A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease.
A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease.
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DOI：
10.1038/s41598-022-17338-1
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发表时间：
2022-08-15
影响因子：
4.6
通讯作者：
Rahim, A. A.
中科院分区：
文献类型：
--
作者：
Poupon-Bejuit, L.;Hughes, M. P.;Liu, W.;Geard, A.;Faour-Slika, N.;Whaler, S.;Massaro, G.;Rahim, A. A.
婴儿神经轴索营养不良（INAD）是一种罕见的儿科神经退行性疾病，由PLA 2G 6基因突变引起，PLA 2G 6基因也是PARK 14连锁的年轻成人发作肌张力障碍帕金森症的致病基因。INAD患者通常在生命的前十年内死亡，目前没有有效的治疗方法。GLP-1受体（GLP-1 R）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特性。因此，我们在INAD小鼠模型中评价了一种新的最近获得许可的GLP-1 R激动剂糖尿病药物的疗效。幼龄INAD小鼠每周一次全身给予高剂量Semaglutide可改善运动功能并延长寿命。对这些治疗作用机制的研究表明，Semaglutide显著增加了关键神经保护分子的水平，同时降低了参与促神经退行性通路的分子水平。在Semaglutide给药小鼠中，凋亡和坏死性凋亡途径中的介质表达也显著降低。观察到神经元损失和神经炎症减少。最后，野生型小鼠中未出现与本研究中使用的semaglutide重复高剂量相关的明显炎症反应。
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.
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DOI：
10.1016/s0140-6736(17)31585-4
发表时间：
2017-10-07
期刊：
Lancet (London, England)
影响因子：
--
作者：
Athauda D;Maclagan K;Skene SS;Bajwa-Joseph M;Letchford D;Chowdhury K;Hibbert S;Budnik N;Zampedri L;Dickson J;Li Y;Aviles-Olmos I;Warner TT;Limousin P;Lees AJ;Greig NH;Tebbs S;Foltynie T
通讯作者：
Foltynie T
影响因子：
2
作者：
Gundersen, HJG;Jensen, EBV;Nielsen, J
通讯作者：
Nielsen, J
影响因子：
4.8
作者：
Hunt D;Raivich G;Anderson PN
通讯作者：
Anderson PN
影响因子：
3.3
作者：
Kimura, R.;Okouchi, M.;Joh, T.
通讯作者：
Joh, T.
DOI：
10.1016/b978-0-444-59565-2.00062-9
发表时间：
2013-01-01
期刊：
PEDIATRIC NEUROLOGY, PT III
影响因子：
--
作者：
Nardocci, Nardo;Zorzi, Giovanna
通讯作者：
Zorzi, Giovanna