Peroxisome proliferator-activated receptor-γ agonists prevent experimental autoimmune encephalomyelitis
Peroxisome proliferator-activated receptor-γ agonists prevent experimental autoimmune encephalomyelitis
复制标题
DOI：
10.1002/ana.10206
复制
发表时间：
2002-06-01
影响因子：
11.2
通讯作者：
Heneka, MT
中科院分区：
文献类型：
--
作者：
Feinstein, DL;Galea, E;Heneka, MT
多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎（EAE）的临床症状的发展涉及T细胞活化和迁移到中枢神经系统、胶质源性炎症分子的产生以及脱髓鞘和轴突损伤。过氧化物酶体增殖物激活受体（过氧化物酶体增殖物激活受体）的配体对神经胶质细胞发挥抗炎作用，减少T细胞的增殖和活化，并诱导髓鞘基因表达。我们在两种EAE模型中证明，口服给予PPAR-γ配体吡格列酮可降低髓鞘少突胶质细胞糖蛋白肽免疫的C57 BL/6小鼠中的晚期慢性疾病的发生率和严重程度，以及髓鞘碱性蛋白免疫的B10.P1小鼠中的复发性疾病的发生率和严重程度。在疾病发作后给予吡格列酮也可减轻临床体征。两种其他PPAR-gamma激动剂可减轻临床症状，提示PPARgamma激活在保护作用中的作用。临床体征的抑制通过减少淋巴细胞浸润、减轻脱髓鞘、减少趋化因子和细胞因子表达以及增加脑中的κ B抑制剂（Ik B）表达而得以证实。吡格列酮还减少了EAE衍生T细胞产生的抗原依赖性干扰素-γ。这些结果表明，口服给药的PPARgamma激动剂可以在脱髓鞘疾病中提供治疗益处。
The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, production of glial-derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPAR-gamma ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.P1 mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPAR-gamma agonists, suggesting a role for PPARgamma activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-gamma production from EAE-derived T cells. These results suggest that orally administered PPARgamma agonists could provide therapeutic benefit in demyelinating disease.