Sodium phenylacetate inhibits adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice at multiple steps
Sodium phenylacetate inhibits adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice at multiple steps
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DOI：
10.4049/jimmunol.170.7.3874
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发表时间：
2003-04-01
影响因子：
4.4
通讯作者：
Pahan, K
中科院分区：
文献类型：
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作者：
Dasgupta, S;Zhou, Y;Pahan, K
实验性过敏性脑脊髓炎（EAE）是多发性硬化症的动物模型。本研究强调了苯乙酸钠（NaPA），一种被批准用于尿素循环障碍的药物，在多个步骤抑制雌性SJL/J小鼠过继转移EAE的疾病过程中的重要性。髓鞘碱性蛋白（MBP）引发的T细胞通过细胞间接触诱导小鼠小胶质细胞NO合成酶（iNOS）的表达和NF-kappaB的激活。然而，用NaPA预处理mbp启动的T细胞明显抑制其诱导小胶质细胞iNOS表达和NF-kappaB活化的能力。与此一致的是，在雌性SJL/J小鼠中，过继性转移mbp -启动的T细胞，而不是经过napa预处理的mbp -启动的T细胞，可诱导EAE的临床症状。此外，与正常供体小鼠分离的mbp - T细胞相比，从napa处理的供体小鼠分离的mbp - T细胞在诱导小胶质细胞iNOS和向受体小鼠转移EAE方面的效率也较低。有趣的是，饮用NaPA的小鼠EAE的临床症状比未饮用NaPA的小鼠要少得多。与NaPA类似，化学合成的NaPA前体苯基丁酸钠也能抑制EAE的发病过程。组织学和免疫细胞化学分析显示，NaPA抑制eae诱导的脊髓单核细胞侵袭，并使脊髓内iNOS、硝基酪氨酸和p65 （NF-kappaB的RelA亚基）的表达正常化。综上所述，我们的研究结果提出了一种可能性，即通过饮用水或牛奶服用NaPA或苯基丁酸钠可能会减少多发性硬化症患者观察到的神经炎症和疾病过程。
Experimental allergic encephalomyelitis (EAE) is the animal model for multiple sclerosis. The present study underlines the importance of sodium phenylacetate (NaPA), a drug approved for urea cycle disorders, in inhibiting the disease process of adoptively transferred EAE in female SJL/J mice at multiple steps. Myelin basic protein (MBP)-primed T cells alone induced the expression of NO synthase (iNOS) and the activation of NF-kappaB in mouse microglial cells through cell-cell contact. However, pretreatment of MBP-primed T cells with NaPA markedly inhibited its ability to induce microglial expression of iNOS and activation of NF-kappaB. Consistently, adoptive transfer of MBP-primed T cells, but not that of NaPA-pretreated MBP-primed T cells, induced the clinical symptoms of EAE in female SJL/J mice. Furthermore, MBP-primed T cells isolated from NaPA-treated donor mice were also less efficient than MBP-primed T cells isolated from normal donor mice in inducing iNOS in microglial cells and transferring EAE to recipient mice. Interestingly, clinical symptoms of EAE were much less in mice receiving NaPA through drinking water than those without NaPA. Similar to NaPA, sodium phenylbutyrate, a chemically synthesized precursor of NaPA, also inhibited the disease process of EAE. Histological and immunocytochemical analysis showed that NaPA inhibited EAE-induced spinal cord mononuclear cell invasion and normalized iNOS, nitrotyrosine, and p65 (the RelA subunit of NF-kappaB) expression within the spinal cord. Taken together, our results raise the possibility that NaPA or sodium phenylbutyrate taken through drinking water or milk may reduce the observed neuroinflammation and disease process in multiple sclerosis patients.