Pharmacology and Biochemistry Department, Faculty of Pharmacy, the British University in Egypt, Cairo, Egypt; Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Life Sci. 2021 Dec 15;287:120132. doi: 10.1016/j.lfs.2021.120132. Epub 2021 Nov 11.
Parkinson's disease (PD) is a progressive neurodegenerative disease that impairs people's lives tremendously. The development of innovative treatment modalities for PD is a significant unmet medical need. The critical function of glucagon-like peptide-1 (GLP-1) in neurodegenerative diseases has raised impetus in investigating the repositioning of a dipeptidyl peptidase IV inhibitor, alogliptin (ALO), as an effective treatment for PD. As a result, the focus of this research was to assess the effect of ALO in a rat rotenone (ROT) model of PD. For 21 days, ROT (1.5 mg/kg) was delivered subcutaneously every other day. ALO (30 mg/kg/day), delivered by gavage for 21 days, recovered motor performance and improved motor coordination in the open-field and rotarod testing. These impacts were highlighted by restoring striatal dopamine content and correcting histological changes that occurred concurrently. The ALO molecular signaling was determined by increasing the quantity of GLP-1 and the protein expression of its downstream signaling pathway, pT172-AMPK/SIRT1/PGC-1α. Furthermore, it curbed neuroinflammation via hampering HMGB1/TLR4/NLRP3 inflammasome activation and conquered striatal microglia activation. Pre-administration of dorsomorphin reversed the neuroprotective effects. In conclusion, the promising neuroprotective effect of ALO highlights the repositioning of ALO as a prospective revolutionary candidate for combating PD.
帕金森病（PD）是一种进行性神经退行性疾病，极大地影响了人们的生活。开发治疗 PD 的创新治疗方法是一个重大的未满足的医疗需求。胰高血糖素样肽-1（GLP-1）在神经退行性疾病中的关键作用促使人们研究二肽基肽酶-4 抑制剂阿格列汀（ALO）重新定位为治疗 PD 的有效药物。因此，本研究的重点是评估 ALO 在 PD 的 ROT 大鼠模型中的作用。连续 21 天，每隔一天皮下给予 ROT（1.5mg/kg）。连续 21 天灌胃给予 ALO（30mg/kg/天），可恢复运动性能并改善旷场和转棒测试中的运动协调性。这些影响是通过恢复纹状体多巴胺含量和纠正同时发生的组织学变化来突出的。ALO 分子信号通过增加 GLP-1 的数量及其下游信号通路 pT172-AMPK/SIRT1/PGC-1α 的蛋白表达来确定。此外，它通过抑制 HMGB1/TLR4/NLRP3 炎性小体激活和克服纹状体小胶质细胞激活来抑制神经炎症。预先给予 Dorsomorphin 逆转了神经保护作用。总之，ALO 有希望的神经保护作用突出了 ALO 作为治疗 PD 的有前途的革命性候选药物的重新定位。
