Preconditioning with a TLR2 specific ligand increases resistance to cerebral ischemia/reperfusion injury.
The brain's resistance to ischemic injury can be transiently augmented by prior exposure to a sub-lethal stress stimulus, i.e. preconditioning. It has been reported that Toll-like receptors (TLRs) are involved in the preconditioning-induced protective effect against ischemic brain injury. In this study, we investigated the effect of preconditioning with a TLR2 specific ligand, Pam3CSK4, on focal cerebral ischemia/reperfusion (I/R) injury in mice. Pam3CSK4 was administered systemically 24 h before the mice were subjected to focal cerebral ischemia (1 h) followed by reperfusion. Cerebral infarct size was determined, blood brain barrier (BBB) permeability was evaluated, and expression of tight-junction proteins were examined after focal cerebral I/R. Results showed that pre-treatment with Pam3CSK significantly reduced brain infarct size (1.9+/-0.5% vs 9.4+/-2.2%) compared with the untreated I/R group. Pam3CSK4 pre-treatment also significantly reduced acute mortality (4.3% vs 24.2%), preserved neurological function (8.22+/-0.64 vs 3.91+/-0.57), and attenuated brain edema (84.61+/-0.08% vs 85.29+/-0.09%) after cerebral I/R. In addition, Pam3CSK4 pre-treatment preserved BBB function as evidenced by decreased leakage of serum albumin (0.528+/-0.026 vs 0.771+/-0.059) and Evans Blue (9.23+/-0.72 microg/mg vs 12.56+/-0.65 microg/mg) into brain tissue. Pam3CSK4 pre-treatment also attenuated the loss of the tight junction protein occludin in response to brain I/R injury. These results suggest that TLR2 is a new target of ischemic preconditioning in the brain and preconditioning with a TLR2 specific ligand will protect the brain from I/R injury.
Hua
Fang
F
Department of Surgery, East Tennessee State University, Johnson City, TN 37614, United States.
Ma
Jing
J
Ha
Tuanzhu
T
Kelley
Jim
J
Williams
David L
DL
Kao
Race L
RL
Kalbfleisch
John H
JH
Browder
I William
IW
Li
Chuanfu
C
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D015153:Blotting, Western; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D002199:Capillary Permeability / Q000187:drug effects; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning / Q000379:methods*; D008024:Ligands; D055666:Lipopeptides; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects; D051379:Mice; D062793:Occludin; D010455:Peptides / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
D008024:Ligands; D055666:Lipopeptides; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; C508075:Pam(3)CSK(4) peptide; D010455:Peptides; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2