Pregnenolone Reduces L-Dopa-Induced Dyskinesias in Female Parkinsonian Monkeys

Pregnenolone is the first neurosteroid synthesized from cholesterol in the brain. Previous studies showed that it reduces the development of levodopa (L-dopa)-induced dyskinesias (LIDs) in rat models of Parkinson's disease (PD).

To examine whether pregnenolone mitigates established LIDs in a non-human primate model.

Ovariectomized female macaques, modeling the postmenopausal hormonal status of most women with PD, were lesioned with MPTP and treated with L-dopa to induce LIDs. Pregnenolone was administered subcutaneously (SC) at 6 or 18 mg/kg or orally (36 mg/kg).

Pregnenolone reduced established LIDs in MPTP-lesioned monkeys while preserving L-dopa's antiparkinsonian effects. The antidyskinetic effect was dose-dependent, with the greatest reduction observed at 18 mg/kg SC, followed by 6 mg/kg SC, and a lesser effect at 36 mg/kg orally, likely due to first-pass metabolism.

Pregnenolone reduces established LIDs in parkinsonian monkeys and may represent a safe, novel therapeutic candidate for dyskinesia treatment in PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.