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Mesial Temporal Lobe Epilepsy (MTLE) Drug-Refractoriness Is Associated With P2X7 Receptors Overexpression in the Human Hippocampus and Temporal Neocortex and May Be Predicted by Low Circulating Levels of miR-22

2022-07-07Journal article Open access
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dc.contributor.authorGuerra Leal, Bárbara
dc.contributor.authorBarros-Barbosa, Aurora
dc.contributor.authorFerreirinha, Fátima
dc.contributor.authorChaves, João
dc.contributor.authorRangel, Rui
dc.contributor.authorSantos, Agostinho
dc.contributor.authorCarvalho, Cláudia
dc.contributor.authorMartins-Ferreira, Ricardo
dc.contributor.authorSamões, Raquel
dc.contributor.authorFreitas, Joel
dc.contributor.authorLopes, João
dc.contributor.authorRamalheira, João
dc.contributor.authorLobo, Maria Graça
dc.contributor.authorMartins da Silva, António
dc.contributor.authorCosta, Paulo P.
dc.contributor.authorCorreia-de-Sá, Paulo
dc.date.accessioned2023-03-21T11:38:05Z
dc.date.available2023-03-21T11:38:05Z
dc.date.issued2022-07-07
dc.description.abstractObjective: ATP-gated ionotropic P2X7 receptors (P2X7R) actively participate in epilepsy and other neurological disorders. Neocortical nerve terminals of patients with Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (MTLE-HS) express higher P2X7R amounts. Overexpression of P2X7R bolsters ATP signals during seizures resulting in glial cell activation, cytokines production, and GABAergic rundown with unrestrained glutamatergic excitation. In a mouse model of status epilepticus, increased expression of P2X7R has been associated with the down-modulation of the non-coding micro RNA, miR-22. MiR levels are stable in biological fluids and normally reflect remote tissue production making them ideal disease biomarkers. Here, we compared P2X7R and miR-22 expression in epileptic brains and in the serum of patients with MTLE-HS, respectively. Methods: Quantitative RT-PCR was used to evaluate the expression of P2X7R in the hippocampus and anterior temporal lobe of 23 patients with MTLE-HS and 10 cadaveric controls. Confocal microscopy and Western blot analysis were performed to assess P2X7R protein amounts. MiR-22 expression was evaluated in cell-free sera of 40 MTLE-HS patients and 48 healthy controls. Results: Nerve terminals of the hippocampus and neocortical temporal lobe of MTLE-HS patients overexpress (p < 0.05) an 85 kDa P2X7R protein whereas the normally occurring 67 kDa receptor protein dominates in the brain of the cadaveric controls. Contrariwise, miR-22 serum levels are diminished (p < 0.001) in MTLE-HS patients compared to age-matched control blood donors, a situation that is more evident in patients requiring multiple (>3) anti-epileptic drug (AED) regimens. Conclusion: Data show that there is an inverse relationship between miR-22 serum levels and P2X7R expression in the hippocampus and neocortex of MTLE-HS patients, which implies that measuring serum miR-22 may be a clinical surrogate of P2X7R brain expression in the MTLE-HS. Moreover, the high area under the ROC curve (0.777; 95% CI 0.629-0.925; p = 0.001) suggests that low miR-22 serum levels may be a sensitive predictor of poor response to AEDs among MTLE-HS patients. Results also anticipate that targeting the miR-22/P2X7R axis may be a good strategy to develop newer AEDs.pt_PT
dc.description.sponsorshipThis research was partial funded by a BICE Tecnifar Grant. The work performed in PC-S’s Lab was partially supported by UP/Santander Totta and Fundação para a Ciência e Tecnologia (FCT, POCTI PTDC/SAU-PUB/28311/2017—EPIRaft grant and Fundo Europeu de Desenvolvimento Regional—FEDER funding and COMPETE—MedInUP projects Pest-OE/SAU/UI215/2014, UID/BIM/4308/2016, UIDB/04308/2020 and UIDP/04308/2020). Unit for Multidisciplinary Research in Biomedicine (UMIB) is funded by the Foundation for Science and Technology (FCT) Portugal (grant numbers UIDB/00215/2020 and UIDP/00215/2020) and ITR—Laboratory for Integrative and Translational Research in Population Health (LA/P/0064/2020). RM-F was in receipt of an FCT PhD studentship (SFRH/BD/137900/2018).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationFront Cell Neurosci. 2022 Jul 7;16:910662. doi: 10.3389/fncel.2022.910662. eCollection 2022.pt_PT
dc.identifier.doi10.3389/fncel.2022.910662pt_PT
dc.identifier.issn1662-5102
dc.identifier.urihttp://hdl.handle.net/10400.18/8584
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontiers Mediapt_PT
dc.relationPest-OE/SAU/UI215/2014pt_PT
dc.relationContribution of neuronal membrane and lipid raft remodelling to the pathophysiology of mesial temporal lobe epilepsy (MTLE): insight into the beneficial effects of the ketogenic diet therapy.
dc.relationCentro de Investigação Farmacológica e Inovação Medicamentosa
dc.relationCenter for Drug Discovery and Innovative Medicines
dc.relationCenter for Drug Discovery and Innovative Medicines
dc.relation.publisherversionhttps://www.frontiersin.org/articles/10.3389/fncel.2022.910662/fullpt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectP2X7 Purinoceptorpt_PT
dc.subjectHippocampuspt_PT
dc.subjectMesotemporal Lobe Epilepsypt_PT
dc.subjectmiR-22pt_PT
dc.subjectmicroRNAspt_PT
dc.subjectRefractory Epilepsypt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleMesial Temporal Lobe Epilepsy (MTLE) Drug-Refractoriness Is Associated With P2X7 Receptors Overexpression in the Human Hippocampus and Temporal Neocortex and May Be Predicted by Low Circulating Levels of miR-22pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleContribution of neuronal membrane and lipid raft remodelling to the pathophysiology of mesial temporal lobe epilepsy (MTLE): insight into the beneficial effects of the ketogenic diet therapy.
oaire.awardTitleCentro de Investigação Farmacológica e Inovação Medicamentosa
oaire.awardTitleCenter for Drug Discovery and Innovative Medicines
oaire.awardTitleCenter for Drug Discovery and Innovative Medicines
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FSAU-PUB%2F28311%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FBIM%2F4308%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04308%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04308%2F2020/PT
oaire.citation.startPage910662pt_PT
oaire.citation.titleFrontiers in Cellular Neurosciencept_PT
oaire.citation.volume16pt_PT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication77eb58c9-6c2b-473c-ae3d-1ffd36275829
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