15-Deoxy-delta12,14-prostaglandin J2, a neuroprotectant or a neurotoxicant?
15-Deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) is a potent ligand for peroxisome proliferators-activated receptor gamma (PPARgamma). However, its various effects independent of PPARgamma have recently been observed. The effect of 15d-PGJ2 on neuronal cells is still controversial. We investigated its effect on neuronal cells (N18D3 cells). When N18D3 cells were treated with 15d-PGJ2, the viability was not changed up to 8 microM, but decreased at higher than 8 microM. The expressions of survival signals, such as p85a phosphatidylinositol 3-kinase, phospho-Akt, and phospho-glycogen synthase kinase-3 beta (Ser-9), slightly increased up to 8 microM, however, decreased at higher than 8 microM. The levels of free radicals and membrane lipid peroxidation and the expression of c-Jun N-terminal Kinase increased in a dose-dependent manner, especially at higher than 8 microM. However, the expressions of death signals, such as cytosolic cytochrome c, activated caspase-3, and cleaved poly(ADP-ribose) polymerase, decreased up to 8 microM, however, increased at higher than 8 microM. In the study to evaluate whether low dose of 15d-PGJ2, up to 8 microM, had protective effect on oxidative stress-injured N18D3 cells, compared to the cells treated with only 100 microM H2O2, the pretreatment with 8 microM 15d-PGJ2 increased the viability and the expressions of the survival signals, but decreased them of the death signals. These results indicate that 15d-PGJ2 could be a neuroprotectant or a neurotoxicant, depending on its concentration. Therefore, some specific optimum dose of 15d-PGJ2 may be a new potential therapeutic candidate for oxidative stress-injury model of neurodegenerative diseases.
Koh
Seong-Ho
SH
Department of Neurology, Institute of Biomedical Science, College of Medicine, Hanyang University, #17 Haengdang-dong, Seongdong-ku, Seoul 133-791, Republic of Korea.
Jung
Boo
B
Song
Chi Won
CW
Kim
Youngchul
Y
Kim
Yong Soon
YS
Kim
Seung Hyun
SH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D045304:Cytochromes c / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005562:Formazans; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects; D013778:Tetrazolium Salts; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014343:Trypan Blue
D053148:Caspase 3; D020169:Caspases; D002867:Chromones; D045304:Cytochromes c; D005562:Formazans; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006861:Hydrogen Peroxide; D007155:Immunologic Factors; D048031:JNK Mitogen-Activated Protein Kinases; D009025:Morpholines; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016877:Oxidants; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D015230:Prostaglandin D2; D051057:Proto-Oncogene Proteins c-akt; D013778:Tetrazolium Salts; D017392:Thiobarbituric Acid Reactive Substances; D014343:Trypan Blue; C097240:15-deoxy-delta(12,14)-prostaglandin J2; C079782:MTT formazan; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494920:Akt1 protein, rat; C505410:Casp3 protein, rat