Department of Pharmacology and Toxicology, University of Navarra, Navarra Institute for Health Research (IdiSNA), C/ Irunlarrea, 1, 31008, Pamplona, Spain.
Department of Anatomy, Histology and Neurosciences, Medical School, Autonoma University of Madrid, 28029, Madrid, Spain.
J Neuroimmune Pharmacol. 2023 Sep;18(3):529-550. doi: 10.1007/s11481-023-10084-9. Epub 2023 Sep 12.
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.
Sirtuin 2（SIRT2）被认为在衰老、炎症、癌症和神经退行性疾病中具有核心作用；然而，其具体功能仍存在争议。最近的研究提出，SIRT2 的药理学抑制可能是包括阿尔茨海默病（AD）在内的几种神经退行性疾病的治疗策略。令人惊讶的是，这些关于 SIRT2 抑制潜在治疗意义的研究均未评估该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 ，没有表现出遗传毒性或致突变性。此外，用 33i 进行药理学治疗，改善了认知功能障碍和长时程增强，减少了 APP/PS1 AD 小鼠模型中的淀粉样蛋白病理和神经炎症。然而，这种治疗增加了外周炎症细胞因子 IL-1β、TNF、IL-6 和 MCP-1 的水平。因此，外周 SIRT2 抑制作用（使用血脑屏障不可渗透的化合物 AGK-2）会恶化认知能力，并增加全身炎症。对人类样本的分析表明，SIRT2 在 AD 患者的大脑中增加，但不在血清中增加。这些结果表明，尽管 SIRT2 的药理学抑制可能对神经退行性疾病有有益的影响，但不建议在外周进行 SIRT2 抑制，应该考虑全身性不良反应。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，不仅对 AD，而且对其他神经退行性疾病也是如此。
