Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
Student Research Committee, Iran University of Medical Sciences, Tehran, Iran.
Metab Brain Dis. 2020 Mar;35(3):539-548. doi: 10.1007/s11011-020-00538-x. Epub 2020 Feb 3.
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.
帕金森病 (PD) 导致多巴胺能神经元丧失，降低了患者的生活质量。本研究旨在探讨同时抑制二肽基肽酶-4 (DPP-4) 和 P2X7 嘌呤能受体对 PD 模型的保护作用及其可能的机制。雄性 Wistar 大鼠采用 6-羟多巴胺 (6-OHDA) 建立 PD 模型。通过 ELISA 测定 SIRT1、SIRT3、mTOR、PGC-1α、PTEN、P53 和 DNA 片段化的表达。通过阿扑吗啡诱导的旋转和窄光束试验测定行为损伤。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。BBG、lin 和 lin+BBG 逆转了 OHDA 损伤大鼠的行为损伤。我们发现，OHDA 损伤大鼠中 SIRT1、SIRT3、PGC-1α 和 mTOR 的水平在中脑和纹状体中均显著降低，而 BBG、lin 和 lin+BBG 可逆转这一现象。同样，在 OHDA 损伤大鼠的中脑和纹状体中发现了显著增加的 PTEN 和 P53 水平，而 BBG、lin 和 lin+BBG 可逆转这一现象。TH 阳性神经元和神经元密度在 BBG、lin 和 lin+BBG 逆转的 OHDA 损伤大鼠中显著降低。综上所述，我们的研究结果表明，同时抑制 DPP-4 和 P2X7 嘌呤能受体在 PD 大鼠模型中具有保护作用，其机制可能与 SIRT1/SIRT3、PTEN-mTOR 通路有关。此外，我们的研究结果表明，与仅抑制一种受体相比，同时抑制 DPP-4 和 P2X7 嘌呤能受体可能对线粒体生物发生有更强的作用。
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