Pharmacology Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
Pharmacology Division, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
Eur J Pharmacol. 2022 Nov 5;934:175316. doi: 10.1016/j.ejphar.2022.175316. Epub 2022 Oct 6.
Huntington disease (HD), an autosomal dominant neurodegenerative disorder characterized by involuntary choreatic movements with cognitive and behavioral disturbances. HD striatum has increased conversion of kynurenine to quinolinic acid (QA) which activates NMDA receptors leading to activation of microglia and increased levels of nuclear factor kappa B (NF-κB) leading to elevated transcription of inducible nitric oxide synthase (iNOS) and various cytokines causing neuronal death via neuroinflammation, oxidative stress, mitochondrial dysfunction and apoptosis. Therefore, inhibiting IKK-NF-κB pathway induced excitotoxicity, oxidative stress and neuroinflammation could be a potential intervention in slowing down the disease progression. QA injection intrastriatally (IS-QA) produce damage mimicking HD where neuroinflammation, oxidative stress and mitochondrial dysfunction play crucial role. Ellagic acid (EA) and vanillic acid (VA) are well reported to possess antioxidant and NF-κB inhibiting effect. Hence, in present study, rats administered IS-QA were treated with EA and VA for 21 days to explore their neuroprotective effects. Behavioral studies, biochemical estimations for oxidative stress and acetylcholinesterase assay were performed. Mitochondrial function was determined by estimating mitochondrial enzyme complexes; inflammatory markers like TNF-α, IL-6, NF-κB by ELISA and apoptosis by caspase-3 levels. Brain damage was determined by histopathology which revealed their neuroprotective effects. Various doses of EA and VA produced improved motor and cognitive functions, oxidative stress and neuroinflammation were also reduced and mitochondrial functioning was improved. In a nutshell, these results signify improved motor and cognitive functions by EA and VA in QA model of HD, along with declined oxidative stress, mitochondrial dysfunction and neuroinflammation.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，其特征为不自主的舞蹈运动以及认知和行为障碍。HD 纹状体中犬尿氨酸向喹啉酸（QA）的转化率增加，这会激活 NMDA 受体，导致小胶质细胞激活和核因子 kappa B（NF-κB）水平升高，从而导致诱导型一氧化氮合酶（iNOS）和各种细胞因子的转录升高，通过神经炎症、氧化应激、线粒体功能障碍和细胞凋亡导致神经元死亡。因此，抑制 IKK-NF-κB 通路诱导的兴奋性毒性、氧化应激和神经炎症可能是减缓疾病进展的潜在干预措施。纹状体注射 QA（IS-QA）会产生类似于 HD 的损伤，其中神经炎症、氧化应激和线粒体功能障碍起着关键作用。鞣花酸（EA）和香草酸（VA）已被广泛报道具有抗氧化和 NF-κB 抑制作用。因此，在本研究中，用 IS-QA 处理的大鼠用 EA 和 VA 治疗 21 天，以探索其神经保护作用。进行了行为研究、氧化应激和乙酰胆碱酯酶测定的生化估算。通过估计线粒体酶复合物来确定线粒体功能；通过 ELISA 测定炎性标志物，如 TNF-α、IL-6、NF-κB，通过 caspase-3 水平测定细胞凋亡。通过组织病理学确定脑损伤，显示出它们的神经保护作用。不同剂量的 EA 和 VA 改善了运动和认知功能，降低了氧化应激和神经炎症，改善了线粒体功能。简而言之，这些结果表明，EA 和 VA 在 HD 的 QA 模型中改善了运动和认知功能，同时降低了氧化应激、线粒体功能障碍和神经炎症。
