TY - JOUR
T1 - Long-term antipsychotic treatments and crossover studies in rats
T2 - Differential effects of typical and atypical agents on the expression of antioxidant enzymes and membrane lipid peroxidation in rat brain
AU - Pillai, Anilkumar
AU - Parikh, Vinay
AU - Terry, Alvin V.
AU - Mahadik, Sahebarao P.
N1 - Funding Information:
Dr. Nabil F. Al-Baldawi and Mr. Mathew R. Elliott are acknowledged for their some initial ELISA studies. This work was partially supported by Janssen Pharmaceutica Research Foundation and Eli Lilly and Company. The authors acknowledge Pfizer for providing Ziprasidone as a gift.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/8
Y1 - 2007/8
N2 - Short-term (<45 days) treatment studies in rats have reported increased oxidative stress and oxidative (i.e., oxygen free radical-mediated) neural cell injury with typical antipsychotics such as haloperidol, but not with the atypicals such as clozapine, olanzapine or risperidone. However, now these and several other atypical antipsychotics that differ in their neurotransmitter receptor affinity profiles are being used for a long-term treatment of schizophrenia. Therefore, understanding of their long-term treatment effects on the expression of antioxidant enzymes and oxidative neural cell injury in rats may be important to explain the possible differential mechanisms underlying their long-term clinical and side effects profiles. The effect of 90 and 180 day exposure to haloperidol (HAL, 2 mg/kg/day), a representative typical antipsychotic was compared to exposure to chlorpromazine (CPZ, 10 mg/kg/day), ziprasidone (ZIP, 12 mg/kg/day), risperidone (RISP, 2.5 mg/kg/day), clozapine (CLOZ, 20 mg/kg/day) or olanzapine (OLZ, 10 mg/kg/day) on the expression of antioxidant defense enzymes and levels of lipid peroxidation in the rat brain. The drug-induced effects on various antioxidant defense enzymes; manganese-superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT) were assessed by determination of their enzymatic activity and protein content. Immunohistochemical analysis was also carried out to assess the cellular levels of MnSOD and CuZnSOD and cellular morphology. The oxidative membrane damage was assessed by determination of levels of the lipid peroxidation product, hydroxyalkanals (HAEs) in the rat brain. Both 90 and 180 days of HAL treatment very significantly decreased the levels of MnSOD (50%) and CuZnSOD (80%) and increased the levels of HAEs compared to vehicle treatment. Smaller reduction was found in CAT (25%) and no change in the glutathione peroxidase (GSHPx). The levels of enzymatic activity correlated generally well with the levels of enzyme protein indicating that the changes were in the expression of net protein. Though atypical antipsychotics like ZIP, RISP and OLZ did not show any change in the HAEs levels up to 90 days, further treatment up to 180 days resulted in significantly increased levels of HAEs in CPZ, ZIP and RISP, but not in OLZ treated rats. Post-treatment with several atypical antipsychotics (OLZ = CLOZ > RISP) for 90 days after 90 day of HAL treatment significantly restored the HAL-induced loss in MnSOD and CuZnSOD activities and increase in lipid peroxidation products as well as cellular morphology. These data may be very helpful in planning long-term use as well as switch over of these antipsychotics for the management of schizophrenia.
AB - Short-term (<45 days) treatment studies in rats have reported increased oxidative stress and oxidative (i.e., oxygen free radical-mediated) neural cell injury with typical antipsychotics such as haloperidol, but not with the atypicals such as clozapine, olanzapine or risperidone. However, now these and several other atypical antipsychotics that differ in their neurotransmitter receptor affinity profiles are being used for a long-term treatment of schizophrenia. Therefore, understanding of their long-term treatment effects on the expression of antioxidant enzymes and oxidative neural cell injury in rats may be important to explain the possible differential mechanisms underlying their long-term clinical and side effects profiles. The effect of 90 and 180 day exposure to haloperidol (HAL, 2 mg/kg/day), a representative typical antipsychotic was compared to exposure to chlorpromazine (CPZ, 10 mg/kg/day), ziprasidone (ZIP, 12 mg/kg/day), risperidone (RISP, 2.5 mg/kg/day), clozapine (CLOZ, 20 mg/kg/day) or olanzapine (OLZ, 10 mg/kg/day) on the expression of antioxidant defense enzymes and levels of lipid peroxidation in the rat brain. The drug-induced effects on various antioxidant defense enzymes; manganese-superoxide dismutase (MnSOD), copper-zinc superoxide dismutase (CuZnSOD) and catalase (CAT) were assessed by determination of their enzymatic activity and protein content. Immunohistochemical analysis was also carried out to assess the cellular levels of MnSOD and CuZnSOD and cellular morphology. The oxidative membrane damage was assessed by determination of levels of the lipid peroxidation product, hydroxyalkanals (HAEs) in the rat brain. Both 90 and 180 days of HAL treatment very significantly decreased the levels of MnSOD (50%) and CuZnSOD (80%) and increased the levels of HAEs compared to vehicle treatment. Smaller reduction was found in CAT (25%) and no change in the glutathione peroxidase (GSHPx). The levels of enzymatic activity correlated generally well with the levels of enzyme protein indicating that the changes were in the expression of net protein. Though atypical antipsychotics like ZIP, RISP and OLZ did not show any change in the HAEs levels up to 90 days, further treatment up to 180 days resulted in significantly increased levels of HAEs in CPZ, ZIP and RISP, but not in OLZ treated rats. Post-treatment with several atypical antipsychotics (OLZ = CLOZ > RISP) for 90 days after 90 day of HAL treatment significantly restored the HAL-induced loss in MnSOD and CuZnSOD activities and increase in lipid peroxidation products as well as cellular morphology. These data may be very helpful in planning long-term use as well as switch over of these antipsychotics for the management of schizophrenia.
KW - Antioxidant enzymes
KW - Atypical antipsychotics
KW - Brain
KW - Lipid peroxidation
KW - Oxidative stress
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U2 - 10.1016/j.jpsychires.2006.01.011
DO - 10.1016/j.jpsychires.2006.01.011
M3 - Article
C2 - 16564057
AN - SCOPUS:33846847640
SN - 0022-3956
VL - 41
SP - 372
EP - 386
JO - Journal of Psychiatric Research
JF - Journal of Psychiatric Research
IS - 5
ER -