15-deoxyprostaglandin-j2 and Reperfusion-Injury

To investigate the effect of PPARγ agonist 15d-PGJ2 treatment on the microglia activation and neurological deficit of ischemia reperfusion in diabetic rat model, adult Sprague-Dawley rats were sacrificed for the research. The rats were randomly categorized into four groups: (1) sham-operated group; (2) standard ischemia group; (3) diabetic ischemia group; (4) diabetic ischemia group with diabetes and treated with 15d-PGJ2. Compared to the sham-operated group, all the ischemic groups have significantly severer neurological deficits, more TNF-α and IL-1 expression, increased labeling of apoptotic cells, increased CD68 positive staining of brain lesion, and increased volume of infarct and cerebral edema in both 24 hours and 7 days after reperfusion. Interestingly, reduced neurological deficits, decreased TNF-α and IL-1 expression, less apoptotic cells and CD68 positive staining, and alleviated infarct and cerebral edema volume were observed when 15d-PGJ2 was intraperitoneally injected after reperfusion in diabetic ischemia group, suggesting its neuroprotective role in regulating microglia activation, which may have a therapeutic application in the future.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Apoptosis; Brain Edema; Brain Infarction; Diabetes Mellitus, Experimental; Interleukin-1; Microglia; PPAR gamma; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tumor Necrosis Factor-alpha

Peroxisome proliferator-activated receptor-γ (PPAR-γ) has recently emerged as potential therapeutic agents for cerebral ischemia-reperfusion (I/R) injury because of anti-neuronal apoptotic actions. However, whether PPAR-γ activation mediates neuronal autophagy in such conditions remains unclear. Therefore, in this study, we investigated the role of PPAR-γ agonist 15-PGJ(2) on neuronal autophagy induced by I/R. The expression of autophagic-related protein in ischemic cortex such as LC3-II, Beclin 1, cathepsin-B and LAMP1 increased significantly after cerebral I/R injury. Furthermore, increased punctate LC3 labeling and cathepsin-B staining occurred in neurons. Treatment with PPAR-γ agonist 15d-PGJ(2) decreased not only autophagic-related protein expression in ischemic cortex, but also immunoreactivity of LC3 and cathepsin-B in neurons. Autophagic inhibitor 3-methyladenine (3-MA) decreased LC3-II levels, reduced the infarct volume, and mimicked some protective effect of 15d-PGJ(2) against cerebral I/R injury. These results indicate that PPAR-γ agonist 15d-PGJ(2) exerts neuroprotection by inhibiting neuronal autophagy after cerebral I/R injury. Although the molecular mechanisms underlying PPAR-γ agonist in mediating neuronal autophagy remain to be determined, neuronal autophagy may be a new target for PPAR-γ agonist treatment in cerebral I/R injury.

Topics: Animals; Autophagy; Brain Ischemia; Cathepsin B; Disease Models, Animal; Humans; Male; Mice; Microtubule-Associated Proteins; Neurons; Neuroprotective Agents; PPAR gamma; Prostaglandin D2; Reperfusion Injury

Necrotizing enterocolitis (NEC) remains a lethal condition for many premature infants. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a member of the nuclear hormone receptor family, has been shown to play a protective role in cellular inflammatory responses; however, its role in NEC is not clearly defined. We sought to examine the expression of PPAR-gamma in the intestine using an ischemia-reperfusion (I/R) model of NEC, and to assess whether PPAR-gamma agonist treatment would ameliorate I/R-induced gut injury. Swiss-Webster mice were randomized to receive sham (control) or I/R injury to the gut induced by transient occlusion of superior mesenteric artery for 45 min with variable periods of reperfusion. I/R injury resulted in early induction of PPAR-gamma expression and activation of NF-kappaB in small intestine. Pretreatment with PPAR-gamma agonist, 15d-PGJ(2), attenuated intestinal NF-kappaB response and I/R-induced gut injury. Activation of PPAR-gamma demonstrated a protective effect on small bowel during I/R-induced gut injury.

Topics: Animals; Cell Line; Enterocolitis, Necrotizing; Humans; Intestine, Small; Mice; Mice, Inbred Strains; NF-kappa B; PPAR gamma; Prostaglandin D2; Reperfusion Injury

The function of peroxisome proliferator-activated receptor-gamma (PPARgamma) in hepatic inflammation and injury is unclear. In this study, we sought to determine the role of PPARgamma in hepatic ischemia/reperfusion injury in mice. Male mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. PPARgamma was found to be constitutively activated in hepatocytes but not in nonparenchymal cells. Upon induction of ischemia, hepatic PPARgamma activation rapidly decreased and remained suppressed throughout the 8-hour reperfusion period. This reduced activation was not a result of decreased protein availability as hepatic nuclear PPARgamma, retinoid X receptor-alpha (RXRalpha), and PPARgamma/RXRalpha heterodimer expression was maintained. Accompanying the decrease in PPARgamma activation was a decrease in the expression of the natural ligand 15-deoxy-Delta(12,14)-prostaglandin J(2). This was associated with reduced interaction of PPARgamma and the coactivator, p300. To determine whether PPARgamma activation is hepatoprotective during hepatic ischemia/reperfusion injury, mice were treated with the PPARgamma agonists, rosiglitazone and connecting peptide. These treatments increased PPARgamma activation and reduced liver injury compared to untreated mice. Furthermore, PPARgamma-deficient mice had more liver injury after ischemia/reperfusion than their wild-type counterparts.. These data suggest that PPARgamma is an important endogenous regulator of, and potential therapeutic target for, ischemic liver injury.

