UCL School of Pharmacy, University College London, London, UK.
Sci Rep. 2022 Aug 15;12(1):13825. doi: 10.1038/s41598-022-17338-1.
Infantile neuroaxonal dystrophy (INAD) is a rare paediatric neurodegenerative condition caused by mutations in the PLA2G6 gene, which is also the causative gene for PARK14-linked young adult-onset dystonia parkinsonism. INAD patients usually die within their first decade of life, and there are currently no effective treatments available. GLP1 receptor (GLP-1R) agonists are licensed for treating type 2 diabetes mellitus but have also demonstrated neuroprotective properties in a clinical trial for Parkinson's disease. Therefore, we evaluated the therapeutic efficacy of a new recently licensed GLP-1R agonist diabetes drug in a mouse model of INAD. Systemically administered high-dose semaglutide delivered weekly to juvenile INAD mice improved locomotor function and extended the lifespan. An investigation into the mechanisms underlying these therapeutic effects revealed that semaglutide significantly increased levels of key neuroprotective molecules while decreasing those involved in pro-neurodegenerative pathways. The expression of mediators in both the apoptotic and necroptotic pathways were also significantly reduced in semaglutide treated mice. A reduction of neuronal loss and neuroinflammation was observed. Finally, there was no obvious inflammatory response in wild-type mice associated with the repeated high doses of semaglutide used in this study.
婴儿神经轴索性营养不良（INAD）是一种罕见的儿科神经退行性疾病，由 PLA2G6 基因突变引起，该基因也是与 PARK14 相关的青年发病的肌张力障碍性帕金森病的致病基因。INAD 患者通常在生命的第一个十年内死亡，目前尚无有效的治疗方法。GLP1 受体（GLP-1R）激动剂被批准用于治疗 2 型糖尿病，但在帕金森病的临床试验中也显示出神经保护作用。因此，我们在 INAD 小鼠模型中评估了一种新的最近获得批准的 GLP-1R 激动剂糖尿病药物的治疗效果。每周向幼年 INAD 小鼠全身给予高剂量司美格鲁肽可改善运动功能并延长寿命。对这些治疗效果的机制进行研究发现，司美格鲁肽可显著增加关键神经保护分子的水平，同时减少参与神经退行性途径的分子。凋亡和坏死性途径中的介质表达也在司美格鲁肽治疗的小鼠中显著降低。观察到神经元丢失和神经炎症减少。最后，在本研究中使用的重复高剂量司美格鲁肽中，未观察到野生型小鼠的明显炎症反应。
