Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases

Resveratrol is a naturally occurring stilbene which has shown promising results as treatment for several neurodegenerative diseases. However, its application is limited due to its low efficacy and bioavailability. Here, we have designed and synthesized alkylated resveratrol prodrugs combining struct...

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Detalhes bibliográficos
Autores: Peñalver, Pablo, Belmonte-Reche, Efres, Adán, Norma, Caro, Marta, Mateos-Martín, María Luisa, Delgado, M., González-Rey, Elena, Morales, Juan Carlos
Formato: artículo
Estado:Versión enviada para evaluación y publicación
Fecha de publicación:2018
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/163397
Acesso em linha:http://hdl.handle.net/10261/163397
Access Level:acceso abierto
Palavra-chave:Inflammation
Neurodegenerative diseases
Neuroprotection
Prodrug
Resveratrol
Zebra fish
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spelling Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseasesPeñalver, PabloBelmonte-Reche, EfresAdán, NormaCaro, MartaMateos-Martín, María LuisaDelgado, M.González-Rey, ElenaMorales, Juan CarlosInflammationNeurodegenerative diseasesNeuroprotectionProdrugResveratrolZebra fishResveratrol is a naturally occurring stilbene which has shown promising results as treatment for several neurodegenerative diseases. However, its application is limited due to its low efficacy and bioavailability. Here, we have designed and synthesized alkylated resveratrol prodrugs combining structural modification to improve antioxidant and anti-inflammatory properties and the preparation of prodrugs to extend drug bioavailability. For comparison we also studied resveratrol prodrugs and alkylated resveratrol derivatives. Methylated and butylated resveratrol derivatives showed the best in vitro neuroprotective and anti-inflammatory activity. The glucosyl- and glucosyl-acyl- prodrugs of these derivatives showed lower toxicity on zebra fish embryo. When neuroprotection was examined on pentylenetetrazole challenged zebra fish, they were capable of reverting neuronal damage but to a lower extent than resveratrol. Nevertheless, 3-O-(6'-O-octanoyl)-β-d-glucopyranoside resveratrol (compound 8) recovered AChE activity over 100% whereas resveratrol only up to 92%. In a 3-nitropropionic acid mice model of Huntington's disease, resveratrol derivative 8 delayed the onset and reduced the severity of HD-like symptoms, by improving locomotor activity and protecting against weight loss. Its effects involved an equal antioxidant but better anti-inflammatory profile than resveratrol as shown by SOD2 expression in brain tissue and circulating levels of IL-6 (11 vs 18 pg/mL), respectively. Finally, the octanoyl chain in compound 8 could be playing a role in inflammation and neuronal development indicating it could be acting as a double-drug, instead of as a prodrugJunata de Andalucía (FQM-7316); Ministerio de Economía y Competitividad (SAF 2014-58354-R); FEDER; EBR; Universidad de GranadaPeer reviewedElsevierConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201820182018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Preprintinfo:eu-repo/semantics/submittedVersionhttp://hdl.handle.net/10261/163397reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1633972026-05-22T06:33:51Z
dc.title.none.fl_str_mv Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases
title Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases
spellingShingle Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases
Peñalver, Pablo
Inflammation
Neurodegenerative diseases
Neuroprotection
Prodrug
Resveratrol
Zebra fish
title_short Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases
title_full Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases
title_fullStr Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases
title_full_unstemmed Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases
title_sort Alkylated resveratrol prodrugs and metabolites as potential therapeutics for neurodegenerative diseases
dc.creator.none.fl_str_mv Peñalver, Pablo
Belmonte-Reche, Efres
Adán, Norma
Caro, Marta
Mateos-Martín, María Luisa
Delgado, M.
González-Rey, Elena
Morales, Juan Carlos
author Peñalver, Pablo
author_facet Peñalver, Pablo
Belmonte-Reche, Efres
Adán, Norma
Caro, Marta
Mateos-Martín, María Luisa
Delgado, M.
González-Rey, Elena
Morales, Juan Carlos
author_role author
author2 Belmonte-Reche, Efres
Adán, Norma
Caro, Marta
Mateos-Martín, María Luisa
Delgado, M.
González-Rey, Elena
Morales, Juan Carlos
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Inflammation
Neurodegenerative diseases
Neuroprotection
Prodrug
Resveratrol
Zebra fish
topic Inflammation
Neurodegenerative diseases
Neuroprotection
Prodrug
Resveratrol
Zebra fish
description Resveratrol is a naturally occurring stilbene which has shown promising results as treatment for several neurodegenerative diseases. However, its application is limited due to its low efficacy and bioavailability. Here, we have designed and synthesized alkylated resveratrol prodrugs combining structural modification to improve antioxidant and anti-inflammatory properties and the preparation of prodrugs to extend drug bioavailability. For comparison we also studied resveratrol prodrugs and alkylated resveratrol derivatives. Methylated and butylated resveratrol derivatives showed the best in vitro neuroprotective and anti-inflammatory activity. The glucosyl- and glucosyl-acyl- prodrugs of these derivatives showed lower toxicity on zebra fish embryo. When neuroprotection was examined on pentylenetetrazole challenged zebra fish, they were capable of reverting neuronal damage but to a lower extent than resveratrol. Nevertheless, 3-O-(6'-O-octanoyl)-β-d-glucopyranoside resveratrol (compound 8) recovered AChE activity over 100% whereas resveratrol only up to 92%. In a 3-nitropropionic acid mice model of Huntington's disease, resveratrol derivative 8 delayed the onset and reduced the severity of HD-like symptoms, by improving locomotor activity and protecting against weight loss. Its effects involved an equal antioxidant but better anti-inflammatory profile than resveratrol as shown by SOD2 expression in brain tissue and circulating levels of IL-6 (11 vs 18 pg/mL), respectively. Finally, the octanoyl chain in compound 8 could be playing a role in inflammation and neuronal development indicating it could be acting as a double-drug, instead of as a prodrug
publishDate 2018
dc.date.none.fl_str_mv 2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Preprint
info:eu-repo/semantics/submittedVersion
format article
status_str submittedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/163397
url http://hdl.handle.net/10261/163397
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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