title: TLR2 ligand induces protection against cerebral ischemia/reperfusion injury via activation of phosphoinositide 3-kinase/Akt signaling.
abstract: This study examined the effect of TLR2 activation by its specific ligand, Pam3CSK4, on cerebral ischemia/reperfusion (I/R) injury. Mice (n = 8/group) were treated with Pam3CSK4 1 h before cerebral ischemia (60 min), followed by reperfusion (24 h). Pam3CSK4 was also given to the mice (n = 8) 30 min after ischemia. Infarct size was determined by triphenyltetrazolium chloride staining. The morphology of neurons in brain sections was examined by Nissl staining. Pam3CSK4 administration significantly reduced infarct size by 55.9% (p < 0.01) compared with untreated I/R mice. Therapeutic treatment with Pam3CSK4 also significantly reduced infarct size by 55.8%. Morphologic examination showed that there was less neuronal damage in the hippocampus of Pam3CSK4-treated mice compared with untreated cerebral I/R mice. Pam3CSK4 treatment increased the levels of Hsp27, Hsp70, and Bcl2, and decreased Bax levels and NF-κB-binding activity in the brain tissues. Administration of Pam3CSK4 significantly increased the levels of phospho-Akt/Akt and phospho-GSK-3β/GSK-3β compared with untreated I/R mice. More significantly, either TLR2 deficiency or PI3K inhibition with LY29004 abolished the protection by Pam3CSK4. These data demonstrate that activation of TLR2 by its ligand prevents focal cerebral ischemic damage through a TLR2/PI3K/Akt-dependent mechanism. Of greater significance, these data indicate that therapy with a TLR2-specific agonist during cerebral ischemia is effective in reducing injury.
authors.affiliation: Department of Surgery, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Yuling
authors.initials: Y
authors.lastname: Chen
authors.forename: Tuanzhu
authors.initials: T
authors.lastname: Ha
authors.forename: Jim
authors.initials: J
authors.lastname: Kelley
authors.forename: John
authors.initials: J
authors.lastname: Schweitzer
authors.forename: John H
authors.initials: JH
authors.lastname: Kalbfleisch
authors.forename: Race L
authors.initials: RL
authors.lastname: Kao
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.forename: Chuanfu
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000276:immunology; D020244:Infarction, Middle Cerebral Artery / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control; D008024:Ligands; D055666:Lipopeptides / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology*; D015427:Reperfusion Injury / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000172:deficiency / Q000378:metabolism
chemical_list: D008024:Ligands; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt