5alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interaction
Although 1-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay therapy for treating Parkinson's disease (PD), its long-term administration is accompanied by the development of motor complications, particularly L-DOPA induced dyskinesia (LID), that dramatically affects patients' quality of...
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Elsevier
2019-01-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996118306053 |
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doaj-19a02c63148348009be80a883732b055 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Silvia Fanni Simona Scheggi Francesca Rossi Elisabetta Tronci Francesco Traccis Roberto Stancampiano Maria Graziella De Montis Paola Devoto Carla Gambarana Marco Bortolato Roberto Frau Manolo Carta |
spellingShingle |
Silvia Fanni Simona Scheggi Francesca Rossi Elisabetta Tronci Francesco Traccis Roberto Stancampiano Maria Graziella De Montis Paola Devoto Carla Gambarana Marco Bortolato Roberto Frau Manolo Carta 5alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interaction Neurobiology of Disease L-DOPA 5alpha-reductase Dutasteride Parkinson's disease Dyskinesia 6-OHDA |
author_facet |
Silvia Fanni Simona Scheggi Francesca Rossi Elisabetta Tronci Francesco Traccis Roberto Stancampiano Maria Graziella De Montis Paola Devoto Carla Gambarana Marco Bortolato Roberto Frau Manolo Carta |
author_sort |
Silvia Fanni |
title |
5alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interaction |
title_short |
5alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interaction |
title_full |
5alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interaction |
title_fullStr |
5alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interaction |
title_full_unstemmed |
5alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interaction |
title_sort |
5alpha-reductase inhibitors dampen l-dopa-induced dyskinesia via normalization of dopamine d1-receptor signaling pathway and d1-d3 receptor interaction |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2019-01-01 |
description |
Although 1-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay therapy for treating Parkinson's disease (PD), its long-term administration is accompanied by the development of motor complications, particularly L-DOPA induced dyskinesia (LID), that dramatically affects patients' quality of life. LID has consistently been related to an excessive dopamine receptor transmission, particularly at the down-stream signaling of the striatal D1 receptors (D1R), resulting in an exaggerated stimulation of cAMP-dependent protein kinase and extracellular signal-regulated kinase (ERK) pathway. We previously reported that pharmacological blockade of 5alpha-reductase (5AR), the rate-limiting enzyme in neurosteroids synthesis, attenuates the severity of a broad set of behavioral alterations induced by D1R and D3R activation, without inducing extrapyramidal symptoms.In line with this evidence, in a recent study, we found that inhibition of 5AR by finasteride (FIN) produced a significant reduction of dyskinesia induced by L-DOPA and direct dopaminergic agonists in 6-OHDA-lesioned rats.In the attempt to further investigate the effect of 5AR inhibitors on dyskinesia and shed light on the mechanism of action, in the present study we compared the effect of FIN and dutasteride (DUTA), a potent dual 5AR inhibitor, on the development of LID, on the therapeutic efficacy of L-DOPA, on the molecular alterations downstream to the D1R, as well as on D1R-D3R interaction.The results indicated that both FIN and DUTA administration significantly reduced development and expression of LID; however, DUTA appeared more effective than FIN at a lower dose and produced its antidyskinetic effect without impacting the ability of L-DOPA to increase motor activation, or ameliorate forelimb use in parkinsonian rats.Moreover, this study demonstrates for the first time that 5AR inhibitors are able to prevent key events in the appearance of dyskinesia, such as L-DOPA-induced upregulation of striatal D1R-related cAMP/PKA/ERK signaling pathways and D1R-D3R coimmunoprecipitation, an index of heteromer formation.These findings are relevant as they confirm the 5AR enzyme as a potential therapeutic target for treatment of dyskinesia in PD, suggesting the first ever evidence that neurosteroidogenesis may affect functional interaction between dopamine D1R and D3R. |
topic |
L-DOPA 5alpha-reductase Dutasteride Parkinson's disease Dyskinesia 6-OHDA |
url |
http://www.sciencedirect.com/science/article/pii/S0969996118306053 |
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doaj-19a02c63148348009be80a883732b0552021-03-22T12:47:29ZengElsevierNeurobiology of Disease1095-953X2019-01-011211201305alpha-reductase inhibitors dampen L-DOPA-induced dyskinesia via normalization of dopamine D1-receptor signaling pathway and D1-D3 receptor interactionSilvia Fanni0Simona Scheggi1Francesca Rossi2Elisabetta Tronci3Francesco Traccis4Roberto Stancampiano5Maria Graziella De Montis6Paola Devoto7Carla Gambarana8Marco Bortolato9Roberto Frau10Manolo Carta11Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, ItalyDepartment of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro 4, 53100 Siena, ItalyDepartment of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, ItalyDepartment of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, ItalyDepartment of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, ItalyDepartment of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, ItalyDepartment of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro 4, 53100 Siena, ItalyDepartment of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, ItalyDepartment of Molecular and Developmental Medicine, University of Siena, Via Aldo Moro 4, 53100 Siena, ItalyDepartment of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E, Salt Lake City, UT 84112, USADepartment of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy; Tourette Syndrome Center, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy; Sleep Medicine Center, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy; National Institute of Neuroscience (INN), University of Cagliari, Monserrato, CA, Italy; Corresponding authors at: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy; Corresponding authors at: Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria SP 8, Monserrato 09042, Italy.Although 1-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay therapy for treating Parkinson's disease (PD), its long-term administration is accompanied by the development of motor complications, particularly L-DOPA induced dyskinesia (LID), that dramatically affects patients' quality of life. LID has consistently been related to an excessive dopamine receptor transmission, particularly at the down-stream signaling of the striatal D1 receptors (D1R), resulting in an exaggerated stimulation of cAMP-dependent protein kinase and extracellular signal-regulated kinase (ERK) pathway. We previously reported that pharmacological blockade of 5alpha-reductase (5AR), the rate-limiting enzyme in neurosteroids synthesis, attenuates the severity of a broad set of behavioral alterations induced by D1R and D3R activation, without inducing extrapyramidal symptoms.In line with this evidence, in a recent study, we found that inhibition of 5AR by finasteride (FIN) produced a significant reduction of dyskinesia induced by L-DOPA and direct dopaminergic agonists in 6-OHDA-lesioned rats.In the attempt to further investigate the effect of 5AR inhibitors on dyskinesia and shed light on the mechanism of action, in the present study we compared the effect of FIN and dutasteride (DUTA), a potent dual 5AR inhibitor, on the development of LID, on the therapeutic efficacy of L-DOPA, on the molecular alterations downstream to the D1R, as well as on D1R-D3R interaction.The results indicated that both FIN and DUTA administration significantly reduced development and expression of LID; however, DUTA appeared more effective than FIN at a lower dose and produced its antidyskinetic effect without impacting the ability of L-DOPA to increase motor activation, or ameliorate forelimb use in parkinsonian rats.Moreover, this study demonstrates for the first time that 5AR inhibitors are able to prevent key events in the appearance of dyskinesia, such as L-DOPA-induced upregulation of striatal D1R-related cAMP/PKA/ERK signaling pathways and D1R-D3R coimmunoprecipitation, an index of heteromer formation.These findings are relevant as they confirm the 5AR enzyme as a potential therapeutic target for treatment of dyskinesia in PD, suggesting the first ever evidence that neurosteroidogenesis may affect functional interaction between dopamine D1R and D3R.http://www.sciencedirect.com/science/article/pii/S0969996118306053L-DOPA5alpha-reductaseDutasterideParkinson's diseaseDyskinesia6-OHDA |