Therapeutic Potential of a Novel Glucagon-like Peptide-1 Receptor Agonist, NLY01, in Experimental Autoimmune Encephalomyelitis
Therapeutic Potential of a Novel Glucagon-like Peptide-1 Receptor Agonist, NLY01, in Experimental Autoimmune Encephalomyelitis
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DOI：
10.1007/s13311-021-01088-5
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发表时间：
2021-07-14
影响因子：
5.7
通讯作者：
Calabresi, Peter A.
中科院分区：
文献类型：
--
作者：
Gharagozloo, Marjan;Smith, Matthew D.;Calabresi, Peter A.
多发性硬化（MS）是一种中枢神经系统（CNS）慢性炎症性疾病，其特征在于脱髓鞘、神经胶质增生和神经变性。虽然目前可用的疾病修饰疗法有效地抑制了对CNS的免疫攻击，但迄今为止还没有直接减轻神经变性的疗法。胰高血糖素样肽-1（GLP-1）是一种维持葡萄糖稳态的小肽激素。一种新的GLP-1受体（GLP-1 R）激动剂NLY 01最近被证明在帕金森病动物模型中具有神经保护作用，目前正在进行2期临床试验。在这项研究中，我们研究了NLY 01在MS小鼠模型（实验性自身免疫性脑脊髓炎（EAE））中的治疗潜力。我们的数据显示，当在疾病发作之前给予时，NLY 01在预防范例中延迟EAE的发作并减轻其严重程度。NLY 01抑制脾脏中免疫细胞的活化，并减少其向CNS的运输。此外，我们发现NLY 01抑制参与白细胞募集到炎症部位的趋化因子的产生。NLY 01在EAE早期阶段的抗炎作用可能阻断视神经中与神经毒性星形胶质细胞相关的基因的表达，从而防止EAE进展阶段的视网膜神经节细胞（RGC）损失。在治疗范例中，NLY 01显著降低复发-缓解型EAE模型中的临床评分和二次发作。GLP-1 R激动剂可通过抑制外周和CNS炎症，从而限制神经元损失，对MS具有双重疗效。
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), characterized by demyelination, gliosis, and neurodegeneration. While the currently available disease-modifying therapies effectively suppress the immune attack on the CNS, there are no therapies to date that directly mitigate neurodegeneration. Glucagon-like peptide-1 (GLP-1) is a small peptide hormone that maintains glucose homeostasis. A novel GLP-1 receptor (GLP-1R) agonist, NLY01, was recently shown to have neuroprotective effects in the animal models of Parkinson's disease and is now in a phase 2 clinical trial. In this study, we investigated the therapeutic potential of NLY01 in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Our data show that NLY01 delays the onset and attenuates the severity of EAE in a prevention paradigm, when given before disease onset. NLY01 inhibits the activation of immune cells in the spleen and reduces their trafficking into the CNS. In addition, we show that NLY01 suppresses the production of chemokines that are involved in leukocyte recruitment to the site of inflammation. The anti-inflammatory effect of NLY01 at the early stage of EAE may block the expression of the genes associated with neurotoxic astrocytes in the optic nerves, thereby preventing retinal ganglion cell (RGC) loss in the progressive stage of EAE. In the therapeutic paradigm, NLY01 significantly decreases the clinical score and second attack in a model of relapsing-remitting EAE. GLP-1R agonists may have dual efficacy in MS by suppressing peripheral and CNS inflammation, thereby limiting neuronal loss.