Behavioral and transcriptomic effects of a novel cannabinoid on a rat valproic acid model of autism

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-04-03 DOI:10.1016/j.neuropharm.2025.110450

Sally Loomis , Diogo G. Silva , Ranjev Savopoulos , Jackie Cilia , Jennifer Li , Mat D. Davis , David Virley , Andrew Foley , Emanuele Loro , Andrew C. McCreary

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引用次数: 0

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social communication, restricted interests, repetitive behavior and irritability. Exposure to valproic acid (VPA) during pregnancy has been shown to increase the risk of autism in children and has led to the development of the in-utero VPA rat model that elicits neurodevelopmental autistic-like features. Offspring exhibit behavioral and neurobiological alterations modelling ASD symptoms. We performed a behavioral and molecular assessment in a rat in-utero VPA model treated with a novel botanical cannabinoid, JZP541.

Male offspring from dams treated with VPA were tested acutely and sub-chronically with JZP541 (10, 30, or 100 mg/kg, intraperitoneally). A behavioral testing battery was performed, and brain frontal cortex and hippocampus used for RNA sequencing.

In utero exposure to VPA resulted in progeny showing behavioral phenotypes characteristic of ASD. JZP541 attenuated these deficits in social, stereotypic, hyperactivity and irritability behavior in a dose-dependent fashion.

VPA exposure was associated with a substantial transcriptional dysregulation impacting multiple key biological processes in a tissue-dependent manner. The expression profiles were integrated with publicly available datasets of autism-associated genes to support the validity of the model used and to focus on the effects of treatment on known autism-relevant transcriptional targets. This approach indicated a strong and dose-dependent reduction of the autism-associated gene expression signature in brain samples from animals dosed with JZP541.

Our findings demonstrate JZP541 was able to ameliorate ASD associated behavioral deficits, and this was supported by improvements in putative transcriptional biomarkers of ASD.

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一种新型大麻素对大鼠丙戊酸自闭症模型的行为和转录组学效应。

自闭症谱系障碍（ASD）是一种复杂的神经发育疾病，其特征是社交障碍、兴趣限制、重复行为和易怒。怀孕期间暴露于丙戊酸（VPA）已被证明会增加儿童患自闭症的风险，并导致子宫内VPA大鼠模型的发展，从而引发神经发育性自闭症样特征。后代表现出模仿ASD症状的行为和神经生物学改变。我们对一种新型植物大麻素JZP541治疗的大鼠子宫内VPA模型进行了行为和分子评估。用JZP541（10、30或100 mg/kg，腹腔注射）对经VPA处理的雄性雄性后代进行急性和亚慢性试验。进行行为测试，并利用大脑额叶皮质和海马体进行RNA测序。子宫内暴露于VPA导致后代表现出ASD特征的行为表型。JZP541以剂量依赖的方式减轻了这些在社交、刻板印象、多动和易怒行为方面的缺陷。VPA暴露与以组织依赖的方式影响多个关键生物过程的实质性转录失调有关。表达谱与公开可用的自闭症相关基因数据集相结合，以支持所使用模型的有效性，并关注治疗对已知自闭症相关转录靶点的影响。该方法表明，在注射了JZP541的动物脑样本中，自闭症相关基因表达特征出现了强烈的剂量依赖性降低。我们的研究结果表明，JZP541能够改善ASD相关的行为缺陷，这得到了ASD转录生物标志物的改善的支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).