Macromolecular Dexamethasone Prodrug Ameliorates Neuroinflammation and Prevents Bone Loss Associated with Traumatic Brain Injury.
Macromolecular Dexamethasone Prodrug Ameliorates Neuroinflammation and Prevents Bone Loss Associated with Traumatic Brain Injury.
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DOI：
10.1021/acs.molpharmaceut.2c00482
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发表时间：
2022-11-07
影响因子：
4.9
通讯作者：
Wang, Dong
中科院分区：
文献类型：
--
作者：
Wei, Xin;Zhao, Gang;Jia, Zhenshan;Zhao, Zhifeng;Chen, Ningrong;Sun, Yuanyuan;Kelso, Matthew;Rathore, Geetanjali;Wang, Dong
在美国，创伤性脑损伤是导致儿童和年轻人死亡和残疾的主要原因之一。在这篇论文中，我们评估了基于N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物的地塞米松(Dex)前药(P-Dex)在脑外伤治疗中的应用。使用受控皮质撞击脑损伤小鼠模型，发现P-Dex在全身给药后被动靶向并持续在创伤/炎症脑组织14天以上。组织学证据支持P-Dex在改善神经炎症和减轻神经变性方面的治疗潜力。在行为学方面，P-Dex治疗的动物在平衡恢复方面显示出统计上的显著改善。脑外伤后早期神经严重度评分改善的趋势也被注意到，但没有统计学意义。在探索可能与P-Dex治疗相关的潜在糖皮质激素副作用时，我们发现TBI小鼠出现骨量减少。有趣的是，与游离地塞米松和生理盐水对照组相比，经P-地塞米松治疗的脑创伤小鼠显示出更高的骨密度和更好的骨微结构参数，这表明P-地塞米松在脑损伤后除了具有神经保护作用外，还具有骨保护作用。
Traumatic brain injury (TBI) is a one of the leading causes of death and disability among children and young adults in the United States. In this manuscript, we assessed the utility of a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based dexamethasone (Dex) prodrug (P-Dex) in treatment of TBI. Using a controlled cortical impact TBI mouse model, P-Dex was found to passively target to and sustain at the traumatic/inflammatory brain tissue for over 14 days after systemic administration. The histological evidence supports P-Dex’s therapeutic potential in ameliorating neuroinflammation and mitigating neurodegeneration. Behaviorally, the P-Dex treated animals showed statistically significant improvement in balance recovery. A trend of neurological severity score improvement at the early time point post-TBI was also noted, but did not achieve statistical significance. While probing the potential glucocorticoid side effects that may associate with P-Dex treatment, we discovered that the TBI mice develop osteopenia. Interestingly, the P-Dex-treated TBI mice demonstrated higher bone mineral density and better bone microarchitecture parameters when compared to the free Dex and the Saline control, revealing osteoprotective effect of P-Dex in addition to its neuronal protection benefits post-TBI.
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3.3
作者：
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