Effect of PPAR-β/δ agonist GW0742 treatment in the acute phase response and blood-brain barrier permeability following brain injury

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 182; pp. 27 - 48
• Main Authors: Chehaibi, Khouloud, le Maire, Laura, Bradoni, Sarah, Escola, Joan Carles, Blanco-Vaca, Francisco, Slimane, Mohamed Naceur
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2017
• Subjects: Acute-Phase Reaction - complications; Acute-Phase Reaction - drug therapy; Acute-Phase Reaction - physiopathology; Animals; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Brain - drug effects; Brain - metabolism; Brain Edema - complications; Brain Edema - drug therapy; Brain Edema - pathology; Brain Edema - physiopathology; Brain Infarction - complications; Brain Infarction - drug therapy; Brain Infarction - pathology; Brain Infarction - physiopathology; Brain Injuries - complications; Brain Injuries - drug therapy; Brain Injuries - physiopathology; Brain Ischemia - complications; Brain Ischemia - drug therapy; Brain Ischemia - pathology; Brain Ischemia - physiopathology; Cerebrovascular Circulation - drug effects; Claudins - genetics; Claudins - metabolism; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - physiopathology; Inflammation Mediators - metabolism; Injections, Intraperitoneal; Internal Medicine; Liver - drug effects; Liver - metabolism; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Mice, Inbred C57BL; Neutrophil Infiltration - drug effects; Occludin - metabolism; Permeability - drug effects; PPAR delta - agonists; PPAR delta - genetics; PPAR delta - metabolism; PPAR-beta - agonists; PPAR-beta - genetics; PPAR-beta - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thiazoles - administration & dosage; Thiazoles - pharmacology; Thiazoles - therapeutic use; Zonula Occludens-1 Protein - genetics; Zonula Occludens-1 Protein - metabolism; CXCL; peroxisome proliferator-activated receptor beta/delta; KO mice; APR; BBB; MIP-2; NF-kB; phosphate-buffered saline; interleukin-8; interleukin-6; macrophage inflammatory protein-2; PPAR-β/δ; Chemokine (C-X-C motif) ligand; EB; PPAR-γ; PBS; occludens-1; IL-1β; IL-8; IL-6; central nervous system; Serum amyloid A; SAA; ZO-1; TJs; GAPDH; peroxisome proliferator-activated receptor gamma; glyceraldehyde 3-phosphate dehydrogenase; TTC; GRO; Nuclear factor; CBF; CNS; dissociation constant; interleukin-1β; Cerebral blood flow; growth-related oncogene; tight junctions; WT; diaminobenzidine; blood-brain barrier; MCAO; polymorphonuclear leukocytes; Knockout mice; DAB; Acute phase response; Middle cerebral artery occlusion; Chemokine receptors; PMN; CCR; Evans Blue; TNF-α; tumor necrosis factor; Kd; wild-type; 2,3,5-triphenyltetrazolium chloride
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2016.10.004

Abstract The systemic response to ischemic stroke is associated with the hepatic acute-phase response (APR) that modulates leucocytes 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 current 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 upon BBB permeability and tight junction (TJ) integrity via claudin-5, occludin and zona occludens-1 expression. C57/BL6 mice were exposed to 1 hour of ischemia and received ten minutes prior to reperfusion either a vehicle solution or GW0742. Hepatic expression of chemokines (C-X-C motif ligand: CXCL1, CXCL2 and CXCL10), serum amyloid A-1 (SAA-1), TNF-α, IL-1β and IL-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 MMP-9 expression and upregulated the expression of TJ proteins. These findings may help to guide the experimental and clinical therapeutic use of PPAR-β/δ agonists against brain injury.