The 5-alpha reductase inhibitor finasteride reduces dyskinesia in a rat model of Parkinson's disease
Levodopa-induced dyskinesia (LID) is a disabling motor complication occurring in Parkinson's disease patients (PD) after long-term l-DOPA treatment. Although its etiology remains unclear, there is accumulating evidence that LID relies on an excessive dopamine receptor transmission, particularly at the downstream signaling of D1 receptors. We previously reported that the pharmacological blockade of 5-alpha reductase (5AR), the rate limiting enzyme in neurosteroids synthesis, rescued a number of behavioral aberrations induced by D1 receptor-selective and non-selective agonists, without inducing extrapyramidal symptoms. Thus, the present study was designed to verify whether the 5AR inhibitor finasteride (FIN) may counteract the dyskinesias induced by dopaminergic agonists in 6-hydroxydopamine (6-OHDA)-lesioned rats. First, we assessed the acute and chronic effect of different doses of FIN (30–60 mg/kg) on LID, in male 6-OHDA-lesioned dyskinetic rats. Thereafter, to fully characterize the therapeutic potential of FIN on LID and its impact on l-DOPA efficacy, we assessed abnormal involuntary movements and forelimb use in hemiparkinsonian male rats chronically injected with FIN (30–60 mg/kg/24 days) either prior to- or concomitant with l-DOPA administration. In addition, to investigate whether the impact of FIN on LID may be ascribed to a modulation of the D1- or D2/D3-receptor function, dyskinesias were assessed in l-DOPA-primed 6-OHDA-lesioned rats that received FIN in combination with selective direct dopaminergic agonists. Finally, we set to investigate whether FIN may produce similar effect in female hemiparkinsonian rats, as seen in males.
The results indicated that FIN administrations significantly dampened LID in all tested treatment regimens, without interfering with the ability of l-DOPA to ameliorate forelimb use in the stepping test. The antidyskinetic effect appears to be due to modulation of both D1- and D2/D3-receptor function, as FIN also reduced abnormal involuntary movements induced by the selective D1 receptor agonist SKF-82958 and the D2/D3 receptor agonist ropinirole. Significant dampening of LID was also observed in female rats, although only at the higher tested dose.
Clinical investigations are warranted to assess whether similar protection from dyskinesia is seen in PD patients.