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

TL;DR

Valproic acid helps glial cells become neurons by raising their internal pH through a specific pathway, offering new insights into its regenerative potential.

Contribution

The study reveals a pH-dependent mechanism by which valproic acid induces neuronal differentiation of satellite glial cells.

Findings

Valproic acid increases intracellular pH during the differentiation of satellite glial cells into neurons.

NHE1 regulates pH changes and is essential for valproic acid-induced neuronal differentiation.

Elevated pH activates β-catenin signaling to promote neuronal differentiation.

Abstract

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.

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