Abstract
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.
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REFERENCES
Kaplan, D. R. and Miller, F. D. 1997. Signal transduction by the neurotrophin receptors. Curr. Opin. Cell Biol. 9:213–221.
Cowley, S., Paterson, H., Kemp, P., and Marshall, C. J. 1994. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77:841–852.
Pang, L., Sawada, T., Decker, S. J., and Saltiel, A. R. 1995. Inhibition of MAP kinase kinase blocks the differentiation of PC-12 cells induced by nerve growth factor. J. Biol. Chem. 270:13585–13588.
Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., and Greenberg, M. E. 1995. Opposing effects of ERK and JNK-p38 MAP kinase on apoptosis. Science 270:1326–1331.
Dudek, H., Datta, S. R., Franke, T. F., Birnbaum, M. J., Yao, R., Cooper, G. M., Segal, R. A., Kaplan, D. R., and Greenberg, M. E. 1997. Regulation of neuronal survival by the serinethreonine protein kinase Akt. Science 275:661–665.
Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., and Greenberg, M. E. 1997. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241.
Pong, K., Xu, R. Y., Baron, W. F., Louis, J. C., and Beck, K. D. 1998. Inhibition of phosphatidylinositol 3–kinase activity blocks cellular differentiation mediated by glial cell line-derived neurotrophic factor in dopaminergic neurons. J. Neurochem. 71: 1912–1919.
Venero, J. L., Hefti, F., and Knusel, B. 1996. Trophic effect