15d-Prostaglandin J₂ Activates Peroxisome Proliferator-Activated Receptor-γ, Promotes Expression of Catalase, and Reduces Inflammation, Behavioral Dysfunction, and Neuronal Loss after Intracerebral Hemorrhage in Rats

Abstract

Peroxisome proliferator-activated receptor-c (PPARc) is a transcription factor that regulates the expression of various gene products that are essential in lipid and glucose metabolism, as well as that of the peroxisome-enriched antioxidant enzyme, catalase. Activation of PPARc is linked to antiinflammatory activities and is beneficial for cardiovascular diseases. However, little is known about its role in intracerebral hemorrhage (ICH). 15-Deoxy-D 12,14 -prostaglandin J 2 (15d-PGJ 2 ) acts as a physiologic agonist for PPARc. In this study, we found that injection of 15d-PGJ 2 into the locus of striatal hematoma increased PPARc-deoxyribonucleic acid (DNA) binding activity and the expression of catalase messenger ribonucleic acid (mRNA) and protein in the perihemorrhagic area. Additionally, 15d-PGJ 2 significantly reduced nuclear factor-jB (NF-jB) activation and prevented neutrophil infiltration measured by myeloperoxidase (MPO) immunoassay, and also reduced cell apoptosis measured by terminal deoxynucleotide transferase dUTP nick-end labeling (TUNEL). In addition, 15d-PGJ 2 reduced behavioral dysfunction produced by the ICH. Altogether, our findings indicate that injection of 15d-PGJ 2 at the onset of ICH is associated with activation of PPARc and elevation of catalase expression, suppression of NF-jB activity, and restricted neutrophil infiltration. All these events predicted reduced behavioral deficit and neuronal damage.

Peroxisome proliferator-activated receptor-γ agonist rosiglitazone reduces secondary damage in experimental spinal cord injury

“…[4][5][6]27 MPO activity and levels of TNFa and IL-1b were significantly increased in the spinal cord tissue of injured rats compared with sham-operated animals 24 h after injury in the present study. In a finding similar to other studies, [17][18][19][20]24 rosiglitazone treatment significantly reduced these increased levels of MPO, TNFa and IL-1b in the present study, thus protecting the spinal cord against secondary degeneration caused by inFammation. It is thought that TZDs confer their neuroprotective effects via the prevention of both microglial activation and inFammatory cytokine/chemokine expression, 28 in concurrence with the findings of the present study.…”

“…[4][5][6][7] PPARg is a ligand-activated transcription factor of the nuclear hormone receptor superfamily, with important roles in glucose and lipid homeostasis. 22 The natural ligand of PPARg is 15-deoxy-Á 12,14 -prostaglandin J 2 (15 d-PDJ 2 ), 23 which has been shown to decrease neurological deEcit after experimental intracerebral haemorrhage, 24 in addition to reducing inflammation and neuronal tissue damage associated with spinal cord trauma. 25 Thiazolidinediones (TZDs) are potent synthetic agonists of PPARg, 22 two of which (rosiglitazone and pioglitazone) are currently approved by the US Food and Drug Administration for treatment of type-2 diabetes.…”

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibition: Robust New Target or Another Big Bust for Stroke Therapeutics?

“…One general approach of increasing interest to clinical neuroscientists, aided by the molecular and genomic revolutions, is the use of drugs that activate endogenous adaptive programs. Indeed, activators of the Nrf2-mediated antioxidant response (Calkins et al, 2009;Smirnova et al, 2011), peroxisome proliferator-activated receptor g-mediated metabolic adaptation and antiinflammatory programs (Zhao et al, 2006), and histone deacetylases inhibitor-induced neuroprotective and repair cassettes (Sleiman et al, 2009;Langley et al, 2009) are examples of how this general approach has been applied. Excitingly, with each of these targets, there is a clear trajectory toward the human bedside.…”

Hematoma Resolution as a Therapeutic Target

“…In addition, PPAR␥ acts as a key genomic homeostatic regulator for intracellular stress by promoting the transcription of gene products that have a key role in antioxidative defense such as catalase 12 and superoxide dismutase, 13 which help not only to improve neuronal resistance, but also protect microglia from damage, thus preserving their phagocytotic (hematoma clearance) functions.…”