Ghareghani Majid, Dokoohaki Shima, Ghanbari Amir, Farhadi Naser, Zibara Kazem, Khodadoust Saeid, Parishani Mohammad, Ghavamizadeh Mehdi, Sadeghi Heibatollah
Cellular and Molecular Research Center, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran.
ER045, Laboratory of Stem Cells, EDST, Biology Department, Faculty of Sciences, Lebanese University, Beirut, Lebanon.
Clin Exp Pharmacol Physiol. 2017 Jan;44(1):52-61. doi: 10.1111/1440-1681.12678.
Melatonin has a beneficial role in adult rat models of multiple sclerosis (MS). In this study, melatonin treatment (10 mg/kg/d) was investigated in young age (5-6 weeks old) Lewis rat model of acute experimental autoimmune encephalomyelitis (EAE) followed by assessing serum levels of lactate and melatonin. Results showed that clinical outcomes were exacerbated in melatonin- (neurological score = 6) vs PBS-treated EAE rats (score = 5). Melatonin caused a significant increase in serum IFN-γ, in comparison to PBS-treated EAE rats whereas no considerable change in IL-4 levels were found, although they were significantly lower than those of controls. The ratio of IFN-γ/IL-4, an indicator of Th-1/Th-2, was significantly higher in PBS- and melatonin- treated EAE rats, in comparison to controls. Moreover, results showed increased lymphocyte infiltration, activated astrocytes (GFAP+ cells) but also higher demyelinated plaques (MBP-deficient areas) in the lumbar spinal cord of melatonin-treated EAE rats. Finally, serum levels of lactate, but not melatonin, significantly increased in the melatonin group, compared to untreated EAE and normal rats. In conclusion, our results indicated a relationship between age and the development of EAE since a negative impact was found for melatonin on EAE recovery of young rats by enhancing IFN-γ, the ratio of Th1/Th2 cells, and astrocyte activation, which seems to delay the remyelination process. While melatonin levels decline in MS patients, lactate might be a potential diagnostic biomarker for prediction of disease progression. Early administration of melatonin in the acute phase of MS might be harmful and needs further investigations.
褪黑素在成年大鼠多发性硬化症（MS）模型中具有有益作用。在本研究中，对年轻（5 - 6周龄）的急性实验性自身免疫性脑脊髓炎（EAE）Lewis大鼠模型进行了褪黑素治疗（10mg/kg/d），随后评估血清乳酸和褪黑素水平。结果显示，与接受磷酸盐缓冲盐水（PBS）治疗的EAE大鼠（评分 = 5）相比，接受褪黑素治疗的大鼠（神经学评分 = 6）临床结局恶化。与接受PBS治疗的EAE大鼠相比，褪黑素使血清干扰素-γ（IFN-γ）显著增加，而白细胞介素-4（IL-4）水平虽显著低于对照组但未发现明显变化。作为Th-1/Th-2指标的IFN-γ/IL-4比值，在接受PBS和褪黑素治疗的EAE大鼠中均显著高于对照组。此外，结果显示接受褪黑素治疗的EAE大鼠腰段脊髓中淋巴细胞浸润增加、星形胶质细胞活化（GFAP +细胞），并且脱髓鞘斑块（髓鞘碱性蛋白缺乏区域）也更多。最后，与未治疗的EAE大鼠和正常大鼠相比，褪黑素组血清乳酸水平显著升高，但褪黑素水平未显著升高。总之，我们的结果表明年龄与EAE的发展之间存在关联，因为发现褪黑素通过增强IFN-γ、Th1/Th2细胞比值和星形胶质细胞活化对年轻大鼠的EAE恢复产生负面影响，这似乎会延迟髓鞘再生过程。虽然MS患者的褪黑素水平会下降，但乳酸可能是预测疾病进展的潜在诊断生物标志物。在MS急性期早期给予褪黑素可能有害，需要进一步研究。
