title: The 5-alpha reductase inhibitor finasteride reduces dyskinesia in a rat model of Parkinson's disease.
abstract: 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 D1receptors. 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 D1receptor-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 (30-60mg/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 (30-60mg/kg/24days) 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 D1receptor agonist SKF-82958 and the D2/D3receptor 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.
authors.affiliation: Dept. of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Frau
authors.affiliation: Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Piazza del Mercato, 15, 25121 Brescia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Savoia
authors.affiliation: Dept. of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fanni
authors.affiliation: Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Piazza del Mercato, 15, 25121 Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Fiorentini
authors.affiliation: Dept. of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.
authors.forename: Camino
authors.initials: C
authors.lastname: Fidalgo
authors.affiliation: Dept. of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Tronci
authors.affiliation: Dept. of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Stancampiano
authors.affiliation: Movement Disorders Center, Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Meloni
authors.affiliation: Movement Disorders Center, Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Cannas
authors.affiliation: Movement Disorders Center, Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marrosu
authors.affiliation: Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT 84112, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
authors.affiliation: Dept. of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Piazza del Mercato, 15, 25121 Brescia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Missale
authors.affiliation: Dept. of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy. Electronic address: manolocarta@unica.it.
authors.forename: Manolo
authors.initials: M
authors.lastname: Carta
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000627:therapeutic use*; D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D001545:Benserazide / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D018120:Finasteride / Q000627:therapeutic use*; D007839:Functional Laterality / Q000187:drug effects; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology; D011596:Psychomotor Disorders / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D007980:Levodopa; D018120:Finasteride; D001545:Benserazide; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase
keywords: 5-Alpha-Reductase; Parkinson's disease; dyskinesia; finasteride; l-DOPA