评估 5-羟色胺受体激动剂在肌萎缩侧索硬化症小鼠模型中的作用。
Evaluation of a 5-HT receptor agonist in a murine model of amyotrophic lateral sclerosis.
机构信息
Mécanismes Centraux et Périphériques de la Neurodégénérescence, U1118, Inserm, UMR-S1118, CRBS, Université de Strasbourg, 1 rue Eugène Boeckel, 67000, Strasbourg Cedex, France.
Laboratoire de Pharmacologie et Toxicologie Neurocardiovasculaire, UR7296, Université de Strasbourg, 67000, Strasbourg, France.
出版信息
Sci Rep. 2021 Dec 8;11(1):23582. doi: 10.1038/s41598-021-02900-0.
Degeneration of brainstem serotonin neurons has been demonstrated in ALS patients and mouse models and was found responsible for the development of spasticity. Consistent with involvement of central serotonin pathways, 5-HT receptor (5-HTR) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1 mouse model and led to microglial degeneration. In ALS patients, a polymorphism in HTR2B gene leading to higher receptor expression in CNS, was associated with increased survival in patients as well as prevention of microglial degeneration. Thus, the aim of our study was to determine the effect of a 5-HTR agonist : BW723C86 (BW), in the Sod1 mouse model. Despite good pharmacokinetic and pharmacological profiles, BW did not ameliorate disease outcome or motor neuron degeneration in a fast progressing mouse model of ALS despite evidence of modulation of microglial gene expression.
脑干部位的血清素神经元退化在 ALS 患者和小鼠模型中得到了证实，并且被认为是痉挛发展的原因。与中枢血清素途径的参与一致，5-HT 受体（5-HTR）在 ALS 小鼠的小胶质细胞中上调。在 Sod1 小鼠模型中，其缺失会使疾病结果恶化，并导致小胶质细胞退化。在 ALS 患者中，HTR2B 基因的一种导致中枢神经系统中受体表达增加的多态性与患者的存活率增加以及小胶质细胞退化的预防有关。因此，我们的研究目的是确定 5-HT 激动剂：BW723C86（BW）在 Sod1 小鼠模型中的作用。尽管具有良好的药代动力学和药理学特性，但 BW 并没有改善疾病结果或运动神经元退化，尽管有证据表明其可以调节小胶质细胞基因表达。
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