Olanzapine and quetiapine protect PC12 cells from beta-amyloid peptide(25-35)-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 beta-amyloid peptide (Abeta(25-35)). 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 Abeta 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 Abeta(25-35) and/or olanzapine, quetiapine, but not serum, for various periods. It was shown that cultures treated with olanzapine + Abeta(25-35), or quetiapine + Abeta(25-35), had significantly higher cell viabilities and lower rates of apoptosis compared with the cultures exposed only to Abeta(25-35). In addition, the drugs blocked the activation of caspase-3 caused by Abeta(25-35). Furthermore, olanzapine and quetiapine prevented Abeta(25-35)-induced overproduction of intracellular reactive oxygen species, Abeta(25-35)-induced decrease in mitochondrial membrane potential, and Abeta(25-35)-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.
Wang
Haitao
H
Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Xu
Haiyun
H
Dyck
Lillian E
LE
Li
Xin-Min
XM
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001569:Benzodiazepines / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003987:Dibenzothiazepines / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D000077152:Olanzapine; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology*; D000069348:Quetiapine Fumarate; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C074636:amyloid beta-protein (25-35); D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D000077152:Olanzapine