Purpose: Recent clinical studies have suggested that treatment with second generation antipsychotic drugs such as olanzapine may prevent progressive alterations of brain structure in patients with schizophrenia. However, the molecular mechanisms underlying these different effects remain to be determined. We investigated the mechanisms of action of olanzapine and haloperidol, on serum withdrawal apoptosis in human neuroblastoma SH-SY5Y cells.
Methods: SH-SY5Y cells were cultured with olanzapine and haloperidol in medium with or without serum. We determined the effects of the drugs on cell viability against serum withdrawal by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Additionally, to explore the drugs' actions, Western blot was performed to examine the expression of key genes involved in GSK-3beta-mediated signaling, notably GSK-3beta, beta-catenin, and Bcl-2.
Results: SH-SY5Y cells suffered about a 38% loss in cell number under serum-free conditions for 48 h. Olanzapine (10-200 muM) up to 100 muM significantly attenuated serum withdrawal-induced cell loss (p<0.01), and a dose of 100 muM also increased cell viability (p<0.05). In contrast, haloperidol (0.01-10 muM) did not affect cell viability but exacerbated cell death at 10 muM under serum-free conditions (p<0.01). Western blot analysis showed that olanzapine, but not haloperidol, prevented the serum withdrawal-induced decrease in levels of neuroprotective proteins such as p-GSK-3beta, beta-catenin, and Bcl-2 (p<0.01), whereas haloperidol robustly reduced the levels of these proteins at a 10 muM dose in serum-starved cells (p<0.05). Moreover, olanzapine alone significantly increased phosphorylation of GSK-3beta under normal conditions (p<0.05).
Conclusions: This study showed that olanzapine may have neuroprotective effects, whereas haloperidol was apparently neurotoxic. The actions of signaling systems associated with GSK-3beta may be key targets for olanzapine and haloperidol, but their effects are distinct. These differences suggest different therapeutic effects of first and second generation antipsychotic drugs in patients with schizophrenia.