Loss of dopaminergic neurons following Parkinson's disease (PD) diminishes quality of life in patients. The present study was carried out to investigate the protective effects of simultaneous inhibition of dipeptidyl peptidase-4 (DPP-4) and P2X7 purinoceptors in a PD model and explore possible mechanisms. The 6-hydroxydopamine (6-OHDA) was used as a tool to establish PD model in male Wister rats. The expressions of SIRT1, SIRT3, mTOR, PGC-1α, PTEN, P53 and DNA fragmentation were evaluated by ELISA assay. Behavioral impairments were determined using apomorphine-induced rotational and narrow beam tests. Dopamine synthesis and TH-positive neurons were detected by tyrosine hydroxylase (TH) immunohistochemistry. Neuronal density was determined by Nissl staining. OHDA-lesioned rats exhibited behavioral impairments that reversed by BBG, lin and lin + BBG. We found significant reduced levels of SIRT1, SIRT3, PGC-1α and mTOR in both mid brain and striatum from OHDA-lesioned rats that reversed by BBG, lin and lin + BBG. Likewise, significant increased levels of PTEN and P53 were found in both mid brain and striatum from OHDA-lesioned rats that was reversed by BBG, lin and lin + BBG. TH-positive neurons and neuronal density were markedly reduced OHDA-lesioned rats that reversed by BBG, lin and lin + BBG. Collectively, our results showed protective effects of simultaneous inhibition of DPP-4 and P2X7 purinoceptors in a rat model of PD can be linked to targeting SIRT1/SIRT3, PTEN-mTOR pathways. Moreover, our findings demonstrated that simultaneous inhibition of DPP-4 and P2X7 purinoceptors might have stronger effect on mitochondrial biogenesis compared to only one.

中文翻译：

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在体内帕金森病模型中同时抑制二肽基肽酶 4 和 P2X7 嘌呤受体。

帕金森病 (PD) 后多巴胺能神经元的丧失会降低患者的生活质量。本研究旨在探讨同时抑制二肽基肽酶-4 (DPP-4) 和 P2X7 嘌呤受体在 PD 模型中的保护作用并探讨可能的机制。6-羟基多巴胺（6-OHDA）被用作建立雄性 Wister 大鼠 PD 模型的工具。通过ELISA检测SIRT1、SIRT3、mTOR、PGC-1α、PTEN、P53和DNA片段的表达。使用阿扑吗啡诱导的旋转和窄束测试来确定行为障碍。通过酪氨酸羟化酶（TH）免疫组织化学检测多巴胺合成和TH阳性神经元。通过尼氏染色测定神经元密度。OHDA 损伤的大鼠表现出行为障碍，可通过 BBG、lin 和 lin + BBG 逆转。我们发现 OHDA 损伤大鼠的中脑和纹状体中 SIRT1、SIRT3、PGC-1α 和 mTOR 水平显着降低，而 BBG、lin 和 lin + BBG 可以逆转这种情况。同样，在 OHDA 损伤的大鼠的中脑和纹状体中发现 PTEN 和 P53 水平显着升高，而 BBG、lin 和 lin + BBG 可以逆转这种情况。OHDA 损伤大鼠的 TH 阳性神经元和神经元密度显着降低，BBG、lin 和 lin + BBG 可以逆转这一情况。总的来说，我们的结果表明，在 PD 大鼠模型中同时抑制 DPP-4 和 P2X7 嘌呤受体的保护作用可能与靶向 SIRT1/SIRT3、PTEN-mTOR 通路有关。此外，我们的研究结果表明，与单独抑制相比，同时抑制 DPP-4 和 P2X7 嘌呤受体可能对线粒体生物合成产生更强的影响。