PI3K/AKT/JNK/p38 signalling pathway‐mediated neural apoptosis in the prefrontal cortex of mice is involved in the antidepressant‐like effect of pioglitazone |
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Authors: | Jie Li Bing Xu Zhi Chen Chanjuan Zhou Li Liao Yinghua Qin Chuangchuang Yang Xiaodong Zhang Zicheng Hu Lin Sun Dan Zhu Peng Xie |
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Affiliation: | 1. Chongqing Key Laboratory of Neurobiology, Chongqing, China;2. Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, Chongqing Medical University, Chongqing, China;3. Department of Neurology, Yongchuan Hospital of Chongqing Medical University, Chongqing, China;4. Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China;5. Key Laboratory of Laboratory Medical Diagnostics of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing, China |
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Abstract: | Numerous studies have reported that inflammation is involved in the pathophysiology of depression. Pioglitazone, a PPAR‐γ agonist, has potential anti‐inflammatory and antidepressive effects. However, the underlying molecular mechanisms of the antidepressant‐like effect of pioglitazone on an inflammation‐related mouse model of depression remain to be fully elucidated. Herein, we aimed to explore the effects of pioglitazone on depressive‐like behaviours of mice exposed to lipopolysaccharides (LPS), and elucidate the underlying mechanisms. We assessed behaviour changes of mice pretreated with pioglitazone exposed to LPS. Additionally, neural apoptosis, and the expression of apoptosis‐related (cleaved caspase‐3, Bax, Bcl‐2, cyt c) and signalling proteins (AKT, JNK, p38) were assessed in the prefrontal cortex (PFC) of these mice. Furthermore, we assessed the influence of anisomycin, a JNK/p38 agonist, and LY294002, a PI3K/AKT inhibitor, on the antidepressant‐like effect of pioglitazone in mice. We show that pioglitazone pretreatment (20 mg/kg, intragastrically) attenuated LPS‐induced (10 ng/μL per site) depressive‐like behaviours. GW9662, a PPAR‐γ antagonist, significantly blocked the antidepressant‐like effect of pioglitazone. Furthermore, at the molecular level, pioglitazone significantly reversed, via PPAR‐γ‐dependent increase in neural apoptosis in the PFC of mice, accompanied by upregulation of the PI3K/AKT pathway and down‐regulation of the JNK/p38 pathway. Moreover, both anisomycin and LY294002 abrogated the antidepressant‐like effect of pioglitazone.; In conclusion, our results showed that PI3K/AKT/JNK/p38 signalling pathway‐mediated neural apoptosis in the PFC of mice may be involved in the antidepressant‐like effect of pioglitazone. This provides novel insights into and therapeutic targets for inflammation‐related depression. |
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Keywords: | inflammation‐related depression JNK/p38 neural apoptosis PI3K/AKT pioglitazone |
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