The regulative effects of levetiracetam on adult hippocampal neurogenesis in mice via Wnt/β-catenin signaling

Abstract

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.

Keywords: Hippocampal neurogenesis; Levetiracetam; Neural stem cell; Wnt/β-catenin.