Paliperidone Prevents Brain Toll-Like Receptor 4 Pathway Activation and Neuroinflammation in Rat Models of Acute and Chronic Restraint Stress

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dc.contributor.authorMac-Dowell Mata, Karina Soledad
dc.contributor.authorCaso Fernández, Javier Rubén
dc.contributor.authorMartín Hernández, D.
dc.contributor.authorMuñoz Madrigal, José Luis
dc.contributor.authorLeza Cerro, Juan Carlos
dc.contributor.authorGarcía Bueno, Borja
dc.date.accessioned2024-01-29T09:43:02Z
dc.date.available2024-01-29T09:43:02Z
dc.date.issued2015-01-24
dc.description.abstractBackground: Alterations in the innate immune/inflammatory system have been proposed to underlie the pathophysiology of psychotic disease, but the mechanisms implicated remain elusive. The main agents of the innate immunity are the family of toll-like receptors (TLRs), which detect circulating pathogen-associated molecular patterns and endogenous damage-associated molecular patterns (DAMPS). Current antipsychotics are able to modulate pro- and anti-inflammatory pathways, but their actions on TLRs remain unexplored. Methods: This study was conducted to elucidate the effects of paliperidone (1mg/Kg i.p.) on acute (6 hours) and chronic (6 hours/day during 21 consecutive days) restraint stress-induced TLR-4 pathway activation and neuroinflammation, and the possible mechanism(s) related (bacterial translocation and/or DAMPs activation). The expression of the elements of a TLR-4-dependent proinflammatory pathway was analyzed at the mRNA and protein levels in prefrontal cortex samples. Results: Paliperidone pre-treatment prevented TLR-4 activation and neuroinflammation in the prefrontal cortices of stressed rats. Regarding the possible mechanisms implicated, paliperidone regulated stress-induced increased intestinal inflammation and plasma lipopolysaccharide levels. In addition, paliperidone also prevented the activation of the endogenous activators of TLR-4 HSP70 and HGMB-1. Conclusions: Our results showed a regulatory role of paliperidone on brain TLR-4, which could explain the therapeutic benefits of its use for the treatment of psychotic diseases beyond its effects on dopamine and serotonin neurotransmission. The study of the mechanisms implicated suggests that gut-increased permeability, inflammation, and bacterial translocation of Gram-negative microflora and HSP70 and HGMB1 expression could be potential adjuvant therapeutic targets for the treatment of psychotic and other stress-related psychiatric pathologies.
dc.description.departmentDepto. de Farmacología y Toxicología
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia e Innovación
dc.description.sponsorshipInstituto de Salud Carlos III
dc.description.sponsorshipCIBERSAM
dc.description.sponsorshipFundación Santander-UCM
dc.description.sponsorshipFundación Mutua Madrileña
dc.description.statuspub
dc.identifier.citationMacDowell KS, Caso JR, Martín-Hernández D, Madrigal JL, Leza JC, García-Bueno B. Paliperidone prevents brain toll-like receptor 4 pathway activation and neuroinflammation in rat models of acute and chronic restraint stress. Int J Neuropsychopharmacol. 2014 Oct 31;18(3):pyu070. doi: 10.1093/ijnp/pyu070. PMID: 25522409.
dc.identifier.doi10.1093/ijnp/pyu070
dc.identifier.issn1469-5111
dc.identifier.issn1461-1457
dc.identifier.officialurlhttps://academic.oup.com/ijnp/article/18/3/pyu070/702462
dc.identifier.relatedurlhttps://pubmed.ncbi.nlm.nih.gov/25522409/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/95794
dc.issue.number3
dc.journal.titleInternational Journal of Neuropsychopharmacology
dc.language.isoeng
dc.page.final11
dc.page.initial1
dc.publisherOxford University Press
dc.relation.projectIDSAF07-63138
dc.relation.projectIDFIS 10/00123
dc.relation.projectIDFIS 13/1102
dc.relation.projectIDGR 58/08
dc.rightsAttribution-NonCommercial 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subject.cdu615.21
dc.subject.cdu615.01/.03
dc.subject.cdu612.8
dc.subject.cdu615.214
dc.subject.keywordAntipsychotics
dc.subject.keywordBacterial translocation
dc.subject.keywordDamage-associated molecular patterns
dc.subject.keywordStress
dc.subject.keywordToll-like receptor-4
dc.subject.ucmCiencias Biomédicas
dc.subject.unesco24 Ciencias de la Vida
dc.titlePaliperidone Prevents Brain Toll-Like Receptor 4 Pathway Activation and Neuroinflammation in Rat Models of Acute and Chronic Restraint Stress
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number18
dspace.entity.typePublication
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