Tetramethylpyrazine nitrone activates the BDNF/Akt/CREB pathway to promote post‐ischaemic neuroregeneration and recovery of neurological functions in rats

• Published in: British journal of pharmacology Vol. 175; no. 3; pp. 517 - 531
• Main Authors: 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, Guo‐Yuan, Wang, Yuqiang, Sun, Yewei, Zhang, Zaijun
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2018; John Wiley and Sons Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cells, Cultured; Cerebral blood flow; Cerebral infarction; Cortex; Culture; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Dose-Response Relationship, Drug; Infarction; Ischemia; Neural stem cells; Neurogenesis; Neurons; Neuroprotection; Nitrogen Oxides - pharmacology; Nitrogen Oxides - therapeutic use; Occlusion; Proto-Oncogene Proteins c-akt - metabolism; Pyrazines - pharmacology; Pyrazines - therapeutic use; Rats; Rats, Sprague-Dawley; Recovery (Medical); Recovery of function; Recovery of Function - drug effects; Recovery of Function - physiology; Regeneration; Regeneration - drug effects; Regeneration - physiology; Research Paper; Research Papers; Rodents; Stroke; Western blotting
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14102

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.