Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ(1-42) peptide in rat hippocampal neurons.
Cannabinoid-profiled agents improve cell survival via reduction of oxidative stress and inflammation, and Nrf2 activation in a toxic model combining hyperglycemia+Aβ(1-42) peptide in rat hippocampal neurons.
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DOI：
10.1016/j.neuint.2020.104817
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发表时间：
2020-11
影响因子：
4.2
通讯作者：
Karasu Ç
中科院分区：
文献类型：
--
作者：
Elmazoglu Z;Rangel-López E;Medina-Campos ON;Pedraza-Chaverri J;Túnez I;Aschner M;Santamaría A;Karasu Ç
阿尔茨海默病 (AD) 是一种多因素神经退行性疾病，与多种毒性机制相关。有证据表明，高血糖会诱发氧化应激、线粒体功能障碍、炎症和兴奋性毒性，所有这些在 AD 发病机制的发生和进展中都发挥着重要作用。内源性大麻素系统（ECS）协调主要的生理反应，包括神经元可塑性、神经保护和氧化还原稳态等。 ECS 的多靶点有效性成为治疗 AD 的潜在方法。在这里，我们表征了内源性大麻素花生四烯酰乙醇酰胺 (AEA) 和 2-花生四烯酰甘油 (2-AG)、合成大麻素 CP 55–940 和 WIN 55,212–2 以及脂肪酸酰胺水解酶 (FAAH) 抑制剂 URB597 对高血糖 + 低聚淀粉样蛋白 β 肽的保护特性(Aβ1-42) 原代海马神经元神经毒性模型表现出多种 AD 特征。用浓度增加的大麻素试剂（1 nM 至 1 μM）处理细胞 6 小时，然后与 150 mM 葡萄糖（GLU，24 小时）共同处理，然后与 500 nM Aβ1–42 一起孵育（24 小时）。细胞活力/存活、活性氧 (ROS) 水平、抗氧化酶（SOD、CAT、GPx 和 GRx）活性、氧化损伤的生物产物（AGE 和 HNE 加合物）和亚硝化应激 (3-NT)、炎症的几个终点（iNOS、IL-1β 和 TNF-α）、淀粉样蛋白定量、线粒体膜电位以及 Nrf2 通路的参与均进行了评估。高葡萄糖 + 淀粉样蛋白 β 1-42 (GLU+Aβ1-42) 联合条件会降低细胞活力和线粒体膜电位，同时加剧氧化损伤和炎症。所有测试的药物均保留了细胞活力并刺激了线粒体膜电位，同时以不同的方式降低了所有评估的毒性终点，其中 URB597 显示出最高功效。除 URB597 外，所有大麻素药物的神经保护功效均导致特定抗氧化活性和 Nrf2 通路调节的部分募集。我们的结果支持这些药物在低浓度下对 GLU+Aβ1-42 的破坏作用具有神经保护潜力，为 AD 疗法的设计提供了新的潜在模式。
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder linked to various converging toxic mechanisms. Evidence suggests that hyperglycemia induces oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity, all of which play important roles in the onset and progression of AD pathogenesis. The endocannabinoid system (ECS) orchestrates major physiological responses, including neuronal plasticity, neuroprotection, and redox homeostasis, to name a few. The multi-targeted effectiveness of the ECS emerges as a potential approach to treat AD. Here we characterized the protective properties of the endocannabinoids arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), the synthetic cannabinoids CP 55–940 and WIN 55,212–2, and the fatty acid amide hydrolase (FAAH) inhibitor URB597, on a combined hyperglycemia+oligomeric amyloid β peptide (Aβ1–42) neurotoxic model in primary hippocampal neurons which exhibit several AD features. Cells were treated with cannabinoid agents at increased concentrations (1 nM to 1 μM) for 6 h, and then co-treated with 150 mM glucose (GLU, 24 h), followed by incubation with 500 nM Aβ1–42 (24 h). Cell viability/survival, reactive oxygen species (ROS) levels, antioxidant enzyme (SOD, CAT, GPx and GRx) activities, biological products of oxidative damage (AGE and HNE adducts) and nitrosative stress (3-NT), several endpoints of inflammation (iNOS, IL-1β and TNF-α), amyloid quantification, mitochondrial membrane potential, and the involvement of the Nrf2 pathway, were all evaluated. The combined high glucose + amyloid beta 1–42 (GLU+Aβ1–42) condition decreased cell viability and mitochondrial membrane potential, while augmenting oxidative damage and inflammation. All agents tested preserved cell viability and stimulated mitochondrial membrane potential, while reducing all the evaluated toxic endpoints in a differential manner, with URB597 showing the highest efficacy. The neuroprotective efficacy of all cannabinoid agents, except for URB597, led to partial recruitment of specific antioxidant activity and Nrf2 pathway regulation. Our results support the neuroprotective potential of these agents at low concentrations against the damaging effects of GLU+Aβ1–42, affording new potential modalities for the design of AD therapies.
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影响因子：
5.1
作者：
Aguilera-Portillo, Gabriela;Rangel-Lopez, Edgar;Santamaria, Abel
通讯作者：
Santamaria, Abel
影响因子：
2.2
作者：
Duzgun, Sukru Aydin;Yerlikaya, Azmi;Boyaci, Ihsan
通讯作者：
Boyaci, Ihsan
DOI：
10.1073/pnas.1400988111
发表时间：
2014-06-03
影响因子：
11.1
作者：
Chiarlone, Anna;Bellocchio, Luigi;Guzman, Manuel
通讯作者：
Guzman, Manuel
影响因子：
15.8
作者：
Chivese, Tawanda;Norris, Shane A.;Levitt, Naomi S.
通讯作者：
Levitt, Naomi S.
影响因子：
3.7
作者：
Colonnello, Aline;Kotlar, Ilan;Santamaria, Abel
通讯作者：
Santamaria, Abel