Moradi Kamyar, Golbakhsh Mohammadreza, Haghighi Farinaz, Afshari Khashayar, Nikbakhsh Rajan, Khavandi Mohammad Mahdi, Faghani Shahriar, Badripour Abolfazl, Etemadi Ali, Ashraf-Ganjouei Amir, Bagheri Sayna, Dehpour Ahmad Reza
Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Department of Orthopedic Surgery, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Int Immunopharmacol. 2020 Sep;86:106743. doi: 10.1016/j.intimp.2020.106743. Epub 2020 Jun 30.
Despite the great search for an effective approach to minimize secondary injury in spinal cord injury (SCI) setting, there have been limited advances. Roflumilast is a selective inhibitor of phosphodiesterase 4 with potent anti-inflammatory properties. Here, we sought to explore Roflumilast efficacy in the improvement of locomotor and sensory deficits of SCI. In an animal setting, 50 male rats were randomly assigned to five groups: an SCI group receiving Placebo, three SCI groups receiving Roflumilast at the doses of 0.25, 0.5, and 1 mg/kg prior to T9 vertebra laminectomy, and a sham-operated group. Locomotor, mechanical, and thermal activities were evaluated for 28 days. At the end of the study, spinal cord samples were taken to assess the relative ratio of microglial subtypes, including M1 and M2, histopathological changes, levels of pro-inflammatory (TNF-α and IL-1β) and anti-inflammatory (IL-10) biomarkers, and cAMP level. Repeated measure analysis revealed significant effect for time-treatment interaction on locomotion [F (24, 270) = 280.7, p < 0.001], thermal sensitivity [F (16, 180) = 4.35, p < 0.001], and mechanical sensitivity [F (16, 180) = 7.96, p < 0.001]. As expected, Roflumilast significantly increased the expression of spinal cAMP. H&E staining exhibited lesser histopathological disruptions in Roflumilast-treated rodents. We also observed a significant reduction in the M1/M2 ratio (p values < 0.001) as well as in pro-inflammatory biomarkers following the administration of Roflumilast to the injured rats. Furthermore, IL-10 level was increased in rodents receiving 1 mg/kg of the reagent. In conclusion, the increased spinal cAMP following Roflumilast therapy might attenuate neuroinflammation via altering microglial activity; therefore, it could be considered as an alternative therapeutic agent for SCI complications.
尽管人们一直在努力寻找一种有效的方法来尽量减少脊髓损伤（SCI）中的继发性损伤，但进展有限。罗氟司特是一种具有强大抗炎特性的磷酸二酯酶4选择性抑制剂。在此，我们试图探讨罗氟司特在改善SCI运动和感觉功能障碍方面的疗效。在动物实验中，50只雄性大鼠被随机分为五组：一组SCI组接受安慰剂，三组SCI组在T9椎体椎板切除术前行腹腔注射0.25、0.5和1mg/kg剂量的罗氟司特，以及一组假手术组。对运动、机械和热活动进行了28天的评估。在研究结束时，采集脊髓样本以评估小胶质细胞亚型（包括M1和M2）的相对比例、组织病理学变化、促炎（TNF-α和IL-1β）和抗炎（IL-10）生物标志物水平以及cAMP水平。重复测量分析显示，时间-治疗交互作用对运动[F（24,270）=280.7，p<0.001]、热敏感性[F（16,180）=4.35，p<0.001]和机械敏感性[F（16,180）=7.96，p<0.001]有显著影响。正如预期的那样，罗氟司特显著增加了脊髓cAMP的表达。苏木精-伊红（H&E）染色显示，接受罗氟司特治疗的啮齿动物的组织病理学破坏较小。我们还观察到，在给受伤大鼠施用罗氟司特后，M1/M2比率（p值<0.001）以及促炎生物标志物显著降低。此外，接受1mg/kg该试剂的啮齿动物的IL-10水平升高。总之，罗氟司特治疗后脊髓cAMP的增加可能通过改变小胶质细胞活性来减轻神经炎症；因此，它可被视为SCI并发症的替代治疗药物。
