Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia
Statins have been proposed for L-DOPA-induced dyskinesia (LID) treatment. Statin anti-dyskinetic effects were related to the inhibition of the Ras-ERK pathway. However, the mechanisms responsible for the anti-LID effect are unclear. Changes in cholesterol homeostasis and oxidative stress- and inflam...
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| Format: | Article |
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MDPI AG
2023-07-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/12/7/1454 |
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| author | Andrea Lopez-Lopez Rita Valenzuela Ana Isabel Rodriguez-Perez María J. Guerra Jose Luis Labandeira-Garcia Ana Muñoz |
| author_facet | Andrea Lopez-Lopez Rita Valenzuela Ana Isabel Rodriguez-Perez María J. Guerra Jose Luis Labandeira-Garcia Ana Muñoz |
| author_sort | Andrea Lopez-Lopez |
| collection | DOAJ |
| description | Statins have been proposed for L-DOPA-induced dyskinesia (LID) treatment. Statin anti-dyskinetic effects were related to the inhibition of the Ras-ERK pathway. However, the mechanisms responsible for the anti-LID effect are unclear. Changes in cholesterol homeostasis and oxidative stress- and inflammation-related mechanisms such as angiotensin II and Rho-kinase (ROCK) inhibition may be involved. The nigra and striatum of dyskinetic rats showed increased levels of cholesterol, ROCK, and the inflammatory marker IL-1β, which were reduced by the angiotensin type-1 receptor (AT1) antagonist candesartan, simvastatin, and the ROCK inhibitor fasudil. As observed for LID, angiotensin II-induced, via AT1, increased levels of cholesterol and ROCK in the rat nigra and striatum. In cultured dopaminergic neurons, angiotensin II increased cholesterol biosynthesis and cholesterol efflux without changes in cholesterol uptake. In astrocytes, angiotensin induced an increase in cholesterol uptake, decrease in biosynthesis, and no change in cholesterol efflux, suggesting a neuronal accumulation of cholesterol that is reduced via transfer to astrocytes. Our data suggest mutual interactions between angiotensin/AT1, cholesterol, and ROCK pathways in LID, which are attenuated by the corresponding inhibitors. Interestingly, these three drugs have also been suggested as neuroprotective treatments against Parkinson’s disease. Therefore, they may reduce dyskinesia and the progression of the disease using common mechanisms. |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T01:22:02Z |
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| series | Antioxidants |
| spelling | doaj.art-e676d6e7573e49ae8eea72dc389f5a362023-11-18T18:06:13ZengMDPI AGAntioxidants2076-39212023-07-01127145410.3390/antiox12071454Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced DyskinesiaAndrea Lopez-Lopez0Rita Valenzuela1Ana Isabel Rodriguez-Perez2María J. Guerra3Jose Luis Labandeira-Garcia4Ana Muñoz5Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, SpainResearch Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, SpainResearch Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, SpainResearch Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, SpainResearch Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, SpainResearch Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, 15782 Santiago de Compostela, SpainStatins have been proposed for L-DOPA-induced dyskinesia (LID) treatment. Statin anti-dyskinetic effects were related to the inhibition of the Ras-ERK pathway. However, the mechanisms responsible for the anti-LID effect are unclear. Changes in cholesterol homeostasis and oxidative stress- and inflammation-related mechanisms such as angiotensin II and Rho-kinase (ROCK) inhibition may be involved. The nigra and striatum of dyskinetic rats showed increased levels of cholesterol, ROCK, and the inflammatory marker IL-1β, which were reduced by the angiotensin type-1 receptor (AT1) antagonist candesartan, simvastatin, and the ROCK inhibitor fasudil. As observed for LID, angiotensin II-induced, via AT1, increased levels of cholesterol and ROCK in the rat nigra and striatum. In cultured dopaminergic neurons, angiotensin II increased cholesterol biosynthesis and cholesterol efflux without changes in cholesterol uptake. In astrocytes, angiotensin induced an increase in cholesterol uptake, decrease in biosynthesis, and no change in cholesterol efflux, suggesting a neuronal accumulation of cholesterol that is reduced via transfer to astrocytes. Our data suggest mutual interactions between angiotensin/AT1, cholesterol, and ROCK pathways in LID, which are attenuated by the corresponding inhibitors. Interestingly, these three drugs have also been suggested as neuroprotective treatments against Parkinson’s disease. Therefore, they may reduce dyskinesia and the progression of the disease using common mechanisms.https://www.mdpi.com/2076-3921/12/7/1454angiotensinbrain cholesteroldyskinesiafasudilL-DOPAneuroinflammation |
| spellingShingle | Andrea Lopez-Lopez Rita Valenzuela Ana Isabel Rodriguez-Perez María J. Guerra Jose Luis Labandeira-Garcia Ana Muñoz Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia Antioxidants angiotensin brain cholesterol dyskinesia fasudil L-DOPA neuroinflammation |
| title | Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia |
| title_full | Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia |
| title_fullStr | Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia |
| title_full_unstemmed | Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia |
| title_short | Interactions between Angiotensin Type-1 Antagonists, Statins, and ROCK Inhibitors in a Rat Model of L-DOPA-Induced Dyskinesia |
| title_sort | interactions between angiotensin type 1 antagonists statins and rock inhibitors in a rat model of l dopa induced dyskinesia |
| topic | angiotensin brain cholesterol dyskinesia fasudil L-DOPA neuroinflammation |
| url | https://www.mdpi.com/2076-3921/12/7/1454 |
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