Role of vascular cystathionine gamma lyase (CSE) / hydrogen sulfide (H2S) in regulating brain perfusion and cognitive function

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.