Gárate, IciarGarcía Bueno, BorjaMuñoz Madrigal, José LuisCaso Fernández, Javier RubénAlou Cervera, LuisGómez-Lus Centelles, María LuisaLeza Cerro, Juan Carlos2024-07-152024-07-152014-01-11Gárate 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;11:8.1742-209410.1186/1742-2094-11-8https://hdl.handle.net/20.500.14352/106106Background The 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. Methods The 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. Results Acute 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. Conclusions The 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.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://doi.org/10.1186/1742-2094-11-8https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-11-8open access615611.02Restraint stressTLR-4 signallingBacterial translocationNeuroinflammationFrontal cortexMicrobiología médicaFarmacología (Medicina)Neurociencias (Medicina)2414 Microbiología3209 Farmacología3205.07 Neurología