Peroxisome-proliferator-activated receptors γ and peroxisome-proliferator-activated receptors β/δ and the regulation of interleukin 1 receptor antagonist expression by pioglitazone in ischaemic brain

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Abstract
Objective The imbalance between the production and release of interleukin-1 (IL-1) ligands, IL-1α, IL-1β 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) γ. We studied in rats the effects of the PPARγ agonist, pioglitazone, on the regulation of IL-1β, 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-1β, 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 PPARγ and PPAR β/δ. Results Cerebral ischaemia increased the expression of IL-1β, IL-1RI and IL-1ra in the ischaemic cortex. Pioglitazone reduced IL-1β, 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 PPARβ/δ, but prevented excitotoxic neuronal injury and death by a PPARγ-dependent mechanism. Conclusion Our data demonstrate that activation of PPARγ and PPAR β/δ by proglitazone in neurones triggers diverse neuroprotective mechanisms. The restoration of the equilibrium between I1-1β and IL-1ra in ischaemic brain tissue limits IL-1β signalling, reduces inflammatory responses and is an important mechanism by which thiazolidinediones improve the recovery from ischaemic stroke.

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