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Tetramethylpyrazine nitrone activates the BDNF/Akt/CREB pathway to promote post‐ischaemic neuroregeneration and recovery of neurological functions in rats
Author(s) -
Zhang Gaoxiao,
Zhang Tao,
Li Ning,
Wu Liangmiao,
Gu Jianbo,
Li Cuimei,
Zhao Chen,
Liu Wei,
Shan Luchen,
Yu Pei,
Yang Xifei,
Tang Yaohui,
Yang GuoYuan,
Wang Yuqiang,
Sun Yewei,
Zhang Zaijun
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14102
Subject(s) - neuroprotection , tetramethylpyrazine , neurogenesis , neuroregeneration , medicine , stroke (engine) , neurotrophic factors , pi3k/akt/mtor pathway , pharmacology , neuroscience , receptor , signal transduction , biology , pathology , microbiology and biotechnology , mechanical engineering , alternative medicine , engineering
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.