title: Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) protects against ceramide-induced cellular toxicity in rat brain astrocytes and neurons by activation of ceramide kinase.
abstract: Peroxisome proliferator-activated receptors (PPARs) are important members of the nuclear receptor superfamily. Ligands of these nuclear receptors (PPARα, β/δ and γ) belong to a wide range of lipophilic substances. In spite of the proven neuroprotective efficacy of PPARβ/δ in models of neurological diseases, the biology of PPARβ/δ in the brain has been much less investigated than that of PPARα and PPARγ. In the present study, we test the hypothesis that neuroprotection induced by PPARβ/δ could rely on the regulation of ceramide metabolism. We found that preincubation of neural cells with the PPARβ/δ agonist L-165041 exerts significant protection against ceramide-induced cell death. Most importantly, L-165041 protects against ceramide-induced cell death not only before the insult, but also after the onset of the insult. To identify the mechanism of protection, we show that L-165041 upregulates ceramide kinase (CerK) expression levels in neural cells. Consistent with that, we detected that pharmacological inhibition of CerK reduces the protective effects of L-165041. To further decipher the mechanism of protection, gene knockdown in astrocytes was studied. Knockdown of PPARβ/δ and CerK in astrocytes was used to verify that the protective effects of L-165041 are CerK- and PPARβ/δ-dependent. We demonstrate that in CerK- or PPARβ/δ-knockdown astrocytes, addition of L-165041 has no protective effect. Thus, we conclude that PPARβ/δ protects neural cells against ceramide-induced cell death via induction and activation of CerK.
authors: Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Straße 44, 39120 Magdeburg, Germany.
authors: Stepan
authors: S
authors: Aleshin
authors: Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für Neurobiochemie, Leipziger Straße 44, 39120 Magdeburg, Germany. Electronic address: georg.reiser@med.ovgu.de.
authors: Georg
authors: G
authors: Reiser
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D002518:Ceramides / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D010642:Phenoxyacetates / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D002518:Ceramides; D018696:Neuroprotective Agents; D047494:PPAR delta; D048068:PPAR-beta; D010642:Phenoxyacetates; D017853:Phosphotransferases (Alcohol Group Acceptor); C066324:ceramide kinase
keywords: Neurodegeneration; Neuroprotection; Peroxisome proliferator-activated receptors; Transcription factor