Dose-Dependent Neuroprotective Effects of Valproate on Motor Function and Striatal D2 Receptor Stability in a 6-OHDA Rat Model of Parkinson’s Disease

TL;DR

This study shows that high-dose valproic acid protects brain dopamine systems and improves motor function in a rat model of Parkinson’s disease.

Contribution

The study reveals a dose-dependent neuroprotective effect of valproic acid on dopaminergic terminals and D2 receptor stability in Parkinson’s disease models.

Findings

High-dose valproic acid (400 mg/kg) preserved motor function and dopamine levels in 6-OHDA-lesioned rats.

Valproic acid at 400 mg/kg normalized striatal D2 receptor expression in the Parkinson’s disease model.

Low-dose valproic acid (200 mg/kg) had minimal and non-significant effects on motor or biochemical outcomes.

Abstract

Parkinson’s disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic neurons, leading to motor dysfunction and compensatory postsynaptic dopamine receptor alterations. Valproic acid (VPA), a histone deacetylase inhibitor, has shown neuroprotective properties; however, its dose-dependent effects on dopaminergic integrity and dopamine D2 receptor (D2R) regulation remain unclear. Adult male Wistar rats received VPA (200 or 400 mg/kg, p.o.) or vehicle for 20 days prior to unilateral 6-hydroxydopamine (6-OHDA) lesioning. Motor performance was evaluated using the beam balance test, exploratory behavior in the open field, striatal dopamine levels by PLC-electrochemical detection, and D2R protein expression by Western blot. The 6-OHDA lesion induced marked motor deficits, reduced striatal dopamine content, and significantly increased D2R expression. VPA at 200 mg/kg produced only minor, non-significant effects. In contrast, VPA at 400 mg/kg preserved motor performance, attenuated dopamine depletion, and normalized striatal D2R expression. These findings demonstrate a clear dose-dependent neuroprotective effect of VPA and indicate that stabilization of postsynaptic D2R expression accompanies preservation of dopaminergic terminals in the 6-OHDA rat model.

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