A novel synthetic compound PHID (8-Phenyl-6a, 7, 8, 9, 9a, 10-hexahydro-6H-isoindolo [5, 6-g] quinoxaline-7, 9-dione) protects SH-SY5Y cells against MPP(+)-induced cytotoxicity through inhibition of reactive oxygen species generation and JNK signaling.
1-Methyl-4-phenylpyridinium ion (MPP(+)), a neurotoxin selective to dopaminergic neurons and an inhibitor of mitochondrial complex I, has been widely used as an etiologic model of Parkinson's disease. In this study, we investigated the protective effects of a novel synthetic compound, 8-Phenyl-6a,7,8,9,9a,10-hexahydro-6H-isoindolo[5,6-g]quinoxaline-7,9-dione (PHID), on MPP(+)-induced cytotoxicity in SH-SY5Y cells. MPP(+) induced apoptosis characterized by generation of reactive oxygen species, caspase-3 activation, poly ADP ribose polymerase proteolysis and increase in Bax/Bcl-2 ratio were blocked by PHID in a dose-dependent fashion. Furthermore, MPP(+)-mediated activation of stress-activated protein kinase/c-Jun N-terminal kinase (JNK) was also inhibited by PHID in a dose-dependent manner. The results indicate that PHID protects against MPP(+)-induced apoptosis by blocking reactive oxygen species stimulation and JNK signaling pathways in SH-SY5Y cells, implicating the novel compound in the prevention of progressive neurodegenerative diseases such as Parkinson's disease.
Department of Biotechnology, Konkuk University, Chungju, 380-701, South Korea.
In Su
IS
Kim
Sushruta
S
Koppula
Byung Wook
BW
Kim
Min Dong
MD
Song
Ju Yeon
JY
Jung
Gwang
G
Lee
Hee Soon
HS
Lee
Dong-Kug
DK
Choi
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011810:Quinoxalines / Q000138:chemical synthesis / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C556801:8-phenyl-6a,7,8,9,9a,10-hexahydro-6H-isoindolo(5,6-g)quinoxaline-7,9-dione; D054833:Isoindoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011810:Quinoxalines; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D015655:1-Methyl-4-phenylpyridinium