A positive allosteric modulator of mGluR5 promotes neuroprotective effects in mouse models of Alzheimer's disease

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dc.creatorPaula Maria Quaglio Bellozi
dc.creatorGiovanni Freitas Gomes
dc.creatorMaria Carolina Machado da Silva
dc.creatorIsabel Vieira de Assis Lima
dc.creatorCarla Ribeiro Álvares Batista
dc.creatorWellerson de Oliveira Carneiro Junior
dc.creatorJuliana Guimarães Dória
dc.creatorÉrica Leandro Marciano Vieira
dc.creatorRafael Pinto Vieira
dc.creatorRossimiriam Pereira de Freitas
dc.creatorCláudia Natália Ferreira
dc.creatorEduardo Candelario-Jalil
dc.creatorTony Wyss-Coray
dc.creatorFabíola Mara Ribeiro
dc.creatorAntônio Carlos Pinheiro de Oliveira
dc.date.accessioned2024-01-31T14:11:01Z
dc.date.accessioned2025-09-09T01:26:46Z
dc.date.available2024-01-31T14:11:01Z
dc.date.issued2019
dc.description.sponsorshipCNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
dc.description.sponsorshipFAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais
dc.description.sponsorshipCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
dc.identifier.doihttps://doi.org/10.1016/j.neuropharm.2019.107785
dc.identifier.issn0028-3908
dc.identifier.urihttps://hdl.handle.net/1843/63545
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofNeuropharmacology
dc.rightsAcesso Restrito
dc.subjectBioquímica
dc.subjectFarmacologia
dc.subjectAlzheimer, Doença de
dc.subjectSistema nervoso - Degeneração
dc.subjectReceptores metabotrópicos de glutamato - Metabolismo
dc.subjectEnzimas alostéricas
dc.subject.otherAlzheimer's disease
dc.subject.otherNeurodegeneration
dc.subject.otherNeuroinflammation
dc.subject.otherMetabotropic glutamate receptors
dc.subject.otherAllosteric modulation
dc.subject.otherCDPPB
dc.titleA positive allosteric modulator of mGluR5 promotes neuroprotective effects in mouse models of Alzheimer's disease
dc.typeArtigo de periódico
local.citation.volume160
local.description.resumoAlzheimer's Disease (AD) is the most prevalent neurodegenerative disorder. Despite advances in the understanding of its pathophysiology, none of the available therapies prevents disease progression. Excess glutamate plays an important role in excitotoxicity by activating ionotropic receptors. However, the mechanisms modulating neuronal cell survival/death via metabotropic glutamate receptors (mGluRs) are not completely understood. Recent data indicates that CDPPB, a positive allosteric modulator of mGluR5, has neuroprotective effects. Thus, this work aimed to investigate CDPPB treatment effects on amyloid-β (Aβ) induced pathological alterations in vitro and in vivo and in a transgenic mouse model of AD (T41 mice). Aβ induced cell death in primary cultures of hippocampal neurons, which was prevented by CDPPB. Male C57BL/6 mice underwent stereotaxic surgery for unilateral intra-hippocampal Aβ injection, which induced memory deficits, neurodegeneration, neuronal viability reduction and decrease of doublecortin-positive cells, a marker of immature neurons and neuronal proliferation. Treatment with CDPPB for 8 days reversed neurodegeneration and doublecortin-positive cells loss and recovered memory function. Fourteen months old T41 mice presented cognitive deficits, neuronal viability reduction, gliosis and Aβ accumulation. Treatment with CDPPB for 28 days increased neuronal viability (32.2% increase in NeuN+ cells) and reduced gliosis in CA1 region (Iba-1+ area by 31.3% and GFAP+ area by 37.5%) in transgenic animals, without inducing hepatotoxicity. However, it did not reverse cognitive deficit. Despite a four-week treatment did not prevent memory loss in aged transgenic mice, CDPPB is protective against Aβ stimulus. Therefore, this drug represents a potential candidate for further investigations as AD treatment.
local.identifier.orcidhttps://orcid.org/0000-0001-6976-9633
local.identifier.orcidhttps://orcid.org/0000-0002-4855-3056
local.identifier.orcidhttps://orcid.org/0000-0002-0200-2902
local.identifier.orcidhttps://orcid.org/0000-0002-1701-4914
local.identifier.orcidhttps://orcid.org/0000-0002-8647-5108
local.identifier.orcidhttps://orcid.org/0000-0002-4147-5614
local.identifier.orcidhttps://orcid.org/0000-0003-3176-1681
local.identifier.orcidhttps://orcid.org/0000-0001-6974-3724
local.identifier.orcidhttps://orcid.org/0000-0003-4545-6821
local.identifier.orcidhttps://orcid.org/0000-0003-3631-1989
local.identifier.orcidhttps://orcid.org/0000-0001-5893-0831
local.identifier.orcidhttps://orcid.org/0000-0001-7042-9433
local.identifier.orcidhttps://orcid.org/0000-0003-3217-4294
local.publisher.countryBrasil
local.publisher.departmentCOLTEC - COLEGIO TECNICO
local.publisher.departmentICB - DEPARTAMENTO DE BIOQUÍMICA E IMUNOLOGIA
local.publisher.departmentICB - DEPARTAMENTO DE FARMACOLOGIA
local.publisher.departmentICX - DEPARTAMENTO DE QUÍMICA
local.publisher.initialsUFMG
local.url.externahttps://www.sciencedirect.com/science/article/pii/S0028390819303430

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