| 1 | Neuropsychopharmacology 2007 Jan 32: 95-102 |
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| PMID | 16641945 |
| Title | Caspase-3 activation in rat frontal cortex following treatment with typical and atypical antipsychotics. |
| Abstract | In schizophrenia, studies indicate that apoptotic susceptibility in cortex may be increased. A role for apoptosis in schizophrenia could potentially contribute to post-mortem evidence of reduced cortical neuropil and neuroimaging studies showing progressive cortical gray matter loss. Interestingly, antipsychotic treatment has been associated with higher cortical levels of anti-apoptotic Bcl-2 protein in rat cortex and preliminary data has suggested a similar association in schizophrenia and bipolar disorder. To better understand the effects of antipsychotics on apoptotic regulation, rats were administered haloperidol, clozapine, quetiapine, or saline daily for 4 weeks. Multiple apoptotic markers, including Bcl-2, pro-apoptotic Bax, anti-apoptotic XIAP, and the downstream protease caspase-3 were measured in frontal cortex using Western blot. Caspase-3 activity, activated caspase-3-positive cell number, and DNA/histone fragmentation levels were also determined. Western blot showed that immunoreactivity of Bax and Bcl-2 bands were unchanged with treatment. However, mean density of the 19 kD activated caspase-3 band was 55% higher with haloperidol (p<0.001), 40% higher with clozapine (p<0.05), and 48% higher with quetiapine (p<0.01) compared to saline control. Specific activity of caspase-3 was also increased across all treatments (p<0.0001), while DNA fragmentation rates remained unchanged. These data suggest that sub-chronic antipsychotic treatment is associated with non-lethal caspase-3 activity. The findings do not support a prominent Bcl-2-mediated neuroprotective role for antipsychotics. Although the association between antipsychotic treatment and increased pro-apoptotic caspase-3 is intriguing, further study is needed to understand its potential effects. |
| SCZ Keywords | schizophrenia |
| 2 | Balkan J. Med. Genet. 2014 Dec 17: 15-23 |
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| PMID | 25937794 |
| Title | Genome-wide methylation profiling of schizophrenia. |
| Abstract | schizophrenia is one of the major psychiatric disorders. It is a disorder of complex inheritance, involving both heritable and environmental factors. DNA methylation is an inheritable epigenetic modification that stably alters gene expression. We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution. We have performed 26 high-resolution genome-wide methylation array analyses to determine the methylation status of 27,627 CpG islands and compared the data between patients and healthy controls. Methylation profiles of DNAs were analyzed in six pools: 220 schizophrenia patients; 220 age-matched healthy controls; 110 female schizophrenia patients; 110 age-matched healthy females; 110 male schizophrenia patients; 110 age-matched healthy males. We also investigated the methylation status of 20 individual patient DNA samples (eight females and 12 males. We found significant differences in the methylation profile between schizophrenia and control DNA pools. We found new candidate genes that principally participate in apoptosis, synaptic transmission and nervous system development (GABRA2, LIN7B, CASP3). Methylation profiles differed between the genders. In females, the most important genes participate in apoptosis and synaptic transmission (XIAP, GABRD, OXT, KRT7), whereas in the males, the implicated genes in the molecular pathology of the disease were DHX37, MAP2K2, FNDC4 and GIPC1. Data from the individual methylation analyses confirmed, the gender-specific pools results. Our data revealed major differences in methylation profiles between schizophrenia patients and controls and between male and female patients. The dysregulated activity of the candidate genes could play a role in schizophrenia pathogenesis. |
| SCZ Keywords | schizophrenia |