Olanzapine and quetiapine protect PC12 cells from β-amyloid peptide25-35-induced oxidative stress and the ensuing apoptosis

We previously found that the atypical antipsychotic drugs (APDs) clozapine, olanzapine, quetiapine, and risperidone reduce PC12 cell death induced by hydrogen peroxide, N-methyl-4-phenylpyridinium ion, or β-amyloid peptide (Aβ25–35). Such neurotoxic substances have in common the capability of causing oxidative stress. Atypical APDs have been used in treating schizophrenia and in treating psychotic symptoms of patients with Alzheimer's disease (AD), in which Aβ is involved by causing oxidative stress. Therefore, we hypothesized that atypical APDs might alleviate oxidative stress in PC12 cells, thus protecting them from apoptosis. PC12 cells were seeded in plates or chambers for 24 hr and cultured for another 24 hr with olanzapine or quetiapine in the medium, and then the cells were cultured in the new medium containing Aβ25–35 and/or olanzapine, quetiapine, but not serum, for various periods. It was shown that cultures treated with olanzapine + Aβ25–35, or quetiapine + Aβ25–35, had significantly higher cell viabilities and lower rates of apoptosis compared with the cultures exposed only to Aβ25–35. In addition, the drugs blocked the activation of caspase-3 caused by Aβ25–35. Furthermore, olanzapine and quetiapine prevented Aβ25–35-induced overproduction of intracellular reactive oxygen species, Aβ25–35-induced decrease in mitochondrial membrane potential, and Aβ25–35-induced changes in activities of the key antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. In consideration of the wealth of evidence linking oxidative stress to the pathophysiology of schizophrenia and AD, these findings give us a new insight into the therapeutic actions of atypical antipsychotics in patients with the disorders. © 2005 Wiley-Liss, Inc.