Prostaglandin E2 Attenuates 7-Ketocholesterol Toxicity by Suppressing Changes in Mitochondria-Associated Cell Death Process

ABSTRACT

BACKGROUND: It has been shown that defects in mitochondrial function are involved in the induction of neuronal cell injury. Prostanoids such as prostaglandin E2 (PGE2) are thought to play an important role in inflammation and neurologic disorders. However, the effect of PGE2 on cholesterol-oxidation-product-induced neuronal cell injury remains uncertain. METHODS: The effect of PGE2 on toxicity of 7-ketocholesterol (7-KCS) was assessed in PC12 cells that were differentiated following treatment with nerve growth factor. The mitochondria-mediated apoptotic process was evaluated by examining the inhibitory effect of PGE2 on 7-KCS-induced toxicity. RESULTS: 7-KCS induced BID cleavage, increased the production of proapoptotic Bax protein, decreased antiapoptotic Bcl-2, increased p53, and promoted cytochrome c release in the cytosolic fraction, which subsequently elicited the activation of caspase-3, DNA fragmentation, and cell death. Treatment with PGE2 inhibited this 7-KCS-induced apoptotic process and cell death. CONCLUSIONS: The results show that PGE2 inhibits 7-KCS-induced toxicity in differentiated PC12 cells by suppressing the mitochondria-mediated apoptotic process. PGE2 may protect against cholesterol-oxidation-product-induced neuronal cell injury.