Brain：一种缓解ALS病人痉挛的新疗法

近日，来自法国斯特拉斯堡的研究者揭示了引发肌肉萎缩性脊髓侧索硬化症(ALS)患者出现痉挛的原因，研究者发现负责血清素释放的神经元的退化是患者痉挛的主要原因，长期研究中，研究者假设，在大脑中扮演血清素受体的分子可以消除病人的痉挛状态。相关研究成果刊登于国际杂志Brain上。

ALS是一种神经变性疾病，每年在100，000个法国人中会有2-3个新增病例。该疾病对于患者控制运动的神经元影响较大，尤其是对运动神经元和中枢运动神经元。运动神经元位于脊髓处，和肌肉直接相联系，负责肌肉的拉伸和收缩。而中枢运动神经元位于大脑处，可以接收运动指令。当疾病发生，神经元就会退化，肌肉就不会被刺激，失去收缩功能，就会使得病人的运动等行为受到严重影响。

麻痹也是该疾病伴生的一种症状，而痉挛是肌肉对刺激的加剧反应现象，其可以引发患者长期、无意识的肌肉拉伸反应，并伴随疼痛产生。在ALS患者中，痉挛经常发生，目前认为这是患者中枢运动神经元的缺失所导致。

这项研究中，研究者揭示了患者的痉挛表现实际上是和位于大脑中另一种类型的产生血清素的神经元的退化有密切关系，在ALS病人和遗传小鼠模型中，研究者发现，血清素神经元会伴随疾病的发展而功能逐渐减弱，而且脊髓中的血清素水平也会在运动症状出现之前明显降低。

某些分子的激活抵御血清素受体可以消除ALS小鼠的痉挛表现，这项研究阐明了ALS患者神经元的退化并不仅仅限制在感知运动神经系统中，因为扮演血清素受体5-HT2B/C的分子可以作为ALS长期的抗痉挛疗法。

编译自：New Development in Relief of Spasms Related to Amyotrophic Lateral Sclerosis

doi:10.1093/brain/aws274
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Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity

Christel Dentel1,2,3, Lavinia Palamiuc1,2, Alexandre Henriques1,2, Béatrice Lannes2,4, Odile Spreux-Varoquaux5,6,7, Lise Gutknecht8,9, Frédérique René1,2, Andoni Echaniz-Laguna1,2,3, Jose-Luis Gonzalez de Aguilar1,2, Klaus Peter Lesch8,10, Vincent Meininger11,12, Jean-Philippe Loeffler1,2 and Luc Dupuis1,2,12,13

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.