Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram-Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury.,ACS Chemical Neuroscience

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Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram-Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-07-09 , DOI: 10.1021/acschemneuro.0c00339
Junfeng Lu ₁ , Chen Chen ₁ , Xiaobing Deng ₂ , Marvin Sh Mak _{3,

4} , Zeyu Zhu ₁ , Xixin He ₅ , Jinhao Liang ₅ , Swetha K Maddili ₆ , Karl W K Tsim ₄ , Yifan Han ₃ , Rongbiao Pi _{6,

7,

8}

Affiliation

Traumatic brain injury (TBI) is a prevalent public healthcare concern frequently instigated by mechanical shock, traffic, or violence incidents, leading to permanent nerve damage, and there is no ideal treatment for it yet. In this study, a series of Rolipram–Tranilast hybrids were designed and synthesized. The neuroprotective activities of the Rolipram–Tranilast hybrids were evaluated both in vitro and in vivo. Compound 5 has been identified as the strongest neuroprotective molecule among the series with robust anti-oxidant and anti-inflammatory potentials. Compound 5 significantly increased the heme oxygenase-1 (HO-1) levels and the phosphorylated cAMP response elements binding protein (p-CREB) while it down-regulated phosphodiesterase-4 B (PDE4B) expression in vitro. Furthermore, compound 5 remarkably attenuated TBI and had a good safety profile in mice. Taken together, our findings suggested that compound 5 could serve as a novel promising lead compound in the treatment of TBI and other central nervous system (CNS) diseases associated with PDE4B and oxidative stress.

中文翻译：

新型多功能咯利普兰-曲尼司特杂化物的设计、合成和生物学评价作为创伤性脑损伤的潜在治疗方法。

创伤性脑损伤 (TBI) 是一个普遍存在的公共医疗保健问题，经常由机械冲击、交通或暴力事件引发，导致永久性神经损伤，目前尚无理想的治疗方法。在这项研究中，设计并合成了一系列咯利普兰-曲尼司特杂化物。咯利普兰-曲尼司特混合物的神经保护活性在体外和体内均进行了评估。化合物5已被确定为该系列中最强的神经保护分子，具有强大的抗氧化和抗炎潜力。化合物5在体外，显着增加血红素加氧酶-1 (HO-1) 水平和磷酸化 cAMP 反应元件结合蛋白 (p-CREB)，同时下调磷酸二酯酶-4 B (PDE4B) 表达。此外，化合物5显着减轻 TBI，并且在小鼠中具有良好的安全性。总而言之，我们的研究结果表明，化合物5可以作为治疗 TBI 和其他与 PDE4B 和氧化应激相关的中枢神经系统 (CNS) 疾病的新型有前景的先导化合物。

更新日期：2020-08-05

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