β‑Lapachone ameliorates L‑DOPA‑induced dyskinesia in a 6‑OHDA‑induced mouse model of Parkinson's disease.

The dopamine precursor 3,4‑dihydroxyphenyl‑ l‑alanine (L‑DOPA) is the most widely used symptomatic treatment for Parkinson's disease (PD); however, its prolonged use is associated with L‑DOPA‑induced dyskinesia in more than half of patients after 10 years of treatment. The present study investigated whether co‑treatment with β‑Lapachone, a natural compound, and L‑DOPA has protective effects in a 6‑hydroxydopamine (6‑OHDA)‑induced mouse model of PD. Unilateral 6‑OHDA‑lesioned mice were treated with vehicle or β‑Lapachone (10 mg/kg/day) and L‑DOPA for 11 days. Abnormal involuntary movements (AIMs) were scored on days 5 and 10. β‑Lapachone (10 mg/kg) co‑treatment with L‑DOPA decreased the AIMs score on both days 5 and 10. β‑Lapachone was demonstrated to have a beneficial effect on the axial and limb AIMs scores on day 10. There was no significant suppression in dopamine D1 receptor‑related and ERK1/2 signaling in the DA‑denervated striatum by β‑Lapachone‑cotreatment with L‑DOPA. Notably, β‑Lapachone‑cotreatment with L‑DOPA increased phosphorylation at the Ser9 site of glycogen synthase kinase 3β (GSK‑3β), indicating suppression of GSK‑3β activity in both the unlesioned and 6‑OHDA‑lesioned striata. In addition, astrocyte activation was markedly suppressed by β‑Lapachone‑cotreatment with L‑DOPA in the striatum and substantia nigra of the unilateral 6‑OHDA model. These findings suggest that β‑Lapachone cotreatment with L‑DOPA therapy may have therapeutic potential for the suppression or management of the development of L‑DOPA‑induced dyskinesia in patients with PD.