已经提出沉默信息素2（SIRT2）在衰老、炎症、癌症和神经退行性疾病中具有核心作用，尽管如此，它的具体功能仍然存在争议。最近的研究提出了使用SIRT2药物抑制作为包括阿尔茨海默病（AD）在内的几种神经退行性疾病的治疗策略。令人惊讶的是，关于SIRT2抑制潜在兴趣的已出版研究并没有评估这种治疗的外周不良副作用。在本研究中，我们证明了特定的SIRT2抑制剂，化合物33i，没有显示出遗传毒性或突变性。此外，药物治疗33i改善了APP/PS1 AD小鼠模型中的认知功能障碍和长时程增强，减少了β淀粉样病变和神经炎症。然而，该治疗增加了外周炎症细胞因子IL-1β、TNF、IL-6和MCP-1的水平。相应地，用于外周SIRT2抑制的血脑屏障不透过的化合物AGK-2恶化了认知能力，并增加了系统性炎症。人体样本分析发现SIRT2在AD患者的大脑中增加，但在血清中没有增加。这些结果表明，尽管SIRT2药物抑制在神经退行性疾病中可能具有益处，但不建议在外周进行药物抑制，应考虑系统性不良副作用。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，也适用于其他神经退行性疾病。© 2023. 作者。

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.© 2023. The Author(s).