Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury.

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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Abstract

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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小分子药物 C381 可减轻重复性轻度创伤后的脑血管损伤
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。
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CiteScore
2.40
自引率
0.00%
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0
审稿时长
8 weeks
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