THERAPY OF CHRONIC RELAPSING EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS AND THE ROLE OF THE BLOOD-BRAIN-BARRIER - ELUCIDATION BY THE ACTION OF BREQUINAR SODIUM
THERAPY OF CHRONIC RELAPSING EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS AND THE ROLE OF THE BLOOD-BRAIN-BARRIER - ELUCIDATION BY THE ACTION OF BREQUINAR SODIUM
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DOI：
10.1016/0165-5728(92)90090-8
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发表时间：
1992-05-01
影响因子：
3.3
通讯作者：
TURK, JL
中科院分区：
文献类型：
--
作者：
ONEILL, JK;BAKER, D;TURK, JL
研究了新型4-喹啉羧酸衍生物布喹那钠对Biozzi AB/H小鼠慢性复发性实验性变态反应性脑脊髓炎CREAE模型的免疫抑制作用。 尽管布喹那钠积极抑制外周免疫应答，但其显示出控制正在进行的中枢神经系统（CNS）疾病的有限潜力。 从接种后第9天（p.i.）开始给药时，25 mg/kg剂量可抑制体内诱导的增殖反应并预防EAE。 然而，当从p.i.或在急性缓解期后观察到对病程的有限影响。 相比之下，在这些时间点用单次高剂量环磷酰胺（200 mg/kg）治疗在控制疾病方面显著有效。 作为观察结果的可能解释，建议对于有效治疗CNS中正在进行的免疫应答的化合物，其必须能够穿过血脑屏障并作用于CNS内活化的疾病诱导细胞。 这一假设得到以下发现的支持：在感染后第12天脑内注射布喹那钠，显著抑制疾病进展。 这表明，旨在控制免疫介导的CNS疾病的策略需要将治疗剂量的化合物递送到CNS中。
The immunosuppressive effect of the novel 4-quinoline carboxylic acid derivative Brequinar sodium on the chronic relapsing experimental allergic encephalomyelitis CREAE model in the Biozzi AB/H mouse was investigated. Although Brequinar sodium actively inhibited peripheral immune responses, it showed a limited potential to control an ongoing disease of the central nervous system (CNS). Doses of 25 mg/kg inhibited in vivo induced proliferative response and prevented EAE when treated from day 9 post-inoculation (p.i.). However, when administered from day 12 p.i. or during the post-acute remission phase-limited effects on the course of disease were observed. By comparison, treatment with a single high dose of cyclophosphamide (200 mg/kg) at these time points was significantly effective in controlling disease. As a possible explanation of the observed results it is suggested that for a compound to be effective in treating an ongoing immune response in the CNS, it must be capable of crossing the blood-brain barrier and act on the disease-inducing cells activated within the CNS. This hypothesis is supported by the finding that intracerebral injections of Brequinar sodium on day 12 p.i. significantly inhibited disease progression. This suggests that strategies aimed at controlling immune-mediated disease of the CNS require therapeutic doses of the compounds to be delivered into the CNS.