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.
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Acknowledgements
Research supported by grants from NIMH MH-01752 (LFJ) and the Investigator Sponsored Trial Program of AstraZeneca (LFJ).
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Presented in part at the Society of Biological Psychiatry, 59th Annual Meeting, New York, NY, April 30, 2004; American College of Neuropsychopharmacology, 43rd Annual Meeting, San Juan, PR, December 14, 2004
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Jarskog, L., Gilmore, J., Glantz, L. et al. Caspase-3 Activation in Rat Frontal Cortex Following Treatment with Typical and Atypical Antipsychotics. Neuropsychopharmacol 32, 95–102 (2007). https://doi.org/10.1038/sj.npp.1301074
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DOI: https://doi.org/10.1038/sj.npp.1301074
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