RT Journal Article
T1 Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress
A1 Gárate, Iciar
A1 García Bueno, Borja
A1 Muñoz Madrigal, José Luis
A1 Caso Fernández, Javier Rubén
A1 Alou Cervera, Luis
A1 Gómez-Lus Centelles, María Luisa
A1 Leza Cerro, Juan Carlos
AB BackgroundThe innate immune response is the first line of defence against invading microorganisms and it is also activated in different neurologic/neurodegenerative pathological scenarios. As a result, the family of the innate immune toll-like receptors (TLRs) and, in particular, the genetic/pharmacological manipulation of the TLR-4 signalling pathway emerges as a potential therapeutic strategy. Growing evidence relates stress exposure with altered immune responses, but the precise role of TLR-4 remains partly unknown.MethodsThe present study aimed to elucidate whether the elements of the TLR-4 signalling pathway are activated after acute stress exposure in rat brain frontal cortex and its role in the regulation of the stress-induced neuroinflammatory response, by means of its pharmacological modulation with the intravenous administration of the TLR-4 specific inhibitor TAK-242. Considering that TLR-4 responds predominantly to lipopolysaccharide from gram-negative bacteria, we checked whether increased intestinal permeability and a resultant bacterial translocation is a potential regulatory mechanism of stress-induced TLR-4 activation.ResultsAcute restraint stress exposure upregulates TLR-4 expression both at the mRNA and protein level. Stress-induced TLR-4 upregulation is prevented by the protocol of antibiotic intestinal decontamination made to reduce indigenous gastrointestinal microflora, suggesting a role for bacterial translocation on TLR-4 signalling pathway activation. TAK-242 pre-stress administration prevents the accumulation of potentially deleterious inflammatory and oxidative/nitrosative mediators in the brain frontal cortex of rats.ConclusionsThe use of TAK-242 or other TLR-4 signalling pathway inhibitory compounds could be considered as a potential therapeutic adjuvant strategy to constrain the inflammatory process taking place after stress exposure and in stress-related neuropsychiatric diseases.
PB BMC
SN 1742-2094
YR 2014
FD 2014-01-11
LK https://hdl.handle.net/20.500.14352/106106
UL https://hdl.handle.net/20.500.14352/106106
LA eng
NO Gárate I, García-Bueno B, Madrigal JL, Caso JR, Alou L, Gómez-Lus ML, Leza JC. Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. J Neuroinflammation. 2014 Jan 11;11:8.
NO Ministerio de Ciencia e Innovación (España)
NO Instituto de Salud Carlos III (España)
NO Centro de Investigación en Red de Salud Mental (España)
NO CIBERSAM
NO Fundación Santander-UCM
NO Fundación Mutua Madrileña
DS Docta Complutense
RD 10 abr 2025