Neuroprotective effect of olanzapine and fluoxetine in rotenone-induced Parkinson's disease in mice: role of antioxidant systems

Abstract

Background: Depression may antedate motor manifestations of Parkinson's disease (PD) and is usually of moderate or mild intensity. Moreover, depression is of major impact on the quality of life in PD patients according to a recent survey. Conversely, drug-induced psychosis is one of the major therapeutic challenges in Parkinson's disease and may occur in up to 6% in otherwise uncomplicated de novo patients when first receiving dopaminergic therapy.
Objective: This study sought to investigate the protective effect of olanzapine and fluoxetine when used alone or in combination against rotenone-induced Parkinsonism in mice.
Methods: Olanzapine (1, 5, 10 mg/kg), fluoxetine (5, 10, 20 mg/kg) or sub-effective doses of olanzapine (1 mg/kg) or fluoxetine (5 mg/kg, respectively) were given to mice orally for 30 days. PD-like behaviour was induced with rotenone (2 mg/kg, i.p., in sunflower oil for 28 days from day 3). The effects on motor coordination were assessed using open field test (OFT), bar test and rotarod test while memory function was investigated using the elevated plus maze test (EPM). On day 28, animals were sacrificed for biochemical estimation of oxidative and nitrosative stress parameters in the brains.
Results: Acute treatment with olanzapine (1, 5, 10 mg/kg) did not affect blood glucose level. However, coadministration of sub-effective doses of olanzapine (1 mg/kg) and fluoxetine (5 mg/kg) showed significant (P<0.01) increase in the level of blood glucose. Subchronic treatment of mice with olanzapine (1, 5 mg/kg) or fluoxetine (10, 20 mg/kg) significantly attenuated rotenoneinduced catalepsy in mice similar to the effect of trihexyphenidyl (reference drug) between days 8 and 16. However, by day 24 of treatment, olanzapine (5, 10 mg/kg) showed a dose-dependent increase in rotenone-induced catalepsy but not fluoxetine or olanzapine-fluoxetine combination. In addition, rotenone induced significant (p<0.01) motor deficit which was reversed by olanzapine (1 mg/kg) but not 5 and 10 mg/kg treatment in OFT. Moreover, fluoxetine treatment enhanced ambulatory activity of the animals. However, pretreatment of mice with olanzapine (1, 5, 10 mg/kg) and fluoxetine (5, 10, 20 mg/kg) failed to prevent rotenone-induced memory deficit on days 9 and 10. In contrast, rotenone increased (P<0.001) brain malondialdehyde and nitrite generation with concomitant decrease in the level of reduced glutathione, catalase and superoxide dismutase. Conversely, olanzapine (1, 5 mg/kg) or fluoxetine (10, 20 mg/kg) treatment significantly attenuated the effect of rotenone.
Conclusion: These findings suggest that olanzapine and fluoxetine (alone or in combination) could protect against rotenone-induced motor deficit through enhancement of  brain antioxidant systems. Thus suggesting that olanzapine and fluoxetine could be used as adjuvants in the treatment of PD.

Keywords: Rotenone; elevated plus maze; bar test; glutathione; malondialdehyde