Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF
In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin w...
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| Format: | Article |
| Language: | English |
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Elsevier
2010-05-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999611000015X |
| _version_ | 1818565828789927936 |
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| author | Elena Puerta Isabel Hervias Lucía Barros-Miñones Joaquin Jordan Ana Ricobaraza Mar Cuadrado-Tejedor Ana García-Osta Norberto Aguirre |
| author_facet | Elena Puerta Isabel Hervias Lucía Barros-Miñones Joaquin Jordan Ana Ricobaraza Mar Cuadrado-Tejedor Ana García-Osta Norberto Aguirre |
| author_sort | Elena Puerta |
| collection | DOAJ |
| description | In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD. |
| first_indexed | 2024-12-14T01:45:57Z |
| format | Article |
| id | doaj.art-e85b6c0b0b534bd69d336c3506141d0a |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-14T01:45:57Z |
| publishDate | 2010-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-e85b6c0b0b534bd69d336c3506141d0a2022-12-21T23:21:34ZengElsevierNeurobiology of Disease1095-953X2010-05-01382237245Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNFElena Puerta0Isabel Hervias1Lucía Barros-Miñones2Joaquin Jordan3Ana Ricobaraza4Mar Cuadrado-Tejedor5Ana García-Osta6Norberto Aguirre7Department of Pharmacology, School of Medicine, University of Navarra, Pamplona, SpainDepartment of Pharmacology, School of Medicine, University of Navarra, Pamplona, SpainDepartment of Pharmacology, School of Medicine, University of Navarra, Pamplona, SpainGroup of Neuropharmacology, Department of Medical Sciences, School of Medicine, University of Castilla-La Mancha, Regional Centre for Biomedical Research, Albacete, SpainDivision of Neurosciences, CIMA, University of Navarra, CIBERNED, Pamplona, SpainDivision of Neurosciences, CIMA, University of Navarra, CIBERNED, Pamplona, SpainDivision of Neurosciences, CIMA, University of Navarra, CIBERNED, Pamplona, SpainDepartment of Pharmacology, School of Medicine, University of Navarra, Pamplona, Spain; Corresponding author. Department of Pharmacology, School of Medicine, University of Navarra, c/ Irunlarrea 1, 31008 Pamplona, Spain. Fax: +34 948 425 649.In this study we tested whether phosphodiesterase 5 (PDE5) inhibitors, sildenafil and vardenafil, would afford protection against 3-nitropropionic acid (3NP), which produces striatal lesions that closely mimic some of the neuropathological features of Huntington's Disease (HD). The neurotoxin was given over 5 days by constant systemic infusion using osmotic minipumps. Animals treated with PDE5 inhibitors (sildenafil or vardenafil) showed improved neurologic scores, reduced the loss of striatal DARPP-32 protein levels and lesion volumes, and decreased calpain activation produced by 3NP. This protective effect was independent of changes in 3NP-induced succinate dehydrogenase inhibition. Furthermore, striatal p-CREB levels along with the expression of BDNF were significantly increased in sildenafil-treated rats. In summary, PDE5 inhibitors protected against 3NP-induced striatal degeneration by reducing calpain activation and by promoting survival pathways. These data encourage further evaluation of PDE5 inhibitors in transgenic mouse models of HD.http://www.sciencedirect.com/science/article/pii/S096999611000015X3-Nitropropionic acidBDNFCalpainCREBExcitotoxicityHuntington's disease |
| spellingShingle | Elena Puerta Isabel Hervias Lucía Barros-Miñones Joaquin Jordan Ana Ricobaraza Mar Cuadrado-Tejedor Ana García-Osta Norberto Aguirre Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF Neurobiology of Disease 3-Nitropropionic acid BDNF Calpain CREB Excitotoxicity Huntington's disease |
| title | Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF |
| title_full | Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF |
| title_fullStr | Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF |
| title_full_unstemmed | Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF |
| title_short | Sildenafil protects against 3-nitropropionic acid neurotoxicity through the modulation of calpain, CREB, and BDNF |
| title_sort | sildenafil protects against 3 nitropropionic acid neurotoxicity through the modulation of calpain creb and bdnf |
| topic | 3-Nitropropionic acid BDNF Calpain CREB Excitotoxicity Huntington's disease |
| url | http://www.sciencedirect.com/science/article/pii/S096999611000015X |
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