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Valproic acid is widely used in treating neurological disorders such as epilepsy, bipolar disorder, and migraine, yet its exact mechanisms of action remain unclear. In this review, we aim to comprehensively outline the multifaceted mechanisms underlying Valproic acid's therapeutic effects. VPA modulates neurotransmitter systems, including gamma-aminobutyric acid (GABA), glutamate, and dopamine, influencing synaptic transmission and neuronal excitability. It enhances GABAergic transmission by inhibiting GABA degradation enzymes, promoting GABA release, and inhibiting reuptake, thereby contributing to its antiepileptic and mood-stabilizing effects. Valproic acid also reduces glutamatergic transmission by inhibiting N-methyl-D-aspartate receptors, thus attenuating glutamate-induced excitotoxicity. Moreover, Valproic acid affects dopaminergic neurotransmission by enhancing dopamine release and inhibiting reuptake, aiding mood stabilization. Another critical mechanism involves Valproic acid's modulation of voltage-gated ion channels, particularly sodium and calcium. Valproic acid reduces neuronal excitability and hyperactivity by inhibiting these channels, which is particularly beneficial in epilepsy treatment. Additionally, Valproic acid inhibits histone deacetylase, increasing histone acetylation and enhancing gene transcription. This epigenetic modulation upregulates neuroprotection, synaptic plasticity, and neurotransmission genes. Furthermore, Valproic acid exhibits neuroprotective properties by attenuating excitotoxicity, oxidative stress, and apoptosis, protecting against neuronal damage. Excipients in tablet formulations play a pivotal role in modifying Valproic acid's mechanisms of action. Sustained-release formulations are essential for maintaining stable plasma concentrations, while enteric coatings protect against gastric degradation, enhancing bioavailability. Excipients can also enhance solubility and improve drug delivery. For instance, surfactants and solubilizers can enhance Valproic acid's dissolution, while disintegrants promote rapid disintegration for faster drug release, which is crucial for acute conditions like seizures. Understanding how different excipients affect Valproic acid's mechanisms provides insights into optimizing therapy and developing novel treatments for neurological disorders.
Sharma et al. (Wed,) studied this question.