Department of Biomedical Sciences, Biotech Research and Innovation Center, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. henrik.hasseldam @ bric.dk
Neuroimmunomodulation. 2010;17(4):252-64. doi: 10.1159/000290041. Epub 2010 Mar 5.
Multiple sclerosis can be characterized by a strong neuroinflammatory and progressive neurodegenerative component leading to prolonged disability. The synthetic compound R(+)WIN55,212-2 is reported to be neuroprotective at moderate doses and both neuroprotective and immunomodulatory at high doses, most likely due to differences in receptor affinities. In order to investigate the effects of neuroprotection and immunomodulation in an animal model of multiple sclerosis, we examined the impact of increasing concentrations of R(+)WIN55,212-2 on the inflammatory profile in CNS during first relapse and related this to demyelination, axonal degeneration and relapse severity.
Experimental autoimmune encephalomyelitis was induced in Dark Agouti rats and treatment with R(+)WIN55,212-2 was initiated at symptom debut. The animals were scored clinically throughout the experiment, and axonal degeneration, demyelination, T cells, microglia/macrophages, TNF-alpha, IL-12, IFN-gamma, IL-10 and the T(H)17 response were estimated at the peak of the first relapse.
Treatment with high-dose R(+)WIN55,212-2 (10 and 20 mg/kg) significantly improved the clinical performance of the animals during relapse. Interestingly, treatment at any dosage did not affect the brain levels of TNF-alpha, IL-12 and IFN-gamma (T(H)1 response), whereas high-dose cannabinoid treatment reduced the number of T cells and microglia/macrophages in addition to the T(H)17 response. At the same time, we observed a significant reduction in axonal degeneration in all treatment groups whereas only high-dose treatment resulted in reduced demyelination.
High-dose R(+)WIN55,212-2 treatment reduces demyelination and axonal degeneration and has immunomodulatory effects which significantly improve clinical performance, whereas a reduction in axonal degeneration on its own, induced by 5 mg/kg R(+)WIN55,212-2, has no impact on first relapse severity.
多发性硬化症的特征是强烈的神经炎症和进行性神经退行性成分，导致长期残疾。合成化合物 R(+)WIN55,212-2 在中等剂量下具有神经保护作用，在高剂量下具有神经保护和免疫调节作用，这很可能是由于受体亲和力的差异。为了在多发性硬化症的动物模型中研究神经保护和免疫调节的作用，我们研究了增加 R(+)WIN55,212-2 浓度对初次复发期间中枢神经系统炎症谱的影响，并将其与脱髓鞘、轴突变性和复发严重程度相关联。
在 Dark Agouti 大鼠中诱导实验性自身免疫性脑脊髓炎，并在症状出现时开始用 R(+)WIN55,212-2 治疗。在整个实验过程中，对动物进行临床评分，并在首次复发高峰时评估轴突变性、脱髓鞘、T 细胞、小胶质细胞/巨噬细胞、TNF-α、IL-12、IFN-γ、IL-10 和 T(H)17 反应。
高剂量 R(+)WIN55,212-2（10 和 20mg/kg）治疗显著改善了动物在复发期间的临床表现。有趣的是，任何剂量的治疗都不会影响大脑中的 TNF-α、IL-12 和 IFN-γ（T(H)1 反应），而大麻素高剂量治疗除了 T(H)17 反应外，还减少了 T 细胞和小胶质细胞/巨噬细胞的数量。同时，我们观察到所有治疗组的轴突变性都显著减少，而只有高剂量治疗导致脱髓鞘减少。
高剂量 R(+)WIN55,212-2 治疗可减少脱髓鞘和轴突变性，并具有免疫调节作用，可显著改善临床表现，而 5mg/kg R(+)WIN55,212-2 诱导的轴突变性减少本身对首次复发严重程度没有影响。
