小分子药物 C381 可减轻重复性轻度创伤后的脑血管损伤

IF 1.8 Q3 CLINICAL NEUROLOGY
Neurotrauma reports Pub Date : 2024-10-22 eCollection Date: 2024-01-01 DOI:10.1089/neur.2024.0060
Lulin Li, Andy Nguyen, Brian Zhao, Ryan Vest, Lakshmi Yerra, Bryan Sun, Jian Luo
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引用次数: 0

摘要

创伤性脑损伤(TBI)仍然是一个重大的公共卫生问题,目前还没有有效的治疗干预措施来改善其持久的后果。对创伤性脑损伤病理生理学的普遍认识表明,血管功能障碍起着核心作用。转化生长因子-β(TGF-β)是一种对血管发育至关重要的多功能细胞因子。TGF-β信号传导异常与多种神经系统疾病相关的血管病变有关。我们最近开发了一种新型小分子药物 C381,它是一种 TGF-β 激活剂,具有恢复溶酶体功能的能力。在这里,我们使用重复性轻度创伤性脑损伤(mTBI)小鼠模型来研究 C381 是否能减轻血管损伤。我们首先采用 RNA-seq 分析方法研究了与 mTBI 相关的基因表达模式,并评估了 C381 在减轻这些变化方面的治疗潜力。我们的研究结果表明,与 mTBI 相关的基因表达特征各不相同,主要涉及与血管完整性和内皮功能相关的通路。值得注意的是,用 C381 治疗可逆转这些 mTBI 诱导的基因表达变化。免疫组化分析进一步证实了这些发现,显示 C381 治疗减轻了受 mTBI 影响的脑组织中的血管损伤。这些研究结果有力地支持了 C381 作为一种新型治疗干预手段对 mTBI 的潜在临床实用性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury.

Traumatic brain injury (TBI) remains a significant public health concern, with no effective therapeutic interventions to ameliorate the enduring consequences. The prevailing understanding of TBI pathophysiology indicates a central role for vascular dysfunction. Transforming growth factor-β (TGF-β) is a multifunctional cytokine crucial for vascular development. Aberrant TGF-β signaling is implicated in vascular pathologies associated with various neurological conditions. We recently developed a novel small molecule drug, C381, a TGF-β activator with the ability to restore lysosomal function. Here we used a mouse model of repetitive mild TBI (mTBI) to examine whether C381 would attenuate vascular injury. We first employed RNA-seq analysis to investigate the gene expression patterns associated with mTBI and evaluated the therapeutic potential of C381 in mitigating these changes. Our results demonstrate distinct mTBI-related gene expression signatures, prominently implicating pathways related to vascular integrity and endothelial function. Notably, treatment with C381 reversed these mTBI-induced gene expression changes. Immunohistochemical analysis further corroborated these findings, revealing that C381 treatment attenuated vascular damage in mTBI-affected brain tissue. These findings strongly support the potential clinical usefulness of C381 as a novel therapeutic intervention for mTBI.

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CiteScore
2.40
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