentrations, 2) OLZ treatment suppressed the expression of myelin basic protein (MBP), and to a greater extent than HPD treatment, and 3) these pharmacological effects may be mediated via the ERK signaling pathway. Our findings suggest a glial mechanism for the antipsychotic action of OLZ, and a role for oligodendrocyte-lineage cells in the pathogenesis and treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Schizophr. Res. 2011 Jan 125: 77-87 |
|---|
| PMID | 20833512 |
| Title | Effects of aripiprazole and haloperidol on progression to schizophrenia-like behavioural abnormalities and apoptosis in rodents. |
| Abstract | Aripiprazole (APZ) is considered a first-line medication for treating first and multiple episodes of schizophrenia, but its effect on preventing the progressive pathophysiology of schizophrenia remains unclear. This study examined the hypothesis that APZ blocks enhanced glutamate release in the medial prefrontal cortex (mPFC) during psychotic episodes of schizophrenia, thereby preventing progression of the pathophysiology. We examined effects of APZ on methamphetamine (METH)-induced increases in glutamate levels in the mPFC, and on repeatedly administered METH-induced progression to schizophrenia-like behavioural abnormalities involving cross-sensitization to the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, deficit of prepulse inhibition (PPI), and expression of TUNEL-positive cells. Additionally, we compared the preventive effects of APZ to those of a conventional antipsychotic: haloperidol (HPD). Results show that APZ (1.0 and 3.0 mg/kg) and HPD (0.1 mg/kg) each blocked METH (2.5 mg/kg)-induced increases in glutamate levels in the mPFC. Furthermore, APZ (3.0 mg/kg) and HPD (0.1 mg/kg), when co-administered repeatedly with METH, each prevented progression to schizophrenia-like behavioural and neuropathological abnormalities. Repeated co-administration of APZ (3.0 mg/kg) with saline did not induce apoptosis, although HPD (0.1 mg/kg) with saline did induce apoptosis. These results indicate that APZ and HPD prevented progressive pathophysiology, which is related to increased glutamate levels, and indicate that repeated administration of HPD, but not APZ, induced apoptosis under conditions without increased glutamate levels. These findings suggest the importance of using APZ and HPD in the appropriate stages of the glutamate-related pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | ISRN Psychiatry 2012 -1 2012: 947149 |
|---|
| PMID | 23738215 |
| Title | T-817MA, but Not Haloperidol and Risperidone, Restores Parvalbumin-Positive ? -Aminobutyric Acid Neurons in the Prefrontal Cortex and Hippocampus of Rats Transiently Exposed to MK-801 at the Neonatal Period. |
| Abstract | The number of parvalbumin (PV)-positive ? -aminobutyric acid (GABA) neurons is decreased in the brain of rats transiently exposed to MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, in the neonatal stage (Uehara et al. (2012)). T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate] is a neuroprotective agent synthesized for the treatment of psychiatric disorders characterized by cognitive disturbances, such as dementia. We herein sought to determine whether T-817MA, haloperidol (HPD), or risperidone (RPD) would ameliorate the decrease in the number of PV-positive GABA neurons in the medial prefrontal cortex (mPFC) and hippocampus of the model animals. Rats were treated with MK-801 (0.2?mg/kg/day) or vehicle on postnatal days (PD) 7-10, and the number of PV-positive neurons in the mPFC and hippocampus were measured on PDs 63. T-817MA (20?mg/kg), HPD (1?mg/kg), or RPD (1?mg/kg) were administered during PDs 49-62. Fourteen-day administration of T-817MA reversed the decrease in the number of PV-positive neurons in the above brain regions of rats given MK-801, whereas HPD and RPD were ineffective. These results indicate that T-817MA provides a novel pharmacologic strategy to enhance cognitive function in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Transl Psychiatry 2012 -1 2: e119 |
|---|
| PMID | 22832963 |
| Title | 13C-phenylalanine breath test detects altered phenylalanine kinetics in schizophrenia patients. |
| Abstract | Phenylalanine is an essential amino acid required for the synthesis of catecholamines including dopamine. Altered levels of phenylalanine and its metabolites in blood and cerebrospinal fluid have been reported in schizophrenia patients. This study attempted to examine for the first time whether phenylalanine kinetics is altered in schizophrenia using L-[1-(13)C]phenylalanine breath test ((13)C-PBT). The subjects were 20 chronically medicated schizophrenia patients (DSM-IV) and the same number of age- and sex-matched controls. (13)C-phenylalanine (99 atom% (13)C; 100 mg) was administered orally and the breath (13)CO(2) /(12)CO(2) ratio was monitored for 120 min. The possible effect of antipsychotic medication (risperidone (RPD) or haloperidol (HPD) treatment for 21 days) on (13)C-PBT was examined in rats. Body weight (BW), age and diagnostic status were significant predictors of the area under the curve of the time course of ?(13)CO(2) (?) and the cumulative recovery rate (CRR) at 120 min. A repeated measures analysis of covariance controlled for age and BW revealed that the patterns of CRR change over time differed between the patients and controls and that ?(13)CO(2) was lower in the patients than in the controls at all sampling time points during the 120 min test, with an overall significant difference between the two groups. Chronic administration of RPD or HPD had no significant effect on (13)C-PBT indices in rats. Our results suggest that (13)C-PBT is a novel laboratory test that can detect altered phenylalanine kinetics in chronic schizophrenia patients. Animal experiments suggest that the observed changes are unlikely to be attributable to antipsychotic medication. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 117-23 |
|---|
| PMID | 24099786 |
| Title | Impaired empathic abilities and reduced white matter integrity in schizophrenia. |
| Abstract | Empathic abilities are impaired in schizophrenia. Although the pathology of schizophrenia is thought to involve disrupted white matter integrity, the relationship between empathic disabilities and altered white matter in the disorder remains unclear. The present study tested associations between empathic disabilities and white matter integrity in order to investigate the neural basis of impaired empathy in schizophrenia. Sixty-nine patients with schizophrenia and 69 age-, gender-, handedness-, education- and IQ level-matched healthy controls underwent diffusion-weighted imaging. Empathic abilities were assessed using the Interpersonal Reactivity Index (IRI). Using tract-based spatial statistics (TBSS), the associations between empathic abilities and white matter fractional anisotropy (FA), a measure of white matter integrity, were examined in the patient group within brain areas that showed a significant FA reduction compared with the controls. The patients with schizophrenia reported lower perspective taking and higher personal distress according to the IRI. The patients showed a significant FA reduction in bilateral deep white matter in the frontal, temporal, parietal and occipital lobes, a large portion of the corpus callosum, and the corona radiata. In schizophrenia patients, fantasy subscales positively correlated with FA in the left inferior fronto-occipital fasciculi and anterior thalamic radiation, and personal distress subscales negatively correlated with FA in the splenium of the corpus callosum. These results suggest that disrupted white matter integrity in these regions constitutes a pathology underpinning specific components of empathic disabilities in schizophrenia, highlighting that different aspects of empathic impairments in the disorder would have, at least partially, distinct neuropathological bases. |
| SCZ Keywords | schizophrenia, schizophrenic |