Abstract
BackgroundPeroxisome proliferator-activated receptors (PPARs, including alpha, beta and gamma subtypes) and their agonists have a protective role in treatment of central nervous system (CNS) diseases. The present study was designed to investigate the expression changes of PPAR-alpha, -beta, -gamma and NF-kappa B in the hippocampus of rats with global cerebral ischemia/reperfusion injury (GCIRI) after treatment with agonists or antagonists of PPAR-gamma.MethodsA rat GCIRI model was established by occlusion of bilateral common carotid arteries and cervical vena retransfusion. GW9662 (5 μg), a selective PPAR- gamma antagonist, was intraventricularly injected at 0.5 h before GCIR; Rosiglitazone (0.8, 2.4 and 7.2 mg/kg), a selective PPAR- gamma agonist, was injected intraperitoneally at 1 h before GCIRI. The expression changes of PPAR-alpha, -beta and -gamma at mRNA and protein levels were detected by RT-PCR and western blotting. The changes of spatial learning and memory (SLM) functions were assessed by using a Morris water maze; the pathohistological changes of hippocampal neurons were evaluated by hematoxylin-eosin (HE) staining; the contents of IL-1, IL-6, IL-10 and TNF-alpha, and the NF- kappa B expression were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were also detected.ResultsThe SLM function and hippocampal neurons were significantly impaired after the occurrence of GCIRI. The MDA, IL-1, IL-6, IL-10, TNF-alpha content and expression of PPARs increased significantly, but the SOD activity and NF-kappa B expression were weakened in the hippocampus. Rosiglitazone treatment significantly protected rats from SLM function impairment and neuron death, and resulted in higher expressions of SOD activity and NF-kappa B, but lower contents of MDA and inflammatory factors. After treatment with rosiglitazone or GW9662, no significant change in PPAR-alpha or -beta expression was detected.ConclusionsRosiglitazone, a PPAR-gamma agonist, plays a protective role in hippocampal neuron damage of GCIRI rats by inhibiting the oxidative stress response and inflammation. The activation or antagonism of PPAR-gamma did not affect the expression of PPAR-alpha or -beta, indicating that the three subtypes of PPARs act in independent pathways in the CNS.
Highlights
Peroxisome proliferator-activated receptors (PPARs, including alpha, beta and gamma subtypes) and their agonists have a protective role in treatment of central nervous system (CNS) diseases
Global cerebral ischemia/reperfusion injury (GCIRI) occurs in patients who are successfully resuscitated from various clinical conditions such as cardiac arrest, asphyxia and shock, which are frequently accompanied by inflammation and can lead to serious neuronal injury, and further to neurodegeneration and learning and memory impairment [12]
Intraventricular administration of pioglitazone 24 h before Middle cerebral artery occlusion (MCAO) significantly reduces the expressions of IL-1, COX-2 and inducible nitric-oxide synthase induced by inflammation [28]. These results demonstrate that PPAR-γ agonists have protective effects on focal cerebral ischaemia-reperfusion injury (IRI), and that the action mechanisms include inhibition of inflammatory reaction and oxidative stress
Summary
Peroxisome proliferator-activated receptors (PPARs, including alpha, beta and gamma subtypes) and their agonists have a protective role in treatment of central nervous system (CNS) diseases. Global cerebral ischemia/reperfusion injury (GCIRI) occurs in patients who are successfully resuscitated from various clinical conditions such as cardiac arrest, asphyxia and shock, which are frequently accompanied by inflammation and can lead to serious neuronal injury, and further to neurodegeneration and learning and memory impairment [12]. Proinflammatory cytokines, such as interleukin (IL)-1β, IL-6 and tissue necrosis factor (TNF)-α, have been implicated as important mediators of injury following cerebral ischemia [13] and contribute to pathogenesis, exacerbating brain tissue damage following ischemia/reperfusion (I/R) injury [14]
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