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.
Guangzhou Magpie Pharmaceuticals Co., LTD., Guangzhou, China.
Br J Pharmacol. 2018 Feb;175(3):517-531. doi: 10.1111/bph.14102. Epub 2017 Dec 22.
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.
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.
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.
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.
内源性前体细胞的神经再生是治疗缺血性中风的一种有吸引力的策略。然而，大多数中风产生的新生神经元会随着时间的推移而死亡。因此，一种既能神经保护又能促进神经发生的药物在中风后可能是有益的。在这里，我们评估了候选神经保护药物四甲基吡嗪硝酮（TBN）对缺血性中风大鼠模型的神经发生和少突胶质细胞发生的影响。
我们使用大脑中动脉闭塞（MCAO）的 Sprague Dawley 大鼠。TBN 通过尾静脉注射在缺血后 3 小时开始给药。通过神经行为和脑梗死评估 TBN 的治疗效果。通过双免疫荧光染色和 Western blot 分析确定神经发生和少突胶质细胞发生的促进作用。使用皮质神经元原代培养物评估 TBN 对体外神经元分化的影响。
TBN 减少了脑梗死，保存和/或恢复了 MCAO 后大鼠的神经功能，并促进了神经发生和少突胶质细胞发生。此外，TBN 刺激了体外皮质神经元原代培养物中的神经元分化。TBN 的促神经发生作用归因于其通过增加脑源性神经营养因子（BDNF）表达激活 AKT/cAMP 反应元件结合蛋白，这一点通过 BDNF 受体 ANA-12 的特异性抑制剂和 PI3K 抑制剂 LY294002 消除了 TBN 的作用而得到证实。
由于 TBN 可以同时提供神经保护和促神经发生作用，因此它可能是缺血性中风急性阶段神经保护和长期功能恢复的一种有前途的治疗方法。
