Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer’s disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In this study, we demonstrate that the specific SIRT2 inhibitor, the compound 33i, does not exhibit genotoxic or mutagenic properties. Moreover, pharmacological treatment with 33i, improved cognitive dysfunction and long-term potentiation, reducing amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of the inflammatory cytokines IL-1β, TNF, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. The analysis of human samples revealed that SIRT2 is increased in the brain but not in the serum of AD patients. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its pharmacological inhibition at the periphery would not be recommended and the systemic adverse side effects should be considered. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.

Graphical Abstract

中文翻译：

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SIRT2 抑制可挽救阿尔茨海默病转基因小鼠模型中的神经退行性病理，但会增加全身炎症

Sirtuin 2 (SIRT2) 被认为在衰老、炎症、癌症和神经退行性疾病中发挥着核心作用；然而，其具体功能仍存在争议。最近的研究提出 SIRT2 药理学抑制可作为包括阿尔茨海默病 (AD) 在内的多种神经退行性疾病的治疗策略。令人惊讶的是，这些已发表的关于 SIRT2 抑制的潜在兴趣的研究都没有评估这种治疗的外周不良副作用。在这项研究中，我们证明了特定的 SIRT2 抑制剂化合物 33i 不表现出遗传毒性或诱变特性。此外，33i 的药物治疗可改善 APP/PS1 AD 小鼠模型中的认知功能障碍和长期增强作用，减少淀粉样蛋白病理和神经炎症。然而，这种治疗增加了炎症细胞因子 IL-1β、TNF、IL-6 和 MCP-1 的外周水平。因此，血脑屏障不渗透性化合物 AGK-2 抑制外周 SIRT2 会导致认知能力恶化并增加全身炎症。对人类样本的分析显示，AD 患者大脑中的 SIRT2 有所增加，但血清中并未增加。这些结果表明，尽管SIRT2药物抑制可能对神经退行性疾病产生有益的影响，但不推荐在外周进行药物抑制，并且应考虑全身不良副作用。这些信息对于最大限度地发挥 SIRT2 抑制的治疗潜力至关重要，不仅适用于 AD，而且适用于其他神经退行性疾病。

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