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The neuroprotective action of amidated-kyotorphin on amyloid β peptide-induced Alzheimer’s disease pathophysiology

2020Journal article Open access
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dc.contributor.authorBelo, Rita F.
dc.contributor.authorMartins, Margarida L. F.
dc.contributor.authorShvachiy, Liana
dc.contributor.authorCosta-Coelho, Tiago
dc.contributor.authorde Almeida-Borlido, Carolina
dc.contributor.authorFonseca-Gomes, João
dc.contributor.authorNeves, Vera
dc.contributor.authorVicente Miranda, Hugo
dc.contributor.authorOuteiro, Tiago F.
dc.contributor.authorCoelho, Joana E
dc.contributor.authorXapelli, Sara
dc.contributor.authorValente, Cláudia A.
dc.contributor.authorHeras, Montserrat
dc.contributor.authorBardaji, Eduard
dc.contributor.authorCastanho, Miguel A. R. B.
dc.contributor.authorDiógenes, Maria José
dc.contributor.authorSebastião, Ana M
dc.date.accessioned2021-02-12T17:17:34Z
dc.date.available2021-02-12T17:17:34Z
dc.date.issued2020
dc.descriptionCopyright © 2020 Belo, Martins, Shvachiy, Costa-Coelho, de Almeida-Borlido, Fonseca-Gomes, Neves, Vicente Miranda, Outeiro, Coelho, Xapelli, Valente, Heras, Bardaji, Castanho, Diogenes and Sebastião. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.pt_PT
dc.description.abstractKyotorphin (KTP, l-tyrosyl-l-arginine) is an endogenous dipeptide initially described to have analgesic properties. Recently, KTP was suggested to be an endogenous neuroprotective agent, namely for Alzheimer's disease (AD). In fact, KTP levels were shown to be decreased in the cerebrospinal fluid of patients with AD, and recent data showed that intracerebroventricular (i.c.v.) injection of KTP ameliorates memory impairments in a sporadic rat model of AD. However, this administration route is far from being a suitable therapeutic strategy. Here, we evaluated if the blood-brain permeant KTP-derivative, KTP-NH2, when systemically administered, would be effective in preventing memory deficits in a sporadic AD animal model and if so, which would be the synaptic correlates of that action. The sporadic AD model was induced in male Wistar rats through i.c.v. injection of amyloid β peptide (Aβ). Animals were treated for 20 days with KTP-NH2 (32.3 mg/kg, intraperitoneally (i.p.), starting at day 3 after Aβ administration) before memory testing (Novel object recognition (NOR) and Y-maze (YM) tests). Animals were then sacrificed, and markers for gliosis were assessed by immunohistochemistry and Western blot analysis. Synaptic correlates were assessed by evaluating theta-burst induced long term potentiation (LTP) of field excitatory synaptic potentials (fEPSPs) recorded from hippocampal slices and cortical spine density analysis. In the absence of KTP-NH2 treatment, Aβ-injected rats had clear memory deficits, as assessed through NOR or YM tests. Importantly, these memory deficits were absent in Aβ-injected rats that had been treated with KTP-NH2, which scored in memory tests as control (sham i.c.v. injected) rats. No signs of gliosis could be detected at the end of the treatment in any group of animals. LTP magnitude was significantly impaired in hippocampal slices that had been incubated with Aβ oligomers (200 nM) in the absence of KTP-NH2. Co-incubation with KTP-NH2 (50 nM) rescued LTP toward control values. Similarly, Aβ caused a significant decrease in spine density in cortical neuronal cultures, and this was prevented by co-incubation with KTP-NH2 (50 nM). In conclusion, the present data demonstrate that i.p. KTP-NH2 treatment counteracts Aβ-induced memory impairments in an AD sporadic model, possibly through the rescuing of synaptic plasticity mechanisms.pt_PT
dc.description.sponsorshipThis study was supported by Santa Casa da Misericórdia de Lisboa (MB37-2017) and Fundação para a Ciência e Tecnologia (FCT): PTDC/NEU-OSD/5644/2014, and PTDC/BIA-VIR/29495/2017. RFB was supported by FCT (PD/BD/114337/2016). JF-G was supported by FCT (PD/BD/114441/2016). JEC was supported by FCT (SFRH/BPD/87647/2012).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationFront Pharmacol. 2020 Jul 9;11:985.pt_PT
dc.identifier.doi10.3389/fphar.2020.00985pt_PT
dc.identifier.eissn1663-9812
dc.identifier.urihttp://hdl.handle.net/10451/46303
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontierspt_PT
dc.relationMB37-2017pt_PT
dc.relationKyotorphin as new pharmacological therapeutic strategy for Alzheimers Disease
dc.relationBDNF receptor cleavage:relevance for Alzheimer´s Disease pathophysiology
dc.relationMICROGLIA DYSREGULATION AS TRIGGER FOR CHRONIC NEUROINFLAMMATION: IMPACT FOR AGING AND NEURODEGENERATIVE DISEASES
dc.relation.publisherversionhttps://www.frontiersin.org/journals/pharmacologypt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAmidated-kyotorphinpt_PT
dc.subjectAlzheimer’s diseasept_PT
dc.subjectAmyloid b peptidept_PT
dc.subjectNovel object recognition testpt_PT
dc.subjectY-Maze alternation testpt_PT
dc.subjectLong-term potentiationpt_PT
dc.subjectMemorypt_PT
dc.subjectSynaptic plasticitypt_PT
dc.titleThe neuroprotective action of amidated-kyotorphin on amyloid β peptide-induced Alzheimer’s disease pathophysiologypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleKyotorphin as new pharmacological therapeutic strategy for Alzheimers Disease
oaire.awardTitleBDNF receptor cleavage:relevance for Alzheimer´s Disease pathophysiology
oaire.awardTitleMICROGLIA DYSREGULATION AS TRIGGER FOR CHRONIC NEUROINFLAMMATION: IMPACT FOR AGING AND NEURODEGENERATIVE DISEASES
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FNEU-OSD%2F5644%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-VIR%2F29495%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F114337%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F114441%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F87647%2F2012/PT
oaire.citation.startPage985pt_PT
oaire.citation.titleFrontiers in Pharmacologypt_PT
oaire.citation.volume11pt_PT
oaire.fundingStream3599-PPCDT
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person.familyNameBelo
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person.givenNameCláudia
person.givenNameMiguel
person.givenNameMaria José
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rcaap.typearticlept_PT
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