Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling
The antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impai...
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| Format: | Article |
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Wiley
2018-01-01
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| Series: | Neural Plasticity |
| Online Access: | http://dx.doi.org/10.1155/2018/4196961 |
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| author | Ginetta Collo Laura Cavalleri Federica Bono Cristina Mora Stefania Fedele Roberto William Invernizzi Massimo Gennarelli Giovanna Piovani Tilo Kunath Mark J. Millan Emilio Merlo Pich PierFranco Spano |
| author_facet | Ginetta Collo Laura Cavalleri Federica Bono Cristina Mora Stefania Fedele Roberto William Invernizzi Massimo Gennarelli Giovanna Piovani Tilo Kunath Mark J. Millan Emilio Merlo Pich PierFranco Spano |
| author_sort | Ginetta Collo |
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| description | The antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impaired neuroplasticity occurring in TRD has been proposed. Since D3R agonists are highly expressed on DA neurons in humans, we studied the effect of ropinirole and pramipexole on structural plasticity using a translational model of human-inducible pluripotent stem cells (hiPSCs). Two hiPSC clones from healthy donors were differentiated into midbrain DA neurons. Ropinirole and pramipexole produced dose-dependent increases of dendritic arborization and soma size after 3 days of culture, effects antagonized by the selective D3R antagonists SB277011-A and S33084 and by the mTOR pathway kinase inhibitors LY294002 and rapamycin. All treatments were also effective in attenuating the D3R-dependent increase of p70S6-kinase phosphorylation. Immunoneutralisation of BDNF, inhibition of TrkB receptors, and blockade of MEK-ERK signaling likewise prevented ropinirole-induced structural plasticity, suggesting a critical interaction between BDNF and D3R signaling pathways. The highly similar profiles of data acquired with DA neurons derived from two hiPSC clones underpin their reliability for characterization of pharmacological agents acting via dopaminergic mechanisms. |
| format | Article |
| id | doaj-art-06206ad6229e4f14aafa3ea2842b7478 |
| institution | Kabale University |
| issn | 2090-5904 1687-5443 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Neural Plasticity |
| spelling | doaj-art-06206ad6229e4f14aafa3ea2842b74782025-02-03T05:57:53ZengWileyNeural Plasticity2090-59041687-54432018-01-01201810.1155/2018/41969614196961Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR SignalingGinetta Collo0Laura Cavalleri1Federica Bono2Cristina Mora3Stefania Fedele4Roberto William Invernizzi5Massimo Gennarelli6Giovanna Piovani7Tilo Kunath8Mark J. Millan9Emilio Merlo Pich10PierFranco Spano11Department of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Biomedicine, University of Basel, Basel, SwitzerlandIRCCS Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyMRC Centre for Regenerative Medicine, Institute for Stem Cell Research, University of Edinburgh, Edinburgh, UKDivision of Psychopharmacology, Institut de Recherches Servier, Croissy-sur-Seine, FranceCNS Therapeutic Area Unit, Takeda Development Center Europe, London, UKDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyThe antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impaired neuroplasticity occurring in TRD has been proposed. Since D3R agonists are highly expressed on DA neurons in humans, we studied the effect of ropinirole and pramipexole on structural plasticity using a translational model of human-inducible pluripotent stem cells (hiPSCs). Two hiPSC clones from healthy donors were differentiated into midbrain DA neurons. Ropinirole and pramipexole produced dose-dependent increases of dendritic arborization and soma size after 3 days of culture, effects antagonized by the selective D3R antagonists SB277011-A and S33084 and by the mTOR pathway kinase inhibitors LY294002 and rapamycin. All treatments were also effective in attenuating the D3R-dependent increase of p70S6-kinase phosphorylation. Immunoneutralisation of BDNF, inhibition of TrkB receptors, and blockade of MEK-ERK signaling likewise prevented ropinirole-induced structural plasticity, suggesting a critical interaction between BDNF and D3R signaling pathways. The highly similar profiles of data acquired with DA neurons derived from two hiPSC clones underpin their reliability for characterization of pharmacological agents acting via dopaminergic mechanisms.http://dx.doi.org/10.1155/2018/4196961 |
| spellingShingle | Ginetta Collo Laura Cavalleri Federica Bono Cristina Mora Stefania Fedele Roberto William Invernizzi Massimo Gennarelli Giovanna Piovani Tilo Kunath Mark J. Millan Emilio Merlo Pich PierFranco Spano Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling Neural Plasticity |
| title | Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling |
| title_full | Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling |
| title_fullStr | Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling |
| title_full_unstemmed | Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling |
| title_short | Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling |
| title_sort | ropinirole and pramipexole promote structural plasticity in human ipsc derived dopaminergic neurons via bdnf and mtor signaling |
| url | http://dx.doi.org/10.1155/2018/4196961 |
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