NS-417, a novel compound with neurotrophic-like effects.
NS-417 (5-(4-Chlorophenyl)-8-methyl-6-7-8-9-tetrahydro-1-H-pyrrolo[3.2-h]isoquinoline-2,3-dione-3-oxim hydrochloric acid salt) belongs to a new chemical series of compounds. NS-417 rescued differentiated PC12 cells from death induced by withdrawal of serum and nerve growth factor. Furthermore, NS-417 stimulated neurotrophic factor-induced neurite outgrowth in undifferentiated PC12 cells. In accordance with this observation, NS-417 potentiated NGF-induced signaling, such as activation of the extracellular signal-regulated kinases ERK1 and ERK2 and the Akt kinase. NS-417 also enhanced ERK activation induced by 10 minutes stimulation with NGF, bFGF or EGF in PC12 cells. In addition to the effect in PC12 cells, NS-417 increased the number of tyrosine hydroxylase (TH) positive cells in cultures established from dissociated E14 rat ventral mesencephali.
Dagø
Lone
L
NeuroSearch, Ballerup, Denmark. ld@nsgene.dk
Peters
Dan
D
Meyer
Morten
M
Hartz
Barbara
B
Kruse
Vibeke
V
Drejer
Jørgen
J
Grønborg
Mette
M
D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008636:Mesencephalon / Q000196:embryology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000172:deficiency / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D016716:PC12 Cells / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D044005:Tetrahydroisoquinolines; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D007546:Isoquinolines; C465861:NS-417 cpd; D010091:Oximes; D011518:Proto-Oncogene Proteins; D044005:Tetrahydroisoquinolines; D020932:Nerve Growth Factor; D014446:Tyrosine 3-Monooxygenase; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases