α-7烟碱受体正性异位调节剂PNU120596通过调节PPAR-α信号通路减轻脂多糖诱发的小鼠抑郁样行为和认知障碍

Sami Alzarea, Shafiqur Rahman
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引用次数: 0

摘要

背景和目的:大脑α7烟碱乙酰胆碱受体(α7 nAChR)在涉及神经炎症的重度抑郁症(MDD)病理生理学中起着关键作用。研究表明,α7 nAChR刺激可通过其在大脑中的内源性配体调节核过氧化物酶体增殖激活受体-α(PPAR-α)的抗炎作用。本研究确定了α7 nAChR调节剂PNU120596对PPAR-α、κB(IκB)和核因子-κB(NF-κB)表达抑制剂以及白细胞介素-1β(IL-1β)水平的影响。我们还评估了 PNU120596 和 PPAR-α 拮抗剂 GW6471 对小鼠抑郁样行为和认知缺陷样行为的联合影响:雄性 C57BL/6J 小鼠接受 PNU120596 治疗,然后全身注射 LPS(1 毫克/千克,静注)。给药 LPS 后,使用 qRT-PCR 评估 PNU120596 对海马和前脑功能区 PPAR-α 和 IκB mRNA 表达的影响。同样,PNU120596 对 PPAR-α 和 NF-κB 免疫活性的影响也是通过免疫荧光法测定的。此外,还使用酶联免疫吸附法测定了 PNU120596 对海马和全脑功能区促炎细胞因子 IL-1β 水平的影响。还使用尾悬试验(TST)、强迫游泳试验(FST)和Y-迷宫试验评估了PNU120596和GW6471对LPS诱导的抑郁样和认知缺陷样行为的联合作用:结果:PNU120596(4 毫克/千克)能显著预防 LPS 引起的海马和前脑功能区 PPAR-α、IκB、p-NF-κB p65 和 IL-1β 的失调。PNU120596的预处理通过减少TST和FST中的静止时间而显示出显著的抗抑郁样作用。同样,PNU120596也能显著减少Y迷宫测试中的认知缺陷行为。PPAR-α拮抗剂GW6471(2 mg/kg)可逆转PNU120596的抗抑郁和促进认知类行为的作用:这些结果表明,PNU120596通过调节海马和前脑功能区的α7 nAChR/PPAR-α信号通路,预防了LPS诱导的MDD和认知样行为。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Alpha-7 Nicotinic Receptor Positive Allosteric Modulator PNU120596 Attenuates Lipopolysaccharide-Induced Depressive-Like Behaviors and Cognitive Impairment by Regulating the PPAR-α Signaling Pathway in Mice.

Background and objective: The brain α7 nicotinic acetylcholine receptor (α7 nAChR) has a critical role in the pathophysiology of Major Depressive Disorder (MDD) involving neuroinflammation. The α7 nAChR stimulation has been shown to modulate the anti-inflammatory effects of nuclear peroxisome proliferator-activated receptor-α (PPAR-α) via its endogenous ligands in the brain. The present study determined the effects of α7 nAChR modulator PNU120596 on PPAR-α, an inhibitor of κB (IκB) and nuclear factor-κB (NF-κB) expression and interleukin-1β (IL-1β) level in the hippocampus and prefrontal cortex (PFC) in an inflammatory mouse model of MDD induced by lipopolysaccharide (LPS). We also evaluated the combined effects of PNU120596 and GW6471, a PPAR-α antagonist, on depressive-like and cognitive deficit-like behaviors in mice.

Materials and methods: Male C57BL/6J mice were treated with PNU120596, followed by systemic LPS (1 mg/kg, i.p.) administration. The effects of PNU120596 on the mRNA expression of PPAR-α and IκB were assessed in the hippocampus and PFC using qRT-PCR following LPS administration. Similarly, the effects of PNU120596 on the immunoreactivity of PPAR-α and NF-κB were measured in the hippocampus and PFC using an immunofluorescence assay. Furthermore, the effects of PNU120596 on pro-inflammatory cytokine IL-1β levels were measured in the hippocampus and PFC using ELISA. The combined effects of PNU120596 and GW6471 were also assessed against LPS-induced depressive-like and cognitive deficit-like behaviors using the Tail Suspension Test (TST), Forced Swim Test (FST), and Y-maze test.

Results: PNU120596 (4 mg/kg) significantly prevented LPS-induced dysregulation of PPAR-α, IκB, p-NF-κB p65, and IL-1β in the hippocampus and PFC. Pretreatment with PNU120596 showed significant antidepressant-like effects by reducing immobility time in the TST and FST. Similarly, pretreatment with PNU120596 significantly reduced cognitive deficit-like behavior in the Y-maze test. The antidepressant and pro-cognitive-like effects of PNU120596 were reversed by PPAR-α antagonist GW6471 (2 mg/kg).

Conclusion: These results suggest that PNU120596 prevented LPS-induced MDD and cognitivelike behavior by regulating α7 nAChR/PPAR-α signaling pathway in the hippocampus and PFC.

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