PEG minocycline-liposomes ameliorate CNS autoimmune disease.
PEG minocycline-liposomes ameliorate CNS autoimmune disease.
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DOI：
10.1371/journal.pone.0004151
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Stüve O
中科院分区：
文献类型：
--
作者：
Hu W;Metselaar J;Ben LH;Cravens PD;Singh MP;Frohman EM;Eagar TN;Racke MK;Kieseier BC;Stüve O
米诺环素是一种口服四环素衍生物，在中枢神经系统（CNS）具有良好的生物利用度。米诺环素是一种有效的基质金属蛋白酶（MMP）-9抑制剂，可减轻多发性硬化（MS）动物模型实验性自身免疫性脑脊髓炎（EAE）的疾病活动性。与长期每日米诺环素治疗人类患者相关的潜在不良反应令人担忧。在这里，我们研究了是否较低频率的治疗与长循环聚乙二醇（PEG）米诺环素脂质体是有效的治疗EAE。在人外周血单核细胞（PBMC）中进行PEG米诺环素-脂质体的体外时间动力学研究，我们确定了用CaCl 2稳定的PEG米诺环素-脂质体制剂有效降低MMP-9活性。静脉注射聚乙二醇米诺环素脂质体，每五天一次改善临床EAE的有效性为每日腹腔注射米诺环素。用PEG米诺环素脂质体治疗动物显著减少CNS浸润白细胞的数量，以及CNS中MMP-9的总体表达。也有一个显着的抑制MMP-9的表达和蛋白水解活性在脾细胞的治疗动物，但不是在CNS浸润性白细胞。因此，进入脑和脊髓的白细胞在所有治疗组中需要相同绝对量的MMP-9，但米诺环素降低了绝对细胞数。我们的数据表明，较低频率的PEG米诺环素-脂质体注射是一种有效的替代药物疗法，每日米诺环素注射治疗中枢神经系统自身免疫性疾病。此外，MMP-9的抑制仍然是EAE和MS患者有希望的治疗靶点。
Minocycline is an oral tetracycline derivative with good bioavailability in the central nervous system (CNS). Minocycline, a potent inhibitor of matrix metalloproteinase (MMP)-9, attenuates disease activity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Potential adverse effects associated with long-term daily minocycline therapy in human patients are concerning. Here, we investigated whether less frequent treatment with long-circulating polyethylene glycol (PEG) minocycline liposomes are effective in treating EAE. Performing in vitro time kinetic studies of PEG minocycline-liposomes in human peripheral blood mononuclear cells (PBMCs), we determined that PEG minocycline-liposome preparations stabilized with CaCl2 are effective in diminishing MMP-9 activity. Intravenous injections of PEG minocycline-liposomes every five days were as effective in ameliorating clinical EAE as daily intraperitoneal injections of minocycline. Treatment of animals with PEG minocycline-liposomes significantly reduced the number of CNS-infiltrating leukocytes, and the overall expression of MMP-9 in the CNS. There was also a significant suppression of MMP-9 expression and proteolytic activity in splenocytes of treated animals, but not in CNS-infiltrating leukocytes. Thus, leukocytes gaining access to the brain and spinal cord require the same absolute amount of MMP-9 in all treatment groups, but minocycline decreases the absolute cell number. Our data indicate that less frequent injections of PEG minocycline-liposomes are an effective alternative pharmacotherapy to daily minocycline injections for the treatment of CNS autoimmune diseases. Also, inhibition of MMP-9 remains a promising treatment target in EAE and patients with MS.
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影响因子：
14.5
作者：
Kieseier, BC;Kiefer, R;Hartung, HP
通讯作者：
Hartung, HP
影响因子：
11.2
作者：
Leppert, D;Waubant, E;Hauser, SL
通讯作者：
Hauser, SL
影响因子：
4.4
作者：
Stüve, O;Youssef, S;Zamvil, SS
通讯作者：
Zamvil, SS
影响因子：
15.9
作者：
Stüve, O;Youssef, S;Zamvil, SS
通讯作者：
Zamvil, SS
影响因子：
3
作者：
Keilhoff, Gerburg;Langnaese, Kristina;Fansa, Hisham
通讯作者：
Fansa, Hisham