Antioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease

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dc.contributor.authorMichalska Dziama, Patrycja
dc.contributor.authorMayo, Paloma
dc.contributor.authorFernández-Mendívil, Cristina
dc.contributor.authorTenti, Giammarco
dc.contributor.authorDuarte, Pablo
dc.contributor.authorBuendia, Izaskun
dc.contributor.authorRamos García, María Teresa
dc.contributor.authorLópez, Manuela G.
dc.contributor.authorMenéndez Ramos, José Carlos
dc.contributor.authorLeón, Rafael
dc.contributor.authorLeón Martínez, Rafael
dc.date.accessioned2024-01-31T12:44:43Z
dc.date.available2024-01-31T12:44:43Z
dc.date.issued2020-07-22
dc.description.abstractAlzheimer’s disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its characteristic neuronal loss has been related to the formation of neurofibrillary tangles mainly composed by hyperphosphorylated tau protein. Hyperphosphorylation of tau protein is related to the over-activity of GSK-3β, a kinase that participates in several pathological mechanisms including neuroinflammation. Neuronal loss is also related to cytosolic Ca2+ homeostasis dysregulation that triggers apoptosis and free radicals production, contributing to oxidative damage and, finally, neuronal death. Under these premises, we have obtained a new family of 4,7-dihydro-2H-pyrazolo[3–b]pyridines as multitarget directed ligands showing potent antioxidant properties and able to scavenge both oxygen and nitrogen radical species, and also, with anti-inflammatory properties. Further characterization has demonstrated their capacity to inhibit GSK-3β and to block L-type voltage dependent calcium channels. Novel derivatives have also demonstrated an interesting neuroprotective profile on in vitro models of neurodegeneration. Finally, compound 4g revokes cellular death induced by tau hyperphosphorylation in hippocampal slices by blocking reactive oxygen species (ROS) production. In conclusion, the multitarget profile exhibited by these compounds is a novel therapeutic strategy of potential interest in the search of novel treatments for Alzheimer’s disease.
dc.description.departmentDepto. de Química en Ciencias Farmacéuticas
dc.description.facultyFac. de Farmacia
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Educación, Cultura y Deporte(España)
dc.description.sponsorshipUniversidad Autónoma de Madrid
dc.description.sponsorshipUniversidad Complutense de Madrid
dc.description.statuspub
dc.identifier.doi10.3390/antiox9080650
dc.identifier.officialurlhttps://doi.org/10.3390/antiox9080650
dc.identifier.urihttps://hdl.handle.net/20.500.14352/97150
dc.issue.number8
dc.journal.titleAntioxidants
dc.language.isoeng
dc.page.initial650
dc.page.total20
dc.relation.projectIDinfo:eu-repo/grantAgreement/13/03737
dc.relation.projectIDinfo:eu-repo/grantAgreement/16/03977
dc.relation.projectIDinfo:eu-repo/grantAgreement/15/03269
dc.relation.projectIDinfo:eu-repo/grantAgreement/FJCI-2016/28282
dc.rightsAttribution 4.0 International
dc.rights.accessRightsopen access
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject.cdu615:54
dc.subject.cdu615.31
dc.subject.keywordAlzheimer’s disease
dc.subject.keywordAnti-inflammatory drugs
dc.subject.keywordMultitarget drugs
dc.subject.keyword4,7-dihydro-2H-pyrazolo[3,4-b]pyridines
dc.subject.keywordGSK-3β inhibitor
dc.subject.keywordVoltage gated calcium channels antagonists
dc.subject.keywordNeuroprotection
dc.subject.ucmCiencias Biomédicas
dc.subject.unesco24 Ciencias de la Vida
dc.titleAntioxidant, Anti-inflammatory and Neuroprotective Profiles of Novel 1,4-Dihydropyridine Derivatives for the Treatment of Alzheimer’s Disease
dc.typejournal article
dc.volume.number9
dspace.entity.typePublication
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relation.isAuthorOfPublication294d039a-95b4-47a5-ac94-510ba921fd75
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relation.isAuthorOfPublication7093c6ce-e368-44f0-a993-8f7212cb1c2a
relation.isAuthorOfPublication.latestForDiscovery298927e3-bd5b-46ad-bdbe-b818ade8cfb1
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