Sodium channel expression within chronic multiple sclerosis plaques
Sodium channel expression within chronic multiple sclerosis plaques
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DOI：
10.1097/nen.0b013e3181462841
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发表时间：
2007-09-01
影响因子：
3.2
通讯作者：
Waxman, Stephen G.
中科院分区：
文献类型：
--
作者：
Black, Joel A.;Newcombe, Jia;Waxman, Stephen G.
多发性硬化症(MS)的特点是髓鞘局灶性破坏、神经胶质瘢痕和轴突损伤，这些损害导致持续的临床缺陷积累。以往的研究表明，钠通道Na(V)1.6和钠钙交换器(NCX)以及轴突损伤的标志物β-淀粉样前体蛋白(β-APP)在急性MS损伤的变性轴突中共同表达。与急性斑块相比，慢性MS病变中轴突变性的发生率较低，尽管目前的证据表明，慢性病变(“慢烧”)中的轴突丢失是累积残疾的主要原因。然而，尽管细胞外环境截然不同，但慢性和急性病变中的轴突变性是否具有共同的机制尚不清楚。本研究检测了钠通道Na(V)1.2和Na(V)1.6以及NCX在脊髓内慢性MS斑块中的表达。NA(V)1.2在慢性皮损中沿脱髓鞘轴突未见表达，但在斑块内的瘢痕和反应性星形胶质细胞中表达。NA(V)1.6免疫反应在斑块内约1/3的脱髓鞘轴突中呈斑块状而不是连续分布，在正常脑白质的Ranvier结节呈强阳性反应。在慢性病变的脱髓鞘轴突中未检测到NCX，但在脱髓鞘轴突周围的瘢痕星形胶质细胞中明显存在NCX。β-APP在脊髓慢性损伤内的轴突中积聚了一小部分，但在表达Na(V)1.6的轴突中并不优先出现。这些观察结果表明，急性和慢性MS病变中轴突变性的机制不同，急性病变中轴突损伤发生在Na(V)1.6和NCX共表达的部位，而在慢性病变中这两个分子的共同表达独立于这两个分子的共同表达。
Multiple sclerosis (MS) is characterized by focal destruction of myelin sheaths, gliotic scars, and axonal damage that contributes to the accumulation of nonremitting clinical deficits. Previous studies have demonstrated coexpression of sodium channel Na(v)1.6 and the sodium-calcium exchanger (NCX), together with beta-amyloid precursor protein (beta-APP), a marker of axonal damage, in degenerating axons within acute MS lesions. Axonal degeneration is less frequent within chronic MS lesions than in acute plaques, although current evidence suggests that axonal loss in chronic lesions ("slow burn") is a major contributor to accumulating disability. It is not known, however, whether axonal degenerations in chronic and acute lesions share common mechanisms, despite radically differing extracellular milieus. In this study, the expression of sodium channels Na(v)1.2 and Na(v)1.6 and of NCX was examined in chronic MS plaques within the spinal cord. Na(v)1.2 immunostaining was not observed along demyelinated axons in chronic lesions but was expressed by scar and reactive astrocytes within the plaque. Na(v)1.6 immunoreactivity, which was intense at nodes of Ranvier in normal appearing white matter in the same sections, was present in approximately one-third of the demyelinated axons within these plaques in a patchy rather than continuous distribution. NCX was not detected in demyelinated axons within chronic lesions, although it was clearly present within the scar astrocytes surrounding the demyelinated axons. beta-APP accumulation occurred in a small percentage of axons within chronic lesions within the spinal cord, but beta-APP was not preferentially present in axons that expressed Na(v)1.6. These observations suggest that different mechanisms underlie axonal degeneration in acute and chronic MS lesions, with axonal injury occurring at sites of coexpression of Na(v)1.6 and NCX in acute lesions but independent of coexpression of these 2 molecules in chronic lesions.