REVERSAL OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS WITH A HYDROXAMATE INHIBITOR OF MATRIX METALLOPROTEASES
REVERSAL OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS WITH A HYDROXAMATE INHIBITOR OF MATRIX METALLOPROTEASES
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DOI：
10.1172/jci117578
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发表时间：
1994-12-01
影响因子：
15.9
通讯作者：
STEINMAN, L
中科院分区：
文献类型：
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作者：
GIJBELS, K;GALARDY, RE;STEINMAN, L
明胶酶属于基质金属蛋白酶，在中枢神经系统的炎性脱髓鞘疾病如多发性硬化中促进组织破坏。我们使用实验性自身免疫性脑脊髓炎（EAE）作为动物模型，以评估异羟肟酸基质金属蛋白酶抑制剂（GM 6001）对炎性脱髓鞘的影响。单剂量的抑制剂，给予腹膜内，提供了足够的水平在动物的脑脊液与EAE诱导至少部分抑制的明胶酶活性的脑脊液。当从疾病诱导或临床体征开始每天给药时，GM 6001分别以剂量依赖性方式抑制临床EAE的发展或逆转临床EAE。停止给药后，动物恢复至与未给药组相同的临床病程。与未处理动物的渗透性增强相比，从临床体征开始处理的动物具有正常的血脑屏障渗透性。这些结果表明，基质金属蛋白酶抑制剂可以逆转正在进行的EAE。这种作用似乎主要是通过在疾病的炎症阶段恢复受损的血脑屏障介导的，因为治疗组之间的脱髓鞘和炎症程度没有差异。
Gelatinases, belonging to the matrix metalloproteases, contribute to tissue destruction in inflammatory demyelinating disorders of the central nervous system such as multiple sclerosis. We used experimental autoimmune encephalomyelitis (EAE) as an animal model to evaluate the effect of a hydroxamate matrix metalloprotease inhibitor (GM 6001) on inflammatory demyelination. A single dose of the inhibitor, given intraperitoneally, provided sufficient levels in the cerebrospinal fluid of animals with EAE to induce at least a partial inhibition of the gelatinase activity in the cerebrospinal fluid. When administered daily either from the time of disease induction or from the onset of clinical signs, GM 6001 suppressed the development or reversed clinical EAE in a dose-dependent way, respectively. Animals returned to the same clinical course as the nontreated group after cessation of treatment. Animals treated from the onset of clinical signs had normal permeability of the blood-brain barrier, compared with the enhanced permeability in nontreated animals. These results indicate that matrix metalloprotease inhibition can reverse ongoing EAE. This effect appears to be mediated mainly through restoration of the damaged blood-brain barrier in the inflammatory phase of the disease, since the degree of demyelination and inflammation did not differ between the treatment groups.