Vildagliptin (Vilda), a dipeptidyl peptidase-4 (DPP-4) inhibitor, has been highlighted as a promising therapeutic agent for neurodegenerative diseases as Alzheimer’s and Parkinson’s diseases. Vilda‘s effect is mostly linked to PI3K/Akt signaling in CNS. Moreover, PI3K/Akt activation reportedly enhanced survival and dampened progression of Huntington’s disease (HD). However, Vilda’s role in HD is yet to be elucidated. Thus, the aim of the study is to uncover the potentiality of Vilda in HD and unfold its link with PI3K/Akt pathway in 3-nitropropionic acid (3NP) rat model. Rats were randomly assigned into 4 groups; group 1 received saline, whereas, groups 2, 3 and 4 received 3NP (10 mg/kg/day; i.p.) for 14 days, concomitantly with Vilda (5 mg/kg/day; p.o.) in groups 3 and 4, and wortmannin (WM), a PI3K inhibitor, (15 μg/kg/day; i.v.) in group 4. Vilda improved cognitive and motor perturbations induced by 3NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. The molecular signaling of Vilda was estimated by elevation of GLP-1 level and protein expressions of survival proteins; p85/p55 (pY458/199)-PI3K, pS473-Akt. Together, it boosted striatal neurotrophic factors and receptor; pS133-CREB, BDNF, pY515-TrKB, which subsequently maintained mitochondrial integrity, as indicated by enhancing both SDH and COX activities, and the redox modulators; Sirt1, Nrf2. Such neuroprotection restored imbalance of neurotransmitters through increasing GABA and suppressing glutamate as well PDE10A. These effects were reversed by WM pre-administration. In conclusion, Vilda purveyed significant anti-Huntington effect which may be mediated, at least in part, via activation of GLP-1/PI3K/Akt pathway in 3NP rat model.

中文翻译：

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Vildagliptin 通过激活 3-硝基丙酸大鼠模型中的 GLP-1 受体/PI3K/Akt/BDNF 通路减轻亨廷顿病。

维格列汀 (Vilda) 是一种二肽基肽酶 4 (DPP-4) 抑制剂，已被强调为治疗阿尔茨海默病和帕金森病等神经退行性疾病的有前景的药物。Vilda 的作用主要与 CNS 中的 PI3K/Akt 信号传导有关。此外，据报道，PI3K/Akt 激活可提高存活率并抑制亨廷顿病 (HD) 的进展。然而，Vilda 在 HD 中的作用还有待阐明。因此，该研究的目的是揭示 Vilda 在 HD 中的潜力，并在 3-硝基丙酸 (3NP) 大鼠模型中揭示其与 PI3K/Akt 通路的联系。大鼠随机分为4组；第 1 组接受生理盐水，而第 2、3 和 4 组接受 3NP（10 mg/kg/天；腹腔内注射）14 天，同时在第 3 组和第 4 组中服用 Vilda（5 mg/kg/天；口服）和渥曼青霉素(WM)，一种 PI3K 抑制剂，(15 μg/kg/天；iv) 在第 4 组中。Vilda 改善了由 3NP 引起的认知和运动扰动，纹状体组织病理学标本和 GFAP 的免疫组织化学检查证实了这一点。Vilda 的分子信号通过 GLP-1 水平的升高和存活蛋白的蛋白表达来估计；p85/p55 (p Y458/199)-PI3K，p S473-Akt。同时，它增强了纹状体神经营养因子和受体；p S133-CREB、BDNF、p Y515-TrKB，随后通过增强 SDH 和 COX 活性以及氧化还原调节剂来维持线粒体完整性；Sirt1，Nrf2。这种神经保护通过增加 GABA 和抑制谷氨酸以及 PDE10A 来恢复神经递质的不平衡。WM 预给药逆转了这些影响。总之，Vilda 提供了显着的抗亨廷顿效应，这可能至少部分通过激活 3NP 大鼠模型中的 GLP-1/PI3K/Akt 通路来介导。