Topics: Animals; C-Peptide; E1A-Associated p300 Protein; Gene Expression Regulation; Hepatocytes; Liver; Liver Diseases; Male; Mice; Mice, Inbred C57BL; PPAR gamma; Prostaglandin D2; Reperfusion Injury; Retinoid X Receptor alpha; Rosiglitazone; Thiazolidinediones

Brain expresses abundant lipocalin-type prostaglandin (PG) D2 (PGD2) synthase but the role of PGD2 and its metabolite, 15-deoxy-Delta(12,14) PGJ2 (15d-PGJ2) in brain protection is unclear. The aim of this study is to assess the effect of 15d-PGJ2 on neuroprotection.. Adenoviral transfer of cyclooxygenase-1 (Adv-COX-1) was used to amplify the production of 15d-PGJ2 in ischemic cortex in a rat focal infarction model. Cortical 15d-PGJ2 in Adv-COX-1-treated rats was increased by 3-fold over control, which was correlated with reduced infarct volume and activated caspase 3, and increased peroxisome proliferator activated receptor-gamma (PPARgamma) and heme oxygenase-1 (HO-1). Intraventricular infusion of 15d-PGJ2 resulted in reduction of infarct volume, which was abrogated by a PPARgamma inhibitor. Rosiglitazone infusion had a similar effect. 15d-PGJ2 and rosiglitazone at low concentrations suppressed H2O2-induced rat or human neuronal apoptosis and necrosis and induced PPARgamma and HO-1 expression. The anti-apoptotic effect was abrogated by PPARgamma inhibition.. 15d-PGJ2 suppressed ischemic brain infarction and neuronal apoptosis and necrosis in a PPARgamma dependent manner. 15d-PGJ2 may play a role in controlling acute brain damage induced by ischemia-reperfusion.

Topics: Adenoviridae; Animals; Apoptosis; Caspase 3; Caspases; Cells, Cultured; Cyclooxygenase 1; Gene Transfer Techniques; Genetic Therapy; Heme Oxygenase-1; Infarction, Middle Cerebral Artery; Male; Necrosis; Neurons; Neuroprotective Agents; PPAR gamma; Prostaglandin D2; Rats; Rats, Long-Evans; Reperfusion Injury; Rosiglitazone; Thiazolidinediones; Vasodilator Agents

Recent studies have demonstrated the anti-inflammatory action of 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)), a derivative of the PGD(2) metabolic pathway. Acute inflammation, including neutrophil activation, plays a critical role in the pathogenesis of ischemia-reperfusion (I/R). The aim of the present study was to determine the effect of 15d-PGJ(2) on I/R-induced gastric mucosal injury in rats.. Gastric mucosal damage was induced in male Wistar rats by clamping the celiac artery for 30 min followed by reperfusion. 15d-PGJ(2) (0.01-1.0 mg/kg) was given to the rats intraperitoneally 1 h before the vascular clamping. The area of gastric mucosal erosions (erosion index) was measured. Thiobarbituric acid reactive substances (TBARS) and tissue-associated myeloperoxidase (MPO) activity were measured in the gastric mucosa as indices of lipid peroxidation and neutrophil infiltration. The expression of tumor necrosis factor-alpha (TNF-alpha) in gastric mucosa was measured by ELISA. In addition, to elucidate whether the protective effects of 15d-PGJ(2) are related to the activation of the PPAR-gamma receptor, we also investigated the effects of a PPAR-gamma antagonist, GW9662.. After 60 min of reperfusion, the area of gastric erosion index had significantly increased from the mean basal levels. The increase in the erosion index was significantly inhibited by pretreatment with 15d-PGJ(2) in a dose-dependent manner. On the other hand, GW9662 reversed the protective effect of 15d-PGJ(2). The concentration of TBARS and MPO activity in the gastric mucosa were both significantly increased after I/R, and pretreatment with 15d-PGJ(2) significantly reduced these increases. The TNF-alpha content was significantly higher in the I/R group than in the sham-operated group. However, the increase in TNF-alpha was significantly inhibited by pretreatment with 15d-PGJ(2).. 15d-PGJ(2) significantly inhibited the severity of acute gastric mucosal injury induced by I/R in rats through PPAR-gamma-dependent mechanisms. This effect may be due, in part, to a reduction in the infiltration of neutrophils into the gastric mucosa, possibly via the inhibition of inflammatory cytokine.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Gastric Mucosa; Male; Peroxidase; PPAR gamma; Prostaglandin D2; Rats; Rats, Wistar; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha