EFFETTO DELL’INIBIZIONE DELLA 5-ALFA REDUTTASI SULLE DISCINESIE IN UN MODELLO ANIMALE DI MALATTIA DI PARKINSON

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 inhibition 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, this study was aimed at investigating whether the pharmacological blockade of 5AR by the two prototypical irreversible inhibitors finasteride (FIN) and dutasteride (DUTA), might elicit antidyskinetic properties in a rodent model of Parkinson's disease. Specifically, we tested the effects of FIN and DUTA on dyskinesias induced by dopaminergic agonists in 6-hydroxydopamine (6-OHDA)-lesioned rats. Acute and chronic effect of different doses of FIN (30-60mg/kg) and DUTA (15-30 mg/Kg), was assessed on LID in male 6-OHDA-lesioned dyskinetic rats. Thereafter, to fully characterize the therapeutic potential of these inhibitors on LID and their impact on l-DOPA efficacy, we tested abnormal involuntary movements and forelimb use in hemiparkinsonian male rats chronically injected with FIN (30-60mg/kg/24days) and DUTA (30-60mg/kg/24days) either prior to- or concomitant with l-DOPA administration. In addition, to investigate whether the antidyskinetic properties 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 both FIN and DUTA 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. To our knowledge, these findings for the first time highlight 5AR enzyme as a new therapeutic target for the treatment of dyskinesia in PD. Clinical investigations are warranted to assess whether similar protection from dyskinesia might be reproduced also in PD patients.