2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram-Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury

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

  • ACS Chem Neurosci. 2020 Aug 5;11(15):2348-2360. 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
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 2 Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
  • 3 Department of Applied Biology and Chemical Technology, Institute of Modern Chinese Medicine, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, China.
  • 4 Division of Life Science and Center for Chinese Medicine, The Hong Kong University of Science and Technology, Hong Kong, China.
  • 5 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 6 School of Medicine, Sun Yat-Sen University, Guangzhou 518000, China.
  • 7 National and Local United Engineering Lab of Drugability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou 510006, China.
  • 8 International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangzhou, Guangzhou 510006, China.
PMID: 32644771 DOI: 10.1021/acschemneuro.0c00339
Abstract

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.

Keywords

CREB; Rolipram; Tranilast; inflammation; neuroprotection; oxidative stress; traumatic brain injury.

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