PMID- 29161771 OWN - NLM STAT- MEDLINE DCOM- 20180814 LR - 20210109 IS - 1476-5381 (Electronic) IS - 0007-1188 (Print) IS - 0007-1188 (Linking) VI - 175 IP - 3 DP - 2018 Feb TI - Tetramethylpyrazine nitrone activates the BDNF/Akt/CREB pathway to promote post-ischaemic neuroregeneration and recovery of neurological functions in rats. PG - 517-531 LID - 10.1111/bph.14102 [doi] AB - BACKGROUND AND PURPOSE: Neuronal regeneration from endogenous precursors is an attractive strategy for the treatment of ischaemic stroke. However, most stroke-generated newborn neurons die over time. Therefore, a drug that is both neuroprotective and pro-neurogenic may be beneficial after stroke. Here, we assessed the neurogenic and oligodendrogenic effects of tetramethylpyrazine nitrone (TBN), a neuroprotective drug candidate for stroke, in a rat model of ischaemic stroke. EXPERIMENTAL APPROACH: We used Sprague Dawley rats with middle cerebral artery occlusion (MCAO). TBN was administered by tail vein injection beginning at 3 h post ischaemia. Therapeutic effect of TBN was evaluated by neurological behaviour and cerebral infarction. Promotion of neurogenesis and oligodendrogenesis was determined by double immunofluorescent staining and Western blotting analyses. Primary cultures of cortical neurons were used to assess the effect of TBN on neuronal differentiation in vitro. KEY RESULTS: TBN reduced cerebral infarction, preserved and/or restored neurological function and promoted neurogenesis and oligodendrogenesis in rats after MCAO. In addition, TBN stimulated neuronal differentiation on primary culture of cortical neurons in vitro. Pro-neurogenic effects of TBN were attributed to its activation of the AKT/cAMP responsive element-binding protein through increasing brain-derived neurotrophic factor (BDNF) expression, as shown by the abolition of the effects of TBN by a specific inhibitor of BDNF receptor ANA-12 and by the PI3K inhibitor LY294002. CONCLUSION AND IMPLICATIONS: As TBN can simultaneously provide neuroprotection and pro-neurogenic effects, it may be a promising treatment for both acute phase neuroprotection and long-term functional recovery after ischaemic stroke. CI - (c) 2017 The British Pharmacological Society. FAU - Zhang, Gaoxiao AU - Zhang G AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. FAU - Zhang, Tao AU - Zhang T AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. FAU - Li, Ning AU - Li N AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. FAU - Wu, Liangmiao AU - Wu L AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. FAU - Gu, Jianbo AU - Gu J AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. AD - Guangzhou Magpie Pharmaceuticals Co., LTD., Guangzhou, China. FAU - Li, Cuimei AU - Li C AD - Guangzhou Magpie Pharmaceuticals Co., LTD., Guangzhou, China. FAU - Zhao, Chen AU - Zhao C AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. FAU - Liu, Wei AU - Liu W AD - Guangzhou Magpie Pharmaceuticals Co., LTD., Guangzhou, China. FAU - Shan, Luchen AU - Shan L AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. FAU - Yu, Pei AU - Yu P AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. FAU - Yang, Xifei AU - Yang X AD - Key Laboratory of Modern Toxicology of Shenzhen, Center for Disease Control and Prevention, Shenzhen, China. FAU - Tang, Yaohui AU - Tang Y AD - Neuroscience and Neuroengineering Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. FAU - Yang, Guo-Yuan AU - Yang GY AD - Neuroscience and Neuroengineering Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China. FAU - Wang, Yuqiang AU - Wang Y AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. FAU - Sun, Yewei AU - Sun Y AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. FAU - Zhang, Zaijun AU - Zhang Z AUID- ORCID: 0000-0002-0690-1673 AD - Institute of New Drug Research and Guangzhou Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171222 PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Nitrogen Oxides) RN - 0 (Pyrazines) RN - 0 (nitrones) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - V80F4IA5XG (tetramethylpyrazine) SB - IM MH - Animals MH - Brain Ischemia/drug therapy/*metabolism MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cells, Cultured MH - Cyclic AMP Response Element-Binding Protein/*metabolism MH - Dose-Response Relationship, Drug MH - Nitrogen Oxides/*pharmacology/therapeutic use MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Pyrazines/*pharmacology/therapeutic use MH - Rats MH - Rats, Sprague-Dawley MH - Recovery of Function/drug effects/physiology MH - Regeneration/drug effects/physiology PMC - PMC5773967 EDAT- 2017/11/22 06:00 MHDA- 2018/08/15 06:00 PMCR- 2019/02/01 CRDT- 2017/11/22 06:00 PHST- 2017/08/13 00:00 [received] PHST- 2017/11/02 00:00 [revised] PHST- 2017/11/07 00:00 [accepted] PHST- 2017/11/22 06:00 [pubmed] PHST- 2018/08/15 06:00 [medline] PHST- 2017/11/22 06:00 [entrez] PHST- 2019/02/01 00:00 [pmc-release] AID - BPH14102 [pii] AID - 10.1111/bph.14102 [doi] PST - ppublish SO - Br J Pharmacol. 2018 Feb;175(3):517-531. doi: 10.1111/bph.14102. Epub 2017 Dec 22.