R-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanone (WIN-2) ameliorates experimental autoimmune encephalomyelitis and induces encephalitogenic T cell apoptosis:: Partial involvement of the CB2 receptor
R-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanone (WIN-2) ameliorates experimental autoimmune encephalomyelitis and induces encephalitogenic T cell apoptosis:: Partial involvement of the CB2 receptor
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DOI：
10.1016/j.bcp.2006.08.018
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发表时间：
2006-12-15
影响因子：
5.8
通讯作者：
Garcia-Merino, Antonio
中科院分区：
文献类型：
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作者：
Sanchez, Antonio J.;Gonzalez-Perez, Paz;Garcia-Merino, Antonio
许多报告表明，大麻素可能有益于多发性硬化症（MS）的对症治疗。我们已经研究了非选择性大麻素受体激动剂WIN-2作为MS的实验性自身免疫性脑脊髓炎（EAE）模型中的抑制药物的治疗特性。在通过髓磷脂反应性T细胞的过继转移在刘易斯大鼠中诱导的被动的EAE中，WIN-2改善了临床体征并减少了脊髓的细胞浸润。由于大麻素参与细胞死亡和存活的调节，我们研究了WIN-2对致脑炎性T细胞群的影响。WIN-2以剂量和时间依赖性方式诱导细胞凋亡的显著增加。在存在CB（SR 141716 A）和CB 2（SR 144528）拮抗剂、百日咳毒素（PTX）和无活性对映体WIN-3的情况下，通过致脑炎T细胞刺激研究了大麻素受体（CB）的潜在参与。SR 144528和PTX可部分阻断WIN-2诱导的细胞凋亡，而WIN-3仅对细胞活力产生轻度影响。这些结果表明CB 2受体与其他受体非依赖性机制或未知的大麻素受体一起部分参与。此外，WIN-2诱导细胞凋亡的外源性途径，如半胱天冬酶-10和-3激活所示。这些结果表明，大麻素诱导的致脑炎性T细胞的凋亡可能在EAE模型中协同抗炎作用。CB 2受体在WIN-2作用中的部分参与可能为非精神活性选择性大麻素激动剂管理MS打开新的治疗大门。(c)2006爱思唯尔公司All rights reserved.
Many reports have shown that cannabinoids might be beneficial in the symptomatic treatment of multiple sclerosis (MS). We have investigated the therapeutic properties of the non-selective cannabinoid receptor agonist WIN-2 as a suppressive drug in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the passive variety of EAE, induced in Lewis rats by adoptive transfer of myelin-reactive T cells, WIN-2 ameliorates the clinical signs and diminishes the cell infiltration of the spinal cord. Due to the involvement of cannabinoids in the regulation of cell death and survival, we investigated the effects of WIN-2 on the encephalitogenic T cell population. WIN-2 induced a profound increase of apoptosis in a dose- and time-dependent manner. The potential involvement of cannabinoid receptors (CB) was investigated by encephalitogenic T cell stimulation in the presence of the CB, (SR141716A) and CB2 (SR144528) antagonists, pertussis toxin (PTX) and the inactive enantiomer WIN-3. WIN-2-induced apoptosis was partially blocked by SR144528 and PTX, whereas, WIN-3 only exerted a mild effect on cell viability. These results point to the partial involvement of CB2 receptor together with other receptor-independent mechanism or by yet unknown cannabinoid receptors. Moreover, WIN-2 induced the extrinsic pathway of apoptosis, as shown by caspase-10 and -3 activation. These results suggest that cannabinoid-induced apoptosis of encephalitogenic T cells may cooperate in their anti-inflammatory action in EAE models. The partial involvement of CB2 receptors in WIN-2 action may open new therapeutic doors in the management of MS by non-psychoactive selective cannabinoid agonists. (c) 2006 Elsevier Inc. All rights reserved.