Department of Neurology, Xinhua Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, People's Republic of China.
Neurochem Res. 2021 May;46(5):1291-1304. doi: 10.1007/s11064-021-03267-4. Epub 2021 Mar 13.
Alleviating microglia-mediated neuroinflammation bears great promise to reduce neurodegeneration. Nicotinamide phosphoribosyltransferase (NAMPT) may exert cytokine-like effect in the brain. However, it remains unclear about role of NAMPT in microglial inflammation. Also, it remains unknown about effect of NAMPT inhibition on microglial inflammation. In the present study, we observed that FK866 (a specific noncompetitive NAMPT inhibitor) dose-dependently inhibited lipopolysaccharide (LPS)-induced proinflammatory mediator (interleukin (IL)-6, IL-1β, inducible nitric oxide synthase, nitric oxide and reactive species) level increase in BV2 microglia cultures. FK866 also significantly inhibited LPS-induced polarization change in microglia. Furthermore, LPS significantly increased NAMPT expression and nuclear factor kappa B (NF-κB) phosphorylation in microglia. FK866 significantly decreased NAMPT expression and NF-κB phosphorylation in LPS-treated microglia. Finally, conditioned medium from microglia cultures co-treated with FK866 and LPS significantly increased SH-SY5Y and PC12 cell viability compared with conditioned medium from microglia cultures treated with LPS alone. Our study strongly indicates that NAMPT may be a promising target for microglia modulation and NAMPT inhibition may attenuate microglial inflammation.
减轻小胶质细胞介导的神经炎症有望减少神经退行性变。烟酰胺磷酸核糖转移酶（NAMPT）可能在大脑中发挥细胞因子样作用。然而，NAMPT 在小胶质细胞炎症中的作用尚不清楚。此外，NAMPT 抑制对小胶质细胞炎症的影响也尚不清楚。在本研究中，我们观察到 FK866（一种特异性非竞争性 NAMPT 抑制剂）可剂量依赖性地抑制 LPS 诱导的 BV2 小胶质细胞培养物中促炎介质（白细胞介素 (IL)-6、IL-1β、诱导型一氧化氮合酶、一氧化氮和活性物质）水平的增加。FK866 还显著抑制 LPS 诱导的小胶质细胞极化变化。此外，LPS 显著增加了小胶质细胞中 NAMPT 的表达和核因子 kappa B（NF-κB）磷酸化。FK866 显著降低了 LPS 处理的小胶质细胞中 NAMPT 的表达和 NF-κB 磷酸化。最后，与单独用 LPS 处理的小胶质细胞培养物的条件培养基相比，用 FK866 和 LPS 共同处理的小胶质细胞培养物的条件培养基显著增加了 SH-SY5Y 和 PC12 细胞的活力。我们的研究强烈表明，NAMPT 可能是小胶质细胞调节的有希望的靶点，并且 NAMPT 抑制可能减轻小胶质细胞炎症。
