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首页> 外文期刊>Journal of Neuroimmunology: Official Bulletin of the Research Committee on Neuroimmunology of the World Federation of Neurology >Preventive but not therapeutic application of Rolipram ameliorates experimental autoimmune encephalomyelitis in Lewis rats.
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Preventive but not therapeutic application of Rolipram ameliorates experimental autoimmune encephalomyelitis in Lewis rats.

机译：咯利普兰的预防性但非治疗性应用可改善Lewis大鼠的实验性自身免疫性脑脊髓炎。

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Experimental autoimmune encephalomyelitis (EAE) in Lewis rats, an animal model mimicking some aspects of multiple sclerosis, was treated with the type IV-specific phosphodiesterase inhibitor Rolipram. Actively induced EAE evoked by immunization with myelin basic protein (MBP) in complete Freund's adjuvant was delayed but only slightly ameliorated in its maximal severity by preventive treatment with Rolipram (2 x 3 mg/kg per day) starting on the day of immunization. Therapeutic administration of Rolipram (2 x 5 mg/kg per day) was begun within hours after onset of first clinical signs of EAE but could not modify the further course of the disease. Both doses had significant side effects. Injection of 5 mg Rolipram/kg provoked transient slackening and unsteady gait while chronic application of 6 mg/kg/day strongly accelerated the weight gain in adolescent rats. EAE adoptively transferred by injection of encephalitogenic T line blasts was shortened and significantly suppressed in its severity by applicationof Rolipram (2 x 5 mg/kg per day) starting on the day of cell transfer. In corresponding lumbar spinal cord sections density of inflammatory infiltration by T cells and macrophages was reduced. Rolipram did not prevent generation of an antigen-specific immune response in vivo. In vitro the drug inconsistently inhibited MBP-induced activation of encephalitogenic T cells. TNF-alpha secretion by encephalitogenic T cells was limited only when T cell proliferation was also affected. In contrast, TNF-alpha production by LPS-activated macrophages was consistently and markedly suppressed by Rolipram. However, since the encephalitogenic T line cells produced at least 100 times more TNF-alpha than the same number of Rolipram-sensitive macrophages, the impact of Rolipram on the total amount of TNF-alpha synthesized in EAE may be limited. Together with our histological findings, the data suggest that relevant immunosuppressive mechanisms of Rolipram may be the inhibition of migration of leukocytes into the central nervous system and to some extent its inhibitory effect on T cell proliferation and macrophage activity. The downregulatory effects of Rolipram may be partially counteracted by its augmenting impact on the production of nitric oxide by macrophages.
机译：用IV型特异性磷酸二酯酶抑制剂Rolipram治疗Lewis大鼠（一种模拟多发性硬化症某些方面的动物模型）中的实验性自身免疫性脑脊髓炎（EAE）。在完全免疫的弗氏佐剂中用髓磷脂碱性蛋白（MBP）进行免疫诱导而诱发的主动诱导的EAE，从免疫当天开始就通过用Rolipram（每天2 x 3 mg / kg）进行预防性治疗而被延迟，但其最大严重程度仅得到轻微改善。在首次出现EAE的临床征兆后数小时内就开始了Rolipram的治疗性给药（每天2 x 5 mg / kg），但不能改变疾病的进一步发展过程。两种剂量都有明显的副作用。注射5 mg Rolipram / kg会引起短暂的松弛和步态不稳，而长期服用6 mg / kg / day则强烈加速了青春期大鼠的体重增加。从细胞转移日开始，通过应用咯利普兰（每天2 x 5 mg / kg），通过注射致脑病性T线胚细胞而过继转移的EAE缩短了，严重程度得到了显着抑制。在相应的腰脊髓节中，T细胞和巨噬细胞的炎症浸润密度降低。咯利普兰不能阻止体内抗原特异性免疫反应的产生。在体外，该药物不一致地抑制了MBP诱导的致脑性T细胞活化。仅当T细胞增殖也受到影响时，致脑病T细胞的TNF-α分泌才受到限制。相反，通过脂多糖激活的巨噬细胞产生的TNF-α一直被Rolipram抑制。但是，由于致脑炎的T线细胞产生的TNF-α数量比相同数量的Rolipram敏感巨噬细胞至少多100倍，因此Rolipram对EAE中合成的TNF-α总量的影响可能受到限制。连同我们的组织学发现，数据表明，咯利普兰相关的免疫抑制机制可能是抑制白细胞向中枢神经系统迁移，并在一定程度上抑制T细胞增殖和巨噬细胞活性。咯利普兰对巨噬细胞产生一氧化氮的增强作用可能部分抵消了它的下调作用。

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