Differential effects of classical and atypical antipsychotic drugs on rotenone-induced neurotoxicity in PC12 cells.
Although classical and atypical antipsychotics may have different effects against neurotoxicity, the underlying mechanisms remain to be elucidated. In the present study, we compared the atypical agents, risperidone (RIP), olanzapine (OLZ), and quetiapine (QTP), with the classical agent haloperidol (HAL) in reducing cytotoxicity induced by rotenone, a mitochondrial complex I inhibitor, in PC12 cells. We also determined whether there were differential effects of RIP and HAL on the expression of brain-derived neurotrophic factor (BDNF), signal transducers and activators of transcription-3 (STAT-3), and the immediate early gene c-fos, as well as intracellular levels of calcium. Exposure to 6 muM rotenone for 24 h resulted in a significant decrease in cell viability and apoptotic alteration. The rotenone-induced cytotoxicity was dose-dependently worsened by pretreatment with HAL, but significantly improved by the aforementioned atypical agents at low doses. Real-time PCR analysis revealed that HAL pretreatment significantly increased BDNF mRNA expression but did not alter c-fos and STAT-3 expression compared to rotenone-exposed cells. Unlike HAL, RIP pretreatment produced a significant elevation of all the three substance mRNA expression and the expression intensity was 2.6- to 4.6-fold greater than HAL. Pretreatment with RIP, but not HAL, also effectively prevented an elevation of intracellular levels of calcium provoked by rotenone. These results suggest that the protective effects of atypical antipsychotics are associated with a greater capacity to enhance pro-cell survival factors, therapeutic biomarker expression, and blockade of calcium influx. This may provide an alternative for explaining therapeutic advantages of atypical agents observed in clinical use.
Tan
Qing-Rong
QR
Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China. tanqingr@fmmu.edu.cn
Wang
Xin-Zhao
XZ
Wang
Chuan-Yue
CY
Liu
Xiao-Jun
XJ
Chen
Yun-Chun
YC
Wang
Huai-Hai
HH
Zhang
Rui-Guo
RG
Zhen
Xue-Chu
XC
Tong
Yao
Y
Zhang
Zhang-Jin
ZJ
D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000145:classification* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity*; D016716:PC12 Cells / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012402:Rotenone / Q000633:toxicity*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D009498:Neurotoxins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D012402:Rotenone; D002118:Calcium