Effect of PPAR-β/δ agonist GW0742 treatment in the acute phase response and blood-brain barrier permeability following brain injury.
The systemic response to ischemic stroke is associated with the hepatic acute phase response (APR) that modulates leukocytes recruitment to the injured brain. The inappropriate recruitment of leukocytes to the brain parenchyma can result in blood-brain barrier (BBB) breakdown. Emerging data suggest that peroxisome proliferator-activated receptor beta/delta (PPAR-β/δ) activation has a potential neuroprotective role in ischemic stroke. However, mechanisms of PPAR-β/δ mediated protection in ischemic insults remain unclear. In the present study, we determined for the first time, the effects of GW0742, a PPAR-β/δ agonist on the APR following brain injury and assessed the effects on BBB permeability and tight junction integrity via claudin-5, occludin, and zona occludens-1 expression. C57/BL6 mice were exposed to 1 hour of ischemia and received 10 minutes before reperfusion either a vehicle solution or GW0742. Hepatic expression of chemokines (C-X-C motif ligand: CXCL1, CXCL2, and CXCL10), serum amyloid A-1, tumor necrosis factor alpha, interleukin-1β, and interleukin-6 was measured, and the extent of brain and hepatic neutrophil infiltration was determined. The results showed that GW0742 treatment decreased infarct volume and edema, reactant production and neutrophil recruitment to the brain and liver, which is a hallmark of the APR. GW0742 significantly reduced BBB leakage and metalloproteinase 9 expression and upregulated the expression of tight junction proteins. These findings may help to guide the experimental and clinical therapeutic use of PPAR-β/δ agonists against brain injury.
Research Unit: UR 12ES09 Dyslipidemia and Atherogenesis, Faculty of Medicine, Monastir, Tunisia. Electronic address: khouloudchehaibi5@gmail.com.
Khouloud
K
Chehaibi
Faculté de Médecine, Université de Nice-Sophia Antipolis, Nice, France.
Laura
L
le Maire
Faculté de Médecine, Université de Nice-Sophia Antipolis, Nice, France.
Sarah
S
Bradoni
Institut d'Investigacions Biomediques (IIB) Sant Pau, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Barcelona, Spain; Departament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Barcelona, Spain.
Joan Carles
JC
Escola
Institut d'Investigacions Biomediques (IIB) Sant Pau, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Barcelona, Spain; Departament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Barcelona, Spain.
Francisco
F
Blanco-Vaca
Research Unit: UR 12ES09 Dyslipidemia and Atherogenesis, Faculty of Medicine, Monastir, Tunisia.
Mohamed Naceur
MN
Slimane
D000210:Acute-Phase Reaction / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D020520:Brain Infarction / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D062793:Occludin / Q000378:metabolism; D047494:PPAR delta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism; D010636:Phenols; D013438:Sulfhydryl Compounds
D057167:Claudins; D018836:Inflammation Mediators; D020780:Matrix Metalloproteinase 9; D062793:Occludin; D047494:PPAR delta; D048068:PPAR-beta; D012333:RNA, Messenger; D013844:Thiazoles; D062826:Zonula Occludens-1 Protein; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds