RT Journal Article
T1 Paliperidone Prevents Brain Toll-Like Receptor 4 Pathway Activation and Neuroinflammation in Rat Models of Acute and Chronic Restraint Stress
A1 Mac-Dowell Mata, Karina Soledad
A1 Caso Fernández, Javier Rubén
A1 Martín Hernández, D.
A1 Muñoz Madrigal, José Luis
A1 Leza Cerro, Juan Carlos
A1 García Bueno, Borja
AB Background: 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.
PB Oxford University Press
SN 1469-5111
SN 1461-1457
YR 2015
FD 2015-01-24
LK https://hdl.handle.net/20.500.14352/95794
UL https://hdl.handle.net/20.500.14352/95794
LA eng
NO MacDowell 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.
NO Ministerio de Ciencia e Innovación
NO Instituto de Salud Carlos III
NO CIBERSAM
NO Fundación Santander-UCM
NO Fundación Mutua Madrileña
DS Docta Complutense
RD 18 jul 2024