Department of Neuroscience, Institute of Biomedical Research August Pi Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Barcelona, Spain.
Mult Scler. 2010 Sep;16(9):1102-8. doi: 10.1177/1352458510375968. Epub 2010 Jul 29.
Methylthioadenosine (MTA) is a natural metabolite with immunomodulatory properties. MTA improves the clinical course and pathology of the animal model of multiple sclerosis, even when therapy is started after disease onset.
Our aim was to compare the efficacy of MTA in ameliorating experimental autoimmune encephalomyelitis (EAE) compared with first line approved therapies, to develop an oral formulation of MTA and to assess its pharmacokinetic profile.
EAE was induced in C57BL/6 mice by immunization with MOG(35-55) peptide in Freund's Adjuvant. Animals were treated with MTA, interferon-beta or glatiramer acetate starting the day of immunization and the clinical score was collected blind. Pharmacokinetic studies were performed in Sprague Dawley rats by administering MTA by intraperitoneal injection and orally, and collecting blood at different intervals. MTA levels were measured by high-performance liquid chromatography.
We found that MTA ameliorated EAE in a dose-response manner. Moreover, the highest dose of MTA (60 mg/kg) was more efficacious than mouse interferon-beta or glatiramer acetate. We developed a salt of MTA for oral administration, with similar dose-response effect in the EAE model. Combination therapy assays between MTA and interferon-beta or glatiramer acetate were more effective than the individual therapies. Finally, oral MTA half-life was 20 min, with a C(max) of 80 mg/L and without signs of obvious toxicity (animal death, behavioural changes, liver enzymes).
In the EAE model MTA is more efficacious than first line therapies for multiple sclerosis, with a dose- response effect and higher efficacy when combined with interferon-beta or glatiramer acetate. Oral MTA was also effective in the animal model of multiple sclerosis.
甲硫腺苷（MTA）是一种具有免疫调节特性的天然代谢物。MTA 可改善多发性硬化症动物模型的临床病程和病理学，即使在疾病发作后开始治疗也是如此。
我们旨在比较 MTA 改善实验性自身免疫性脑脊髓炎（EAE）的疗效与一线批准的治疗方法，开发 MTA 的口服制剂并评估其药代动力学特征。
通过用 MOG（35-55）肽在福氏佐剂中免疫 C57BL/6 小鼠来诱导 EAE。动物从免疫之日开始用 MTA、干扰素-β或那他珠单抗治疗，并进行盲法临床评分。通过腹腔内注射和口服给予 MTA 并在不同时间间隔采集血液，在 Sprague Dawley 大鼠中进行药代动力学研究。通过高效液相色谱法测量 MTA 水平。
我们发现 MTA 以剂量反应方式改善 EAE。此外，MTA 的最高剂量（60mg/kg）比小鼠干扰素-β或那他珠单抗更有效。我们开发了 MTA 的一种口服盐，在 EAE 模型中具有相似的剂量反应效应。MTA 与干扰素-β或那他珠单抗联合治疗的测定比单独治疗更有效。最后，口服 MTA 的半衰期为 20 分钟，Cmax 为 80mg/L，且无明显毒性迹象（动物死亡、行为改变、肝酶）。
在 EAE 模型中，MTA 比多发性硬化症的一线治疗更有效，具有剂量反应效应，与干扰素-β或那他珠单抗联合使用时疗效更高。口服 MTA 对多发性硬化症的动物模型也有效。
