Pharmaceutical Sciences, Food and Nutrition School, Federal University of Mato Grosso do Sul (UFMS), Campo Grande 79051-470, Brazil.
School of Medicine, Federal University of Mato Grosso do Sul (UFMS), Campo Grande 79051-470, Brazil.
ACS Chem Neurosci. 2023 Dec 20;14(24):4298-4310. doi: 10.1021/acschemneuro.3c00443. Epub 2023 Dec 4.
Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-β oligomers (AβO) in the brain, neuroinflammation, oxidative stress, and cognitive decline. Grandisin, a tetrahydrofuran neolignan, exhibits relevant anti-inflammatory and antioxidant properties. Interestingly, grandisin-based compounds were shown to prevent AβO-induced neuronal death in vitro. However, no study has assessed the effect of these compounds on the AD animal model. This study focuses on a triazole grandisin analogue (TGA) synthesized using simplification and bioisosteric drug design, which resulted in improved potency and solubility compared with the parent compound. This study aimed to investigate the possible in vivo effects of TGA against AβO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AβO (90 μM) or vehicle injections. 24 h after surgery, animals received intraperitoneal treatment with TGA (1 mg/kg) or vehicle, administered on a 14 day schedule. One day after treatment completion, a novel object recognition task (NORT) was performed. Memantine (10 mg/kg) was administered as a positive control. NORT retention sessions were performed on days 8 and 16 after AβO injection. Immediately after retention sessions, animals were euthanized for cortex and hippocampus collection. Specimens were subjected to oxidative stress and cytokine analyses. TGA reduced the level of cortex/hippocampus lipoperoxidation and prevented cognitive impairment in AβO-injected mice. Additionally, TGA reduced tumor necrosis factor (TNF) and interferon-γ (IFN-γ) levels in the hippocampus. By contrast, memantine failed to prevent cortex/hippocampus lipid peroxidation, recognition memory decline, and AβO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AβO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AβO-injected mice. Moreover, TGA exhibited a persistent neuroprotective effect compared to memantine, reflecting an innovative profile of this promising agent against neurodegenerative diseases, such as AD.
阿尔茨海默病（AD）是一种神经退行性疾病，由大脑中淀粉样β寡聚体（AβO）的积累、神经炎症、氧化应激和认知能力下降引起。格兰地辛是一种四氢呋喃新木脂素，具有相关的抗炎和抗氧化特性。有趣的是，基于格兰地辛的化合物已被证明可防止体外 AβO 诱导的神经元死亡。然而，尚无研究评估这些化合物对 AD 动物模型的影响。本研究重点研究了一种三唑格兰地辛类似物（TGA），该化合物是通过简化和生物等排药物设计合成的，与母体化合物相比，其效力和溶解度均得到了提高。本研究旨在研究 TGA 对 AβO 诱导的 AD 的可能体内作用。雄性 C57/Bl6 小鼠接受立体定向脑室内 AβO（90 μM）或载体注射。手术后 24 小时，动物接受腹腔内 TGA（1 mg/kg）或载体治疗，14 天为一个疗程。治疗完成后一天，进行新物体识别任务（NORT）。给予美金刚（10 mg/kg）作为阳性对照。AβO 注射后第 8 天和第 16 天进行 NORT 保留测试。保留测试后立即处死动物，收集皮质和海马组织。标本进行氧化应激和细胞因子分析。TGA 降低了皮质/海马丙二醛水平，并预防了 AβO 注射小鼠的认知障碍。此外，TGA 降低了海马中的肿瘤坏死因子（TNF）和干扰素-γ（IFN-γ）水平。相比之下，美金刚未能防止皮质/海马丙二醛脂质过氧化、识别记忆下降以及 AβO 诱导的 TNF 和 IFN-γ 水平升高。因此，美金刚未能避免 AβO 引起的持续认知障碍。结果表明，TGA 通过在 AβO 注射小鼠中发挥抗氧化和抗炎作用，可能预防记忆障碍。此外，与美金刚相比，TGA 表现出持久的神经保护作用，反映了这种有前途的药物针对神经退行性疾病（如 AD）的创新特征。
