Melatonin–sulforaphane hybrid <scp>ITH</scp>12674 induces neuroprotection in oxidative stress conditions by a ‘drug–prodrug’ mechanism of action

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dc.contributor.authorEgea, Javier
dc.contributor.authorBuendia, Izaskun
dc.contributor.authorParada, Esther
dc.contributor.authorNavarro González De Mesa, Elisa
dc.contributor.authorRada, Patricia
dc.contributor.authorCuadrado, Antonio
dc.contributor.authorLópez, Manuela G.
dc.contributor.authorGarcía García, Antonio
dc.contributor.authorLeón Martínez, Rafael
dc.date.accessioned2024-01-16T08:43:49Z
dc.date.available2024-01-16T08:43:49Z
dc.date.issued2015-02-10
dc.description.abstractBackground and purpose: Neurodegenerative diseases are a major problem afflicting ageing populations; however, there are no effective treatments to stop their progression. Oxidative stress and neuroinflammation are common factors in their pathogenesis. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of oxidative stress, and melatonin is an endogenous hormone with antioxidative properties that reduces its levels with ageing. We have designed a new compound that combines the effects of melatonin with Nrf2 induction properties, with the idea of achieving improved neuroprotective properties. Experimental approach: Compound ITH12674 is a hybrid of melatonin and sulforaphane designed to exert a dual drug-prodrug mechanism of action. We obtained the proposed hybrid in a single step. To test its neuroprotective properties, we used different in vitro models of oxidative stress related to neurodegenerative diseases and brain ischaemia. Key results: ITH12674 showed an improved neuroprotective profile compared to that of melatonin and sulforaphane. ITH12674 (i) mediated a concentration-dependent protective effect in cortical neurons subjected to oxidative stress; (ii) decreased reactive oxygen species production; (iii) augmented GSH concentrations in cortical neurons; (iv) enhanced the Nrf2-antioxidant response element transcriptional response in transfected HEK293T cells; and (v) protected organotypic cultures of hippocampal slices subjected to oxygen and glucose deprivation and re-oxygenation from stress by increasing the expression of haem oxygenase-1 and reducing free radical production. Conclusion and implications: ITH12674 combines the signalling pathways of the parent compounds to improve its neuroprotective properties. This opens a new line of research for such hybrid compounds to treat neurodegenerative diseases.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Medicina
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.refereedTRUE
dc.description.sponsorshipUnión Europea
dc.description.sponsorshipInstituto de Salud Carlos III
dc.description.sponsorshipMinisterio de Economia y Competitividad
dc.description.statuspub
dc.description.statuspub
dc.identifier.citationEgea J, Buendia I, Parada E, Navarro E, Rada P, Cuadrado A, López MG, García AG, León R. Melatonin-sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a 'drug-prodrug' mechanism of action. Br J Pharmacol. 2015 Apr;172(7):1807-21. doi: 10.1111/bph.13025
dc.identifier.doi10.1111/bph.13025
dc.identifier.essn1476-5381
dc.identifier.issn0007-1188
dc.identifier.officialurlhttps://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.13025
dc.identifier.relatedurlhttps://pubmed.ncbi.nlm.nih.gov/25425158/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/93255
dc.journal.titleBritish Journal of Pharmacology
dc.language.isoeng
dc.language.isoeng
dc.page.final1821
dc.page.initial1807
dc.publisherWiley
dc.relation.projectIDCP11/00165
dc.relation.projectIDMarie Curie Actions FP7 (FP7-People-2012-CIG-322156)
dc.relation.projectIDSAF2012-3222
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.cdu577.2
dc.subject.ucmCiencias Biomédicas
dc.subject.ucmCiencias Biomédicas
dc.subject.unesco24 Ciencias de la Vida
dc.subject.unesco24 Ciencias de la Vida
dc.titleMelatonin–sulforaphane hybrid <scp>ITH</scp>12674 induces neuroprotection in oxidative stress conditions by a ‘drug–prodrug’ mechanism of action
dc.typejournal article
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number172
dspace.entity.typePublication
relation.isAuthorOfPublicationd0e22d4d-2011-4a9f-bd9c-609855dba391
relation.isAuthorOfPublication7093c6ce-e368-44f0-a993-8f7212cb1c2a
relation.isAuthorOfPublication.latestForDiscoveryd0e22d4d-2011-4a9f-bd9c-609855dba391
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