Peroxisome proliferator-activated receptorsgamma (PPARgamma) differently modulate the interleukin-6 expression in the peri-infarct cortical tissue in the acute and delayed phases of cerebral ischaemia.
Interleukin-6 (IL-6) exerts neuroprotective effects after cerebral ischaemia but can also exacerbate inflammation and induce neuronal death. The current study investigates the role of cerebral peroxisome proliferator-activated receptor(s) gamma (PPARgamma) in the regulation of IL-6 expression in the peri-infarct cortical tissue in rats exposed to focal cerebral ischaemia. Pioglitazone, a high-affinity PPARgamma ligand, was infused intracerebroventricularly (i.c.v.) via osmotic minipumps over a 5-day period before, during and 24 h or 48 h after middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion. The expression of PPARgamma and IL-6 in cortical tissue adjacent to the ischaemic core was studied 24 h and 48 h after MCAO. Pioglitazone augmented the ischaemia-induced upregulation of PPARgamma at both time points. Cerebral ischaemia substantially increased IL-6 expression in the peri-infarct cortical tissue. Twenty-four hours after MCAO, the majority of microglial cells/macrophages showed an intense IL-6 immunoreactivity. IL-6 was also localized in neurons, but the distribution of neurons positively stained for IL-6 at the border of the infarct was very heterogeneous. Pioglitazone effectively decreased the number of IL-6-immunoreactive cells and IL-6 protein levels at 24 h but not at 48 h after MCAO. Pioglitazone treatment reduced the infarct size and improved neurological functions. The present study demonstrates that cerebral PPARgamma suppresses the expression of IL-6 in ischaemic brain tissue during the initial phase of ischaemic stroke, in which the overproduction of IL-6 may aggravate neuronal damage, but not at later time points, when IL-6 promotes neuroprotection and inhibits neuronal death.
Patzer
Andreas
A
Institute of Pharmacology, University Hospital of Schleswig-Holstein, Kiel, Germany.
Zhao
Yi
Y
Stöck
Ivonne
I
Gohlke
Peter
P
Herdegen
Thomas
T
Culman
Juraj
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D009410:Nerve Degeneration / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D000093242:Interleukin-6 Inhibitors
D000893:Anti-Inflammatory Agents; D007004:Hypoglycemic Agents; D015850:Interleukin-6; D047495:PPAR gamma; D000077205:Pioglitazone; D045162:Thiazolidinediones; D000093242:Interleukin-6 Inhibitors