title: Design, Synthesis, and Biological Evaluation of Novel Tetramethylpyrazine Derivatives as Potential Neuroprotective Agents.
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.
authors.affiliation: Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine, Jinan University College of Pharmacy.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Chen
authors.forename: Guolian
authors.initials: G
authors.lastname: Tan
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.forename: Gaoxiao
authors.initials: G
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Yi
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.forename: Yewei
authors.initials: Y
authors.lastname: Sun
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020122:tert-Butylhydroperoxide / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D011719:Pyrazines; D020122:tert-Butylhydroperoxide; C017953:tetramethylpyrazine