title: Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy.
abstract: TBN, a novel tetramethylpyrazine derivative armed with a powerful free radical-scavenging nitrone moiety, has been reported to reduce cerebral infarction in rats through multi-functional mechanisms of action. Here we study the therapeutic effects of TBN on non-human primate model of stroke. Thirty male Cynomolgus macaques were subjected to stroke with 4 hours ischemia and then reperfusion. TBN were injected intravenously at 3 or 6 hours after the onset of ischemia. Cerebral infarction was examined by magnetic resonance imaging at 1 and 4 weeks post ischemia. Neurological severity scores were evaluated during 4 weeks observation. At the end of experiment, protein markers associated with the stroke injury and TBN treatment were screened by quantitative proteomics. We found that TBN readily penetrated the blood brain barrier and reached effective therapeutic concentration after intravenous administration. It significantly reduced brain infarction and modestly preserved the neurological function of stroke-affected arm. TBN suppressed over-expression of neuroinflammatory marker vimentin and decreased the numbers of GFAP-positive cells, while reversed down-regulation of myelination-associated protein 2', 3'-cyclic-nucleotide 3'-phosphodiesterase and increased the numbers of NeuN-positive cells in the ipsilateral peri-infarct area. TBN may serve as a promising new clinical candidate for the treatment of ischemic stroke.
authors.affiliation: Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China.
authors.forename: Zaijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China.
authors.forename: Gaoxiao
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China.
authors.forename: Yewei
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Chemistry, the University of Hong Kong, Hong Kong, China.
authors.forename: Samuel S W
authors.initials: SS
authors.lastname: Szeto
authors.affiliation: Department of Chemistry, the University of Hong Kong, Hong Kong, China.
authors.forename: Henry C H
authors.initials: HC
authors.lastname: Law
authors.affiliation: Department of Chemistry, the University of Hong Kong, Hong Kong, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Quan
authors.affiliation: Department of Chemistry, the University of Hong Kong, Hong Kong, China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.affiliation: Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Yu
authors.affiliation: Kunming Biomed International and National Engineering Research Center of Biomedicine and Animal Science, Kunming, 650500, China.
authors.forename: Eiketsu
authors.initials: E
authors.lastname: Sho
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
authors.forename: Michael K W
authors.initials: MK
authors.lastname: Siu
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
authors.forename: Simon M Y
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Department of Chemistry, the University of Hong Kong, Hong Kong, China.
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Chu
authors.affiliation: Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China.
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D020520:Brain Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D008252:Macaca fascicularis; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology*; D012545:Schiff Bases / Q000737:chemistry / Q000494:pharmacology; D020521:Stroke / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism
chemical_list: D015415:Biomarkers; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011719:Pyrazines; D012545:Schiff Bases