gw0742 and Nerve-Degeneration

Experimental study of spinal cord injury (SCI) using an organotypic slice culture.. To clarify the protective mechanism of PPAR-δ agonist GW0742 in the injured spinal cord using an in vitro model.. In vivo data suggest that ligands of the δ isoform have activity in a number of disease models that are partly driven by the inflammatory response. Moreover, reports from in vivo studies using models of ischemia reperfusion and Parkinson disease also have shown neuroprotection conferred by PPAR-δ. The biological role and function of PPAR-δ remains relatively unclear.. Spinal cord from 6-week-old mice was cut into transverse slices of 400-μm thickness to generate the organotypic slice cultures. The slices were injured using a weight dropped onto the center of the slice. PPAR-δ agonist was applied at 10 μM at 1 hour before injury.. Our study shows that GW0742 incubation (10 μM) at 1 hour before transverse lesion significantly reduced (1) p38 mitogen-activated protein kinase (MAPK), (2) c-Jun N-terminal kinase (JNK/SAP kinase), (3) NF-κB activation, (4) loss of neurotrophic factors (BDNF, GDNF), (5) COX-2 expression, and (6) cell death.. GW0742 reduces the cellular and molecular changes occurring in SCI by targeting different downstream pathways modulating PPAR-δ receptors.

Topics: Animals; Mice; Models, Biological; Nerve Degeneration; Neuroprotective Agents; Organ Culture Techniques; PPAR delta; Protein Isoforms; Spinal Cord; Spinal Cord Injuries; Thiazoles

The ligand-activated transcription factor peroxisome proliferator-activated receptor beta (PPARbeta) is present in the brain and is implicated in the regulation of genes with potential roles in neurotoxicity. We sought to examine the role of PPARbeta in neuronal cell death by using the PPARbeta ligand GW0742. Primary cultures of rat cerebellar granule neurons were prepared from 7-day-old pups. Reverse transcriptase-polymerase chain reaction and in situ hybridization were used to verify that PPARbeta mRNA was present in neurons. After 10-12 days in culture, the neuronal cells were incubated in the presence of GW0742, and cell death was measured with a lactate dehydrogenase release (LDH) assay. After 24 hr of exposure, PPARbeta activation by GW0742 was not inherently toxic to cerebellar granule neurons. However, toxicity was observed after 48 hr, with cell death mediated via an apoptotic mechanism. In an effect opposite to that observed with PPARalpha-activating ligands, PPARbeta activation exhibited neuroprotective properties. Treatment with GW0742 significantly reduced cell death during a 12-hr exposure to low-KCl media. These results clearly reinforce very specific roles for the PPAR isoforms in neurons and suggest that PPARbeta is worthy of further investigation regarding its potential role as a therapeutic target in neurodegenerative states.

Topics: Animals; Animals, Newborn; Cell Death; Cells, Cultured; Cerebellum; L-Lactate Dehydrogenase; Nerve Degeneration; Neurons; Neurotoxins; Potassium Deficiency; Proto-Oncogene Proteins c-jun; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Thiazoles; Transcription Factors