Valproic Acid Promotes the Differentiation of Satellite Glial Cells into Neurons via the pH-Dependent Pathway.

Valproic acid (VPA) is a widely prescribed antiepileptic agent whose teratogenic potential has been recognized. In recent years, VPA has been shown to promote neuronal regeneration; however, the exact molecular mechanisms are not fully understood. This study elucidates the pH-dependent pathway through which VPA promotes the differentiation of satellite glial cells (SGCs) into neurons. We observed sustained intracellular pH elevation during the VPA-induced neural differentiation of SGCs, and the modulation of intracellular pH was shown to influence this differentiation process. Then, we found that VPA regulates intracellular pH through NHE1 (sodium-hydrogen exchanger 1), and that the pharmacological inhibition of NHE1 not only attenuated intracellular pH elevation but also substantially impaired VPA-induced neuronal differentiation. Finally, our results showed that the elevated intracellular pH promoted the neuronal differentiation of SGCs by activating β-catenin signaling. These findings provide novel insights into the mechanisms of VPA-induced neurogenesis, advancing our understanding of its pharmacological profile and informing its potential therapeutic application in neuronal regeneration strategies.