Peroxisome-proliferator-activated receptors gamma and peroxisome-proliferator-activated receptors beta/delta and the regulation of interleukin 1 receptor antagonist expression by pioglitazone in ischaemic brain.
OBJECTIVE
The imbalance between the production and release of interleukin-1 (IL-1) ligands, IL-1alpha, IL-1beta and IL-1 receptor antagonist (IL-1ra) in ischaemic brain exaggerates inflammatory responses and contributes to neuronal death. Cerebral ischaemia also upregulates the peroxisome-proliferator-activated receptor (PPAR) gamma. We studied in rats the effects of the PPARgamma agonist, pioglitazone, on the regulation of IL-1beta, IL-1ra and IL-1 receptor I (IL-1RI) expression in ischaemic brain after occlusion of the middle cerebral artery for 90 min.


METHODS
Pioglitazone or vehicle was infused intracerebroventricularly over a 5-day period before, during and 24 or 48 h after middle cerebral artery occlusion. The expression of IL-1beta, IL-1ra and IL-1RI in the peri-infarct cortex was investigated by immunohistochemistry, Western blotting and immunofluorescence staining. The mechanisms of the IL-1ra regulation by pioglitazone and the neuroprotection under excitotoxic neuronal injury were studied in primary cortical neurones expressing PPARgamma and PPAR beta/delta.


RESULTS
Cerebral ischaemia increased the expression of IL-1beta, IL-1RI and IL-1ra in the ischaemic cortex. Pioglitazone reduced IL-1beta, but upregulated IL-1ra and increased the number of IL-1ra immunoreactive cells. In primary cortical neurones, pioglitazone stimulated the IL-1ra production via activation of the PPARbeta/delta, but prevented excitotoxic neuronal injury and death by a PPARgamma-dependent mechanism.


CONCLUSIONS
Our data demonstrate that activation of PPARgamma and PPAR beta/delta by proglitazone in neurones triggers diverse neuroprotective mechanisms. The restoration of the equilibrium between I1-1beta and IL-1ra in ischaemic brain tissue limits IL-1beta signalling, reduces inflammatory responses and is an important mechanism by which thiazolidinediones improve the recovery from ischaemic stroke.
Glatz
Torben
T
Institute of Experimental and Clinical Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Stöck
Ivonne
I
Nguyen-Ngoc
Miriam
M
Gohlke
Peter
P
Herdegen
Thomas
T
Culman
Juraj
J
Zhao
Yi
Y
D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism*; D002544:Cerebral Infarction / Q000378:metabolism / Q000517:prevention & control; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism* / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047495:PPAR gamma / Q000378:metabolism* / Q000494:pharmacology; D048068:PPAR-beta / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism* / Q000494:pharmacology; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D018696:Neuroprotective Agents; D047495:PPAR gamma; D048068:PPAR-beta; D047492:Peroxisome Proliferator-Activated Receptors; D017472:Receptors, Interleukin-1; D045162:Thiazolidinediones; D000077205:Pioglitazone