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鼻内给予催产素可抑制 NGLY1 缺乏症小鼠模型的癫痫样行为。

Intranasal oxytocin suppresses seizure-like behaviors in a mouse model of NGLY1 deficiency.

机构信息

Takeda-CiRA Joint Program, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.

Global Advanced Platform, R&D Research, Takeda Pharmaceutical Co., Ltd. 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.

出版信息

Commun Biol. 2024 Apr 22;7(1):460. doi: 10.1038/s42003-024-06131-7.

DOI:10.1038/s42003-024-06131-7
PMID:38649481
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11035592/
Abstract

NGLY1 deficiency is a genetic disease caused by biallelic mutations of the Ngly1 gene. Although epileptic seizure is one of the most severe symptoms in patients with NGLY1 deficiency, preclinical studies have not been conducted due to the lack of animal models for epileptic seizures in NGLY1 deficiency. Here, we observed the behaviors of male and female Ngly1 mice by video monitoring and found that these mice exhibit spontaneous seizure-like behaviors. Gene expression analyses and enzyme immunoassay revealed significant decreases in oxytocin, a well-known neuropeptide, in the hypothalamus of Ngly1 mice. Seizure-like behaviors in Ngly1 mice were transiently suppressed by a single intranasal administration of oxytocin. These findings suggest the therapeutic potential of oxytocin for epileptic seizure in patients with NGLY1 deficiency and contribute to the clarification of the disease mechanism.

摘要

NGLY1 缺乏症是一种由 Ngly1 基因的双等位基因突变引起的遗传疾病。尽管癫痫发作是 NGLY1 缺乏症患者最严重的症状之一，但由于缺乏 NGLY1 缺乏症的动物癫痫模型，因此尚未进行临床前研究。在这里，我们通过视频监测观察了雄性和雌性 Ngly1 小鼠的行为，发现这些小鼠表现出自发性癫痫样行为。基因表达分析和酶免疫测定显示，Ngly1 小鼠的下丘脑中一种已知的神经肽催产素显著减少。单次鼻内给予催产素可短暂抑制 Ngly1 小鼠的癫痫样行为。这些发现表明催产素对 NGLY1 缺乏症患者癫痫发作具有治疗潜力，并有助于阐明疾病机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/0dfcb3925f89/42003_2024_6131_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/c1aeb1602f63/42003_2024_6131_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/64b781f8aba7/42003_2024_6131_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/169d6cf1b616/42003_2024_6131_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/12f867ef40e7/42003_2024_6131_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/d58894358efd/42003_2024_6131_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/0dfcb3925f89/42003_2024_6131_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/c1aeb1602f63/42003_2024_6131_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/64b781f8aba7/42003_2024_6131_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/169d6cf1b616/42003_2024_6131_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/12f867ef40e7/42003_2024_6131_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/d58894358efd/42003_2024_6131_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/110d/11035592/0dfcb3925f89/42003_2024_6131_Fig6_HTML.jpg

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本文引用的文献

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NGLY1 deficiency: estimated incidence, clinical features, and genotypic spectrum from the NGLY1 Registry.NGLY1 缺乏症：来自 NGLY1 登记处的估计发病率、临床特征和基因型谱。
Orphanet J Rare Dis. 2022 Dec 17;17(1):440. doi: 10.1186/s13023-022-02592-3.
2
AAV9-NGLY1 gene replacement therapy improves phenotypic and biomarker endpoints in a rat model of NGLY1 Deficiency.腺相关病毒9型-NGLY1基因替代疗法改善了NGLY1缺乏大鼠模型的表型和生物标志物终点。
Mol Ther Methods Clin Dev. 2022 Oct 3;27:259-271. doi: 10.1016/j.omtm.2022.09.015. eCollection 2022 Dec 8.
3
Expanding the NGLY1 deficiency phenotype: Case report of an atypical patient.
扩展 NGLY1 缺乏表型：一例非典型患者的病例报告。
Eur J Med Genet. 2022 Aug;65(8):104558. doi: 10.1016/j.ejmg.2022.104558. Epub 2022 Jun 30.
4
Delineating the epilepsy phenotype of NGLY1 deficiency.明确 NGLY1 缺乏症的癫痫表型。
J Inherit Metab Dis. 2022 May;45(3):571-583. doi: 10.1002/jimd.12494. Epub 2022 Mar 11.
5
Correction to: Reversibility of motor dysfunction in the rat model of NGLY1 deficiency.对《NGLY1缺乏大鼠模型中运动功能障碍的可逆性》的修正
Mol Brain. 2021 Aug 16;14(1):127. doi: 10.1186/s13041-021-00825-3.
6
Tracing the NGLY1 footprints: insights from Drosophila.追踪 NGLY1 的足迹：来自果蝇的见解。
J Biochem. 2022 Feb 21;171(2):153-160. doi: 10.1093/jb/mvab084.
7
Nasal oxytocin for the treatment of psychiatric disorders and pain: achieving meaningful brain concentrations.鼻腔给予催产素治疗精神障碍和疼痛：实现有意义的脑浓度。
Transl Psychiatry. 2021 Jul 10;11(1):388. doi: 10.1038/s41398-021-01511-7.
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Safety and tolerability of chronic intranasal oxytocin in older men: results from a randomized controlled trial.老年男性长期鼻内使用催产素的安全性和耐受性：一项随机对照试验的结果
Psychopharmacology (Berl). 2021 Sep;238(9):2405-2418. doi: 10.1007/s00213-021-05862-3. Epub 2021 May 12.
9
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