U692, INSERM, 67085 Strasbourg, France.
Brain. 2013 Feb;136(Pt 2):483-93. doi: 10.1093/brain/aws274. Epub 2012 Oct 31.
Spasticity is a common and disabling symptom observed in patients with central nervous system diseases, including amyotrophic lateral sclerosis, a disease affecting both upper and lower motor neurons. In amyotrophic lateral sclerosis, spasticity is traditionally thought to be the result of degeneration of the upper motor neurons in the cerebral cortex, although degeneration of other neuronal types, in particular serotonergic neurons, might also represent a cause of spasticity. We performed a pathology study in seven patients with amyotrophic lateral sclerosis and six control subjects and observed that central serotonergic neurons suffer from a degenerative process with prominent neuritic degeneration, and sometimes loss of cell bodies in patients with amyotrophic lateral sclerosis. Moreover, distal serotonergic projections to spinal cord motor neurons and hippocampus systematically degenerated in patients with amyotrophic lateral sclerosis. In SOD1 (G86R) mice, a transgenic model of amyotrophic lateral sclerosis, serotonin levels were decreased in brainstem and spinal cord before onset of motor symptoms. Furthermore, there was noticeable atrophy of serotonin neuronal cell bodies along with neuritic degeneration at disease onset. We hypothesized that degeneration of serotonergic neurons could underlie spasticity in amyotrophic lateral sclerosis and investigated this hypothesis in vivo using tail muscle spastic-like contractions in response to mechanical stimulation as a measure of spasticity. In SOD1 (G86R) mice, tail muscle spastic-like contractions were observed at end-stage. Importantly, they were abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists. In line with this, 5-hydroxytryptamine-2b receptor expression was strongly increased at disease onset. In all, we show that serotonergic neurons degenerate during amyotrophic lateral sclerosis, and that this might underlie spasticity in mice. Further research is needed to determine whether inverse agonists of 5-hydroxytryptamine-2b/c receptors could be of interest in treating spasticity in patients with amyotrophic lateral sclerosis.
痉挛是一种常见且使人丧失能力的症状，见于包括肌萎缩侧索硬化症在内的中枢神经系统疾病患者，该病影响上下运动神经元。在肌萎缩侧索硬化症中，痉挛传统上被认为是大脑皮层上运动神经元变性的结果，尽管其他神经元类型的变性，特别是 5-羟色胺能神经元的变性，也可能是痉挛的一个原因。我们对 7 例肌萎缩侧索硬化症患者和 6 例对照者进行了病理学研究，观察到中枢 5-羟色胺能神经元发生退行性变，表现为突出的神经原变性，有时伴有神经元细胞体丢失。此外，患者的 5-羟色胺能远位投射到脊髓运动神经元和海马系统退行性变。在 SOD1（G86R）转基因肌萎缩侧索硬化症小鼠模型中，在运动症状出现之前，脑干和脊髓中的 5-羟色胺水平降低。此外，在疾病发病时，明显可见 5-羟色胺能神经元细胞体萎缩和神经原变性。我们假设 5-羟色胺能神经元的变性可能是肌萎缩侧索硬化症痉挛的基础，并在活体中通过机械刺激引起的尾部肌肉痉挛样收缩来研究该假说，将其作为痉挛的测量指标。在 SOD1（G86R）小鼠中，尾部肌肉痉挛样收缩在疾病晚期出现。重要的是，它们被 5-羟色胺 2B/2C 受体反向激动剂所消除。与此一致的是，在疾病发病时 5-羟色胺 2B 受体的表达强烈增加。总之，我们表明在肌萎缩侧索硬化症中 5-羟色胺能神经元发生变性，并且这可能是在小鼠中发生痉挛的基础。进一步的研究需要确定 5-羟色胺 2B/2C 受体的反向激动剂是否对治疗肌萎缩侧索硬化症患者的痉挛有意义。
