Adult hippocampal neurogenesis plays the pivotal roles in central nervous system diseases. Recently, it has been reported that levetiracetam (LEV), a new antiepileptic drug with novel chemical construction and unique pharmacological properties, suppressed aberrant adult subventricular zone (SGZ) neurogenesis in kainite-induced epileptic mice, while promoted adult SGZ neuroblast differentiation in normal mice. These studies indicate LEV can modulate adult hippocampal neurogenesis, but the exact mechanism remained unknown. Thus, the present study aimed to investigate the effects of subchronic and chronic LEV treatments on neural stem cell by lineage tracing in adult hippocampal dentate gyrus of mice, as well as the potential mechanism related to Wnt/β-catenin signaling pathway. The data showed that both subchronic and chronic LEV treatments had no effects on body weight, locomotor activity and anxiety-like behavior in mice. Notably, subchronic LEV treatment significantly suppressed the proliferation of intermediate progenitor cell and neuroblast, decreased the number of intermediate progenitor cell and neuroblast, but increased the number of quiescent neural stem cell. On the contrary, chronic LEV treatment promoted the proliferation of neural stem cell, intermediate progenitor cell and neuroblast, increased the number of neural stem cell, intermediate progenitor cell and neuroblast, and promoted differentiation of newborn immature neuron and mature neuron. Furthermore, subchronic LEV treatment decreased the level of Wnt 3a and nuclear β-Catenin expression, which led to the inhibition on Wnt/β-catenin signaling pathway. Chronic LEV treatment increased the level of Wnt 3a, cytosolic β-catenin and nuclear β-Catenin, decreased the expression of GSK-3β, p-Tyr216-GSK-3β and Axin2, resulting in the enhancement of Wnt/β-catenin signaling pathway. These results demonstrated that LEV significantly suppressed or promoted adult hippocampal neurogenesis in mice by subchronic or chronic treatment possibly through the regulation of Wnt/β-catenin signaling pathway. Our findings provided the new perspectives of LEV on adult hippocampal neurogenesis underlying its clinical application.

中文翻译：

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左乙拉西坦通过Wnt /β-catenin信号传导对小鼠成年海马神经发生的调节作用。

成人海马神经发生在中枢神经系统疾病中起关键作用。最近，有报道说，新的抗癫痫药左乙拉西坦（LEV）具有新颖的化学结构和独特的药理特性，可抑制由Kainite诱发的癫痫小鼠的异常成年脑室下区（SGZ）神经发生，同时促进正常小鼠的成年SGZ神经母细胞分化。 。这些研究表明LEV可以调节成年海马神经发生，但确切的机制尚不清楚。因此，本研究旨在通过成年小鼠海马齿状回的谱系追踪研究亚慢性和慢性LEV治疗对神经干细胞的影响，以及与Wnt /β-catenin信号通路相关的潜在机制。数据显示，亚慢性和慢性LEV治疗对小鼠的体重，运动能力和焦虑样行为均无影响。值得注意的是，亚慢性LEV处理显着抑制了中间祖细胞和神经母细胞的增殖，减少了中间祖细胞和神经母细胞的数量，但增加了静止神经干细胞的数量。相反，慢性LEV治疗促进神经干细胞，中间祖细胞和成神经细胞的增殖，增加神经干细胞，中间祖细胞和成神经细胞的数量，并促进新生的未成熟神经元和成熟神经元的分化。此外，亚慢性LEV处理降低了Wnt 3a的水平和核β-连环蛋白的表达，从而抑制了Wnt /β-catenin信号通路。慢性LEV治疗可增加Wnt 3a，胞质β-catenin和核β-Catenin的水平，降低GSK-3β，p-Tyr216-GSK-3β和Axin2的表达，从而增强Wnt /β-catenin信号通路。这些结果表明，通过亚慢性或慢性治疗，LEV可能通过调节Wnt /β-catenin信号通路来显着抑制或促进小鼠成年海马神经发生。我们的发现提供了LEV对成人海马神经发生的新观点，并为其临床应用奠定了基础。这些结果表明，通过亚慢性或慢性治疗，LEV可能通过调节Wnt /β-catenin信号通路来显着抑制或促进小鼠成年海马神经发生。我们的发现提供了LEV对成人海马神经发生的新观点，并为其临床应用奠定了基础。这些结果表明，通过亚慢性或慢性治疗，LEV可能通过调节Wnt /β-catenin信号通路来显着抑制或促进小鼠成年海马神经发生。我们的发现提供了LEV对成人海马神经发生的新观点，并为其临床应用奠定了基础。