Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord.
Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord.
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DOI：
10.1016/j.nbd.2011.06.004
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发表时间：
2011-10
影响因子：
6.1
通讯作者：
Deng, Wenbin
中科院分区：
文献类型：
--
作者：
Chechneva, Olga V.;Mayrhofer, Florian;Daugherty, Daniel J.;Pleasure, David E.;Hong, Jau-Shyong;Deng, Wenbin
关键词：
右美沙芬（DM）是一种右旋吗啡喃，是一种广泛使用的咳嗽药成分。相对高剂量的DM联合奎尼丁用于治疗多发性硬化症（MS）患者的情绪障碍。然而，在较低剂量下，吗啡类通过抑制活化的小胶质细胞中NOX 2依赖性超氧化物的产生来发挥抗炎活性。在这里，我们研究了高（10 mg/kg，i. p.，“DM-10”）和低剂量（0.1 mg/kg，i. p.，“DM-0.1”）剂量的DM对小鼠实验性自身免疫性脑脊髓炎（EAE）（MS的动物模型）的发展和进展的影响。有趣的是，在重度EAE中观察到低剂量DM治疗的轻微晚期衰减，其特征在于慢性病程和大量CD 45+细胞（包括T淋巴细胞、巨噬细胞和中性粒细胞）的脊髓浸润。此外，在不太严重的EAE形式中，其中在脊髓中观察到较低水平的CD 4+和CD 8 + T细胞、Iba 1+小胶质细胞/巨噬细胞并且没有显著的嗜中性粒细胞浸润，用DM-0.1治疗明显更有益。这种作用在疾病高峰期最为显著，并与抑制NOX 2表达和减少单核细胞和淋巴细胞浸润到脊髓中有关。此外，低剂量DM长期治疗导致腰椎脊髓脱髓鞘减少和轴突丢失减少。我们的研究是第一个报告，表明低剂量DM是有效的治疗EAE的中度。我们的研究结果表明，低剂量吗啡喃治疗糖尿病可能代表了一个新的有前途的保护策略，治疗MS。
Dextromethorphan (DM) is a dextrorotary morphinan and a widely used component of cough medicine. Relatively high doses of DM in combination with quinidine are used for the treatment of mood disorders for patients with multiple sclerosis (MS). However, at lower doses, morphinans exert anti-inflammatory activities through the inhibition of NOX2-dependent superoxide production in activated microglia. Here we investigated the effects of high (10 mg/kg, i.p., “DM-10”) and low (0.1 mg/kg, i.p., “DM-0.1”) doses of DM on the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found no protection by high dose DM treatment. Interestingly, a minor late attenuation by low dose DM treatment was seen in severe EAE that was characterized by a chronic disease course and a massive spinal cord infiltration of CD45+ cells including T-lymphocytes, macrophages and neutrophils. Furthermore, in a less severe form of EAE, where lower levels of CD4+ and CD8+ T-cells, Iba1+ microglia/macrophages and no significant infiltration of neutrophils were seen in the spinal cord, the treatment with DM-0.1 was remarkably more beneficial. The effect was the most significant at the peak of disease and was associated with an inhibition of NOX2 expression and a decrease in infiltration of monocytes and lymphocytes into the spinal cord. In addition, chronic treatment with low dose DM resulted in decreased demyelination and reduced axonal loss in the lumbar spinal cord. Our study is the first report to show that low dose DM is effective in treating EAE of moderate severity. Our findings reveal that low dose morphinan DM treatment may represent a new promising protective strategy for treating MS.
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影响因子：
25
作者：
Liu, LiPing;Belkadi, Abdelmadjid;Darnall, Lindsey;Hu, Taofang;Drescher, Caitlin;Cotleur, Anne C.;Padovani-Claudio, Dolly;He, Tao;Choi, Karen;Lane, Thomas E.;Miller, Robert H.;Ransohoff, Richard M.
通讯作者：
Ransohoff, Richard M.
影响因子：
6.2
作者：
Berard, Jennifer L.;Wolak, Kevin;David, Samuel
通讯作者：
David, Samuel
DOI：
10.1073/pnas.0402890101
发表时间：
2004-10-12
影响因子：
11.1
作者：
Hayashi, T;Su, TP
通讯作者：
Su, TP
DOI：
10.1124/jpet.102.043166
发表时间：
2003-04-01
影响因子：
3.5
作者：
Liu, YX;Qin, LY;Hong, JS
通讯作者：
Hong, JS
影响因子：
4.8
作者：
Huppert, Jula;Closhen, Dorothea;Kuhlmann, Christoph R. W.
通讯作者：
Kuhlmann, Christoph R. W.