Department of Anaesthesiology, University of Illinois at Chicago, Jesse Brown Medical Centre, Chicago, IL 60612, USA.
Brain. 2011 Mar;134(Pt 3):665-77. doi: 10.1093/brain/awq362. Epub 2011 Feb 4.
The endogenous neurotransmitter noradrenaline exerts anti-inflammatory and neuroprotective effects in vitro and in vivo. Several studies report that noradrenaline levels are altered in the central nervous system of patients with multiple sclerosis and rodents with experimental autoimmune encephalomyelitis, which could contribute to pathology. Since the major source of noradrenaline are neurons in the locus coeruleus, we hypothesized that alterations in noradrenaline levels are a consequence of stress or damage to locus coeruleus neurons. In C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide 35-55 to develop chronic disease, cortical and spinal cord levels of noradrenaline were significantly reduced versus control mice. Immunohistochemical staining revealed increased astrocyte activation in the ventral portion of the locus coeruleus in immunized mice. The immunized mice showed neuronal damage in the locus coeruleus detected by a reduction of average cell size of tyrosine hydroxylase stained neurons. Analysis of the locus coeruleus of multiple sclerosis and control brains showed a significant increase in astrocyte activation, a reduction in noradrenaline levels, and neuronal stress indicated by hypertrophy of tyrosine hydroxylase stained cell bodies. However, the magnitude of these changes was not correlated with extent of demyelination or of cellular infiltrates. Together these findings demonstrate the presence of inflammation and neuronal stress in multiple sclerosis as well as in experimental autoimmune encephalomyelitis. Since reduced noradrenaline levels could be permissive for increased inflammation and neuronal damage, these results suggest that methods to raise noradrenaline levels or increase locus coeruleus function may be of benefit in treating multiple sclerosis.
内源性神经递质去甲肾上腺素在体外和体内具有抗炎和神经保护作用。几项研究报告称，多发性硬化症患者和实验性自身免疫性脑脊髓炎啮齿动物的中枢神经系统中去甲肾上腺素水平发生改变，这可能导致疾病发生。由于去甲肾上腺素的主要来源是蓝斑核中的神经元，我们假设去甲肾上腺素水平的改变是蓝斑核神经元应激或损伤的结果。在接受髓鞘少突胶质细胞糖蛋白肽 35-55 免疫以发展为慢性疾病的 C57BL/6 小鼠中，皮质和脊髓中的去甲肾上腺素水平与对照小鼠相比显著降低。免疫组织化学染色显示，免疫小鼠蓝斑核腹侧部分的星形胶质细胞激活增加。免疫小鼠的蓝斑核出现神经元损伤，酪氨酸羟化酶染色神经元的平均细胞大小减少可检测到这种损伤。对多发性硬化症和对照大脑的蓝斑核分析显示，星形胶质细胞激活显著增加，去甲肾上腺素水平降低，以及酪氨酸羟化酶染色细胞体肥大表明神经元应激。然而，这些变化的幅度与脱髓鞘或细胞浸润的程度无关。这些发现共同表明多发性硬化症以及实验性自身免疫性脑脊髓炎存在炎症和神经元应激。由于去甲肾上腺素水平降低可能允许炎症和神经元损伤增加，这些结果表明，提高去甲肾上腺素水平或增加蓝斑核功能的方法可能有益于多发性硬化症的治疗。
