title: Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress.
abstract: BACKGROUND
  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.
authors.forename: Iciar
authors.initials: I
authors.lastname: Gárate
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University Complutense, 28040 Madrid, Spain. bgbueno@med.ucm.es.
authors.forename: Borja
authors.initials: B
authors.lastname: García-Bueno
authors.forename: José Luis Muñoz
authors.initials: JL
authors.lastname: Madrigal
authors.forename: Javier R
authors.initials: JR
authors.lastname: Caso
authors.forename: Luis
authors.initials: L
authors.lastname: Alou
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Gómez-Lus
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Leza
mesh_terms: D000818:Animals; D018988:Bacterial Translocation / Q000187:drug effects / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology; D005625:Frontal Lobe / Q000473:pathology*; D007113:Immunity, Innate / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000139:chemically induced / Q000150:complications; D013449:Sulfonamides / Q000627:therapeutic use*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D013449:Sulfonamides; D051197:Toll-Like Receptor 4; D014404:Tubulin; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2