title: Tetramethylpyrazine Nitrone Improves Neurobehavioral Functions and Confers Neuroprotection on Rats with Traumatic Brain Injury.
abstract: Oxidative stress is one of the major secondary injury mechanisms after traumatic brain injury (TBI). 2-[[(1,1-Dimethylethyl)oxidoimino]-methyl]-3,5,6-trimethylpyrazine (TBN), a derivative of the clinically used anti-stroke drug tetramethylpyrazine armed with a powerful free radical-scavenging nitrone moiety, has been demonstrated promising therapeutic efficacy in ischemic stroke and Parkinson's models. The present study aims to investigate the effects of TBN on behavioral function and neuroprotection in rats subjected to TBI. TBN (90 mg/kg) was administered twice daily for 7 days by intravenous injection following TBI. TBN improved neuronal behavior functions after brain injury, including rotarod test and adhesive paper removal test. Compared with the TBI model group, TBN treatment significantly protected NeuN-positive neurons, while decreased glial fibrillary acidic protein (GFAP)-positive cells. The number of 4-hydroxynonenal (4-HNE)-positive and 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells around the damaged area after TBI were significantly decreased in the TBN treatment group. In addition, TBN effectively reversed the altered expression of Bcl-2, Bax and caspase 3, and the down-regulation of nuclear factor erythroid-derived 2-like 2 (Nrf-2) and hemeoxygenase-1 (HO-1) proteins expression stimulated by TBI. In conclusion, TBN improves neurobehavioral functions and protects neurons against TBI. This protective effect may be achieved by anti-neuronal apoptosis, alleviating oxidative stress damage and up-regulating Nrf-2 and HO-1 expression.
authors.affiliation: Institute of New Drug Research, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.|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, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.|Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Institute of New Drug Research, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.|Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute of New Drug Research, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.|Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Gu
authors.affiliation: Institute of New Drug Research, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.|Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China.
authors.forename: Cuimei
authors.initials: C
authors.lastname: Li
authors.affiliation: Institute of New Drug Research, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.|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: Institute of New Drug Research, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.|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: Institute of New Drug Research, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China. zaijunzhang@163.com.|Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, 510632, China. zaijunzhang@163.com.
authors.forename: Zaijun
authors.identifier: http://orcid.org/0000-0002-0690-1673
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of New Drug Research, Jinan University College of Pharmacy, Huangpu Road, Guangzhou, 510632, China.|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; D017209:Apoptosis / Q000187:drug effects; D000070642:Brain Injuries, Traumatic / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley
chemical_list: D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D011719:Pyrazines; C015388:nitrones; C505410:Casp3 protein, rat; D053148:Caspase 3; C017953:tetramethylpyrazine
keywords: Apoptosis; HO-1; Neuroprotection; Nrf-2; Oxidative stress