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Design, Synthesis, and Biological Evaluation of Novel Tetramethylpyrazine Derivatives as Potential Neuroprotective Agents.

Authors
  • Chen, Haiyun1
  • Tan, Guolian
  • Cao, Jie
  • Zhang, Gaoxiao
  • Yi, Peng
  • Yu, Pei
  • Sun, Yewei
  • Zhang, Zaijun
  • Wang, Yuqiang
  • 1 Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy.
Type
Published Article
Journal
Chemical and Pharmaceutical Bulletin
Publisher
Pharmaceutical Society of Japan
Publication Date
Jan 01, 2017
Volume
65
Issue
1
Pages
56–65
Identifiers
DOI: 10.1248/cpb.c16-00699
PMID: 27746410
Source
Medline
License
Unknown

Abstract

Oxidative stress plays a crucial role in neurological diseases, resulting in excessive production of reactive oxygen species, mitochondrial dysfunction and cell death. In this work, we designed and synthesized a series of tetramethylpyrazine (TMP) derivatives and investigated their abilities for scavenging free radicals and preventing against oxidative stress-induced neuronal damage in vitro. Among them, compound 22a, consisted of TMP, caffeic acid and a nitrone group, showed potent radical-scavenging activity. Compound 22a had broad neuroprotective effects, including rescuing iodoacetic acid-induced neuronal loss, preventing from tert-butylhydroperoxide (t-BHP)-induced neuronal injury. Compound 22a exerted its neuroprotective effect against t-BHP injury via activation of the phosphatidyl inositol 3-kinase (PI3K)/Akt signaling pathway. Furthermore, in a rat model of permanent middle cerebral artery occlusion, compound 22a significantly improved neurological deficits, and alleviated the infarct area and brain edema. In conclusion, our results suggest that compound 22a could be a potential neuroprotective agent for the treatment of neurological disease, particularly ischemic stroke.

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