Department of Neurology, The First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, No. 2 Fuxue Lane, Wenzhou City, Zhejiang Province 325000, PR China.
Brain Res. 2012 Nov 5;1483:13-9. doi: 10.1016/j.brainres.2012.09.016. Epub 2012 Sep 14.
Our previous studies showed that ligands to type 2 imidazoline receptors (I₂R), including 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) and Idazoxan, were effective in reducing spinal cord inflammation caused by experimental autoimmune encephalomyelitis (EAE). In the present study, we determined the effective therapeutic time window of 2-BFI and found that administration of 2-BFI in mice before the appearance of ascending flaccid paralysis (1-10 days post immunization), but not during the period when neurological deficits occurred (11-20 days post immunization), significantly ameliorated EAE-induced neurobehavioral deficits, reduced the infiltration of inflammatory cells into the spinal cord, and reduced the level of demyelination. More interestingly, giving 2-BFI during 1-10 days post immunization selectively suppressed IL-17 levels in the peripheral blood, which strongly suggests that IL-17 may be a good early marker to indicate EAE progression and that 2-BFI may target CD4⁺ T lymphocytes, especially Th17 cells to reduce IL-17 expression. Collectively, these studies led us to envisage that 2-BFI can be a useful drug to treat multiple sclerosis (MS) when used in combination with an early indicator of MS progression, such as IL-17.
我们之前的研究表明，2 型咪唑啉受体（I₂R）的配体，包括 2-(2-苯并呋喃基）-2-咪唑啉（2-BFI）和伊达唑兰，可有效减轻实验性自身免疫性脑脊髓炎（EAE）引起的脊髓炎症。在本研究中，我们确定了 2-BFI 的有效治疗时间窗，发现 2-BFI 在出现上行弛缓性瘫痪（免疫后 1-10 天）之前给予小鼠，而不是在出现神经功能缺损期间（免疫后 11-20 天）给予，可显著改善 EAE 引起的神经行为缺陷，减少炎症细胞浸润到脊髓，并减少脱髓鞘水平。更有趣的是，在免疫后 1-10 天给予 2-BFI 选择性抑制外周血中的白细胞介素 17（IL-17）水平，这强烈表明 IL-17 可能是一个很好的早期标志物来指示 EAE 进展，而 2-BFI 可能针对 CD4⁺T 淋巴细胞，特别是 Th17 细胞，来减少 IL-17 的表达。总之，这些研究使我们设想，2-BFI 可以与 MS 进展的早期标志物（如 IL-17）联合使用，成为治疗多发性硬化症（MS）的有用药物。
