title: CEP11004, a novel inhibitor of the mixed lineage kinases, suppresses apoptotic death in dopamine neurons of the substantia nigra induced by 6-hydroxydopamine.
abstract: There is much evidence that the kinase cascade which leads to the phosphorylation of c-jun plays an important signaling role in the mediation of programmed cell death. We have previously shown that c-jun is phosphorylated in a model of induced apoptotic death in dopamine neurons of the substantia nigra in vivo. To determine the generality and functional significance of this response, we have examined c-jun phosphorylation and the effect on cell death of a novel mixed lineage kinase inhibitor, CEP11004, in the 6-hydroxydopamine model of induced apoptotic death in dopamine neurons. We found that expression of total c-jun and Ser73-phosphorylated c-jun is increased in this model and both colocalize with apoptotic morphology. CEP11004 suppresses apoptotic death to levels of 44 and 58% of control values at doses of 1.0 and 3.0 mg/kg, respectively. It also suppresses, to approximately equal levels, the number of profiles positive for the activated form of capase 9. CEP11004 markedly suppresses striatal dopaminergic fiber loss in these models, to only 22% of control levels. We conclude that c-jun phosphorylation is a general feature of apoptosis in living dopamine neurons and that the mixed lineage kinases play a functional role as up-stream mediators of cell death in these neurons.
authors.affiliation: Department of Neurology, The College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Anindita
authors.initials: A
authors.lastname: Ganguly
authors.forename: Tinmarla Frances
authors.initials: TF
authors.lastname: Oo
authors.forename: Margarita
authors.initials: M
authors.lastname: Rzhetskaya
authors.forename: Robert
authors.initials: R
authors.lastname: Pratt
authors.forename: Olga
authors.initials: O
authors.lastname: Yarygina
authors.forename: Takashi
authors.initials: T
authors.lastname: Momoi
authors.forename: Nikolai
authors.initials: N
authors.lastname: Kholodilov
authors.forename: Robert E
authors.initials: RE
authors.lastname: Burke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects* / Q000201:enzymology; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D002227:Carbazoles; D004298:Dopamine; D004791:Enzyme Inhibitors; D007211:Indoles; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016627:Oxidopamine; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C469298:CEP-11004; C486651:Map3k9 protein, rat