一种新的基质金属蛋白酶抑制剂ONO-4817对实验性自身免疫性脑脊髓炎的治疗作用

目的　探讨一种新合成的含氧肟酸的基质金属蛋白酶 ( MMP)抑制剂 ONO-481 7对实验性自身免疫性脑脊髓炎 ( EAE)的治疗效果。方法　给 EAE大鼠口服 ONO-481 7,观察临床症状、T淋巴细胞增殖以及血清肿瘤坏死因子 ( TNF) -α水平。结果　 ONO-481 7能显著改善 EAE临床症状 ( P <0 .0 1 ) ,同时明显抑制 T淋巴细胞增殖 ( P <0 .0 1 ) ,显著降低大鼠血清 TNF-α水平 ( P <0 .0 5 )。结论　研究表明 ,ONO-481 7通过抑制 MMPs活性、T淋巴细胞增殖和减少 TNF-α生成 ,进而能显著减轻血脑屏障 ( BBB)的破坏 ,又可抑制炎细胞浸润和髓鞘破坏 ,从而有效缓解 EAE。

Suppression of Active Experimental Autoimmune Encephalomyelitis in Lewis Rats by Using Compound ONO-4817,a New Inhibitor of Matrix Metalloproteinases

Objective To explore the clinical effects of ONO-4817, a new synthetic hydroxamic acid-based combined inhibitor of matrix metalloproteinases (MMPs) activity, on experimental autoimmune encephalo-myelitis (EAE). Methods The rats of EAE were treated with ONO-4817 by oral and then were examined for the development of neurological sign, T cell proliferative responses and serum tumor necrosis factor (TNF)-α concentrations. Results The clinical signs were suppressed significantly in ONO-4817 group EAE (P<0.01). Furthermore, T cell proliferation was significantly inhibited (P<0.01) and the serum TNF-α concentration was significantly decreased (P<0.05) in ONO-4817-treated rats. Conclusions By inhibiting of MMPs activities, suppressing T cell proliferation and by decreasing TNF-α production, ONO-4817 would reduce the blood-brain barrier (BBB) breakdown, inflammatory cell recruitment, and myelin sheath damage significantly and therefore efficiently ameliorate EAE.