Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario Via C, Valeria Gazzi, 98100 Messina, Italy.
J Neuroinflammation. 2012 Apr 10;9:66. doi: 10.1186/1742-2094-9-66.
Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting.
We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI.
Twenty-four hr following induction of SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in TNF-α, IL-1β, PAR, NAMPT, Bax, MPO activity, NF-κB activation, astrogliosis and microglial activation was observed. Meanwhile, the expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased significantly. Treatment with FK866 (10 mg/kg), the best known and characterized NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved perilesional gray and white matter, restored anti-apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF-α, IL-1β, Bax expression and NF-κB activity.We show for the first time that FK866, a specific inhibitor of NAMPT, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. We also show that NAMPT protein levels are increased upon SCI in the perilesional area which can be corrected by administration of FK866.
Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors.
新出现的数据表明烟酰胺磷酸核糖转移酶（NAMPT）参与了癌症和炎症的发病机制。NAMPT 抑制剂已被证明在关节炎和内毒素性休克的炎症动物模型以及自身免疫性脑炎中是有益的。鉴于炎症反应在脊髓损伤（SCI）中的作用，本研究在该背景下研究了 NAMPT 抑制剂的作用。
我们研究了 NAMPT 抑制剂 FK866 在 SCI 实验性压迫模型中的作用。
在 SCI 诱导后 24 小时，观察到明显的功能缺陷伴随着广泛的水肿、脱髓鞘、神经元丢失，以及 TNF-α、IL-1β、PAR、NAMPT、Bax、髓过氧化物酶（MPO）活性、NF-κB 激活、星形胶质细胞和小胶质细胞激活的显著增加。同时，神经营养因子 BDNF、GDNF、NT3 和抗凋亡 Bcl-2 的表达显著下降。在 SCI 后 1 小时和 6 小时用最佳的、最著名的 NAMPT 抑制剂 FK866（10mg/kg）治疗，可挽救运动功能，保留损伤周边的灰质和白质，恢复抗凋亡和神经营养因子，防止中性粒细胞、小胶质细胞和星形胶质细胞的激活，并抑制 NAMPT、PAR、TNF-α、IL-1β、Bax 表达和 NF-κB 活性的升高。我们首次表明，在 SCI 后给予特定的 NAMPT 抑制剂 FK866，能够减轻继发性炎症损伤，并部分减少永久性损伤。我们还表明，在损伤周边区域，SCI 后 NAMPT 蛋白水平升高，FK866 可纠正这一升高。
我们的发现表明，与 SCI 相关的炎症成分是这些抑制剂的主要作用靶点。
