研究大麻酚衍生物 VCE-003.2 在实验性突触核蛋白病小鼠模型中作为一种疾病调节剂的作用。

IF 4.7 2区 心理学 Q1 BEHAVIORAL SCIENCES Behavioral and Brain Functions Pub Date : 2024-11-01 DOI:10.1186/s12993-024-00256-9
Sonia Burgaz, Elisa Navarro, Santiago Rodríguez-Carreiro, Carmen Navarrete, Martin Garrido-Rodríguez, Isabel Lastres-Becker, Julia Chocarro, José L Lanciego, Eduardo Muñoz, Javier Fernández-Ruiz
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引用次数: 0

摘要

背景:大麻酚衍生物VCE-003.2在过氧化物酶体增殖体激活受体-γ上具有活性,在基于线粒体功能障碍(6-羟基多巴胺缺失小鼠)和神经炎症(LPS缺失小鼠)的帕金森病(PD)实验模型中具有神经保护作用。现在,我们的目标是探索 VCE-003.2 在涉及蛋白质失调(PD 发病机制中的另一个关键事件)的 PD 模型中的神经保护特性:为此,我们将编码α-突触核蛋白基因突变形式的 9 号血清型腺相关病毒载体(AAV9-SynA53T)单侧投放到小鼠黑质(SNpc)中。该模型会导致小鼠运动障碍和黑质中酪氨酸羟化酶标记神经元的逐渐丧失:连续14天口服20毫克/千克的VCE-003.2可改善注射了AAV9-SynA53T的小鼠在各种运动测试中的表现,这与SNpc中酪氨酸羟化酶标记神经元的保留有关。VCE-003.2还减少了SNpc中反应性小胶质细胞和星形胶质细胞的增生。此外,我们还对注射了 AAV9-SynA53T 并接受 VCE-003.2 或药物治疗的小鼠以及对照组动物的纹状体进行了转录组分析。这项分析旨在确定因病理学和/或 VCE-003.2 治疗而发生特异性改变的基因家族。我们的数据揭示了病理诱导的与线粒体功能、溶酶体细胞通路、免疫反应和脂质代谢相关的基因变化。相比之下,VCE-003.2 治疗主要通过干扰素信号转导影响免疫反应:我们的研究拓宽了 VCE-003.2 的神经保护潜力,以前曾描述过 VCE-003.2 对线粒体功能障碍、氧化应激、神经胶质反应性和帕金森病神经炎症的作用。现在,我们证明了它对帕金森病的另一个关键致病因素--α-突触核蛋白失调--的疗效。此外,我们的研究还揭示了 VCE-003.2 的分子机制,揭示了它在调节干扰素信号传导中的作用。这些发现以及良好的 ADMET 特征增强了 VCE-003.2 的临床前研究兴趣,有助于其未来在帕金森病领域的临床开发。
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Investigation in the cannabigerol derivative VCE-003.2 as a disease-modifying agent in a mouse model of experimental synucleinopathy.

Background: The cannabigerol derivative VCE-003.2, which has activity at the peroxisome proliferator-activated receptor-γ has afforded neuroprotection in experimental models of Parkinson's disease (PD) based on mitochondrial dysfunction (6-hydroxydopamine-lesioned mice) and neuroinflammation (LPS-lesioned mice). Now, we aim to explore VCE-003.2 neuroprotective properties in a PD model that also involves protein dysregulation, other key event in PD pathogenesis.

Methods: To this end, an adeno-associated viral vector serotype 9 coding for a mutated form of the α-synuclein gene (AAV9-SynA53T) was unilaterally delivered in the substantia nigra pars compacta (SNpc) of mice. This model leads to motor impairment and progressive loss of tyrosine hydroxylase-labelled neurons in the SNpc.

Results: Oral administration of VCE-003.2 at 20 mg/kg for 14 days improved the performance of mice injected with AAV9-SynA53T in various motor tests, correlating with the preservation of tyrosine hydroxylase-labelled neurons in the SNpc. VCE-003.2 also reduced reactive microgliosis and astrogliosis in the SNpc. Furthermore, we conducted a transcriptomic analysis in the striatum of mice injected with AAV9-SynA53T and treated with either VCE-003.2 or vehicle, as well as control animals. This analysis aimed to identify gene families specifically altered by the pathology and/or VCE-003.2 treatment. Our data revealed pathology-induced changes in genes related to mitochondrial function, lysosomal cell pathways, immune responses, and lipid metabolism. In contrast, VCE-003.2 treatment predominantly affected the immune response through interferon signaling.

Conclusion: Our study broadens the neuroprotective potential of VCE-003.2, previously described against mitochondrial dysfunction, oxidative stress, glial reactivity and neuroinflammation in PD. We now demonstrate its efficacy against another key pathogenic event in PD as α-synuclein dysregulation. Furthermore, our investigation sheds light on the molecular mechanisms underlying VCE-003.2 revealing its role in regulating interferon signaling. These findings, together with a favorable ADMET profile, enhance the preclinical interest of VCE-003.2 towards its future clinical development in PD.

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来源期刊
Behavioral and Brain Functions
Behavioral and Brain Functions 医学-行为科学
CiteScore
5.90
自引率
0.00%
发文量
11
审稿时长
6-12 weeks
期刊介绍: A well-established journal in the field of behavioral and cognitive neuroscience, Behavioral and Brain Functions welcomes manuscripts which provide insight into the neurobiological mechanisms underlying behavior and brain function, or dysfunction. The journal gives priority to manuscripts that combine both neurobiology and behavior in a non-clinical manner.
期刊最新文献
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