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Neuroprotective effects of olanzapine against rotenone-induced toxicity in PC12 cells
Ya-Jie Xiong1, Yun-Zhen Song1, Ying Zhu2
1Department of Pharmacology, Soochow University, Suzhou, 215000, China.
Abstract:
Olanzapine is an antipsychotic drug used to treat patients with schizophrenia due to its lower incidence of extrapyramidal symptoms. Previous studies have shown that olanzapine activates AMP-activated protein kinase (AMPK), and induce autophagy in SH-SY5Y cell line. In this study, we investigated whether olanzapine protected against rotenone-induced neurotoxicity in PC12 cells. We showed that treatment with olanzapine increased the phosphorylation of AMPK in both dose- and time-dependent manners in PC12 cells. In addition, olanzapine activated autophagy and increased autophagic vacuoles. Furthermore, olanzapine pretreatment could protect PC12 cells from rotenone-induced apoptosis. Besides, olanzapine pretreatment could suppress the rotenone-induced depolarization of mitochondrial potential and thus protect the cells. Moreover, pretreatment with specific AMPK inhibitor compound C or with autophagy inhibitor 3-methyladenine impaired the protective effect of olanzapine on rotenone-treated PC12 cells. In summary, our results show for the first time that olanzapine ameliorates rotenone-induced injury by activating autophagy through AMPK pathway.
Insights
Olanzapine protects against rotenone-induced neurotoxicity by activating AMP-activated protein kinase (AMPK) and autophagy in PC12 cells. This antipsychotic drug may offer a novel therapeutic strategy for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Olanzapine is an antipsychotic medication for schizophrenia, known for fewer extrapyramidal symptoms.
- Previous research indicates olanzapine activates AMP-activated protein kinase (AMPK) and induces autophagy in neuronal cell lines.
Purpose of the Study:
- To investigate the neuroprotective effects of olanzapine against rotenone-induced toxicity in PC12 cells.
- To elucidate the role of AMPK and autophagy in mediating olanzapine's protective mechanisms.
Main Methods:
- PC12 cells were treated with olanzapine and/or rotenone.
- AMPK phosphorylation, autophagy activation, autophagic vacuoles, apoptosis, and mitochondrial membrane potential were assessed.
- Specific inhibitors for AMPK (Compound C) and autophagy (3-methyladenine) were used to block pathways.
Main Results:
- Olanzapine treatment increased AMPK phosphorylation and activated autophagy in PC12 cells.
- Olanzapine pretreatment protected PC12 cells from rotenone-induced apoptosis and mitochondrial dysfunction.
- Inhibition of AMPK or autophagy abolished the neuroprotective effects of olanzapine.
Conclusions:
- Olanzapine demonstrates neuroprotective effects against rotenone-induced injury in PC12 cells.
- These protective effects are mediated through the activation of the AMPK-autophagy pathway.
- Olanzapine's mechanism involves enhancing cellular defense against oxidative stress and mitochondrial damage.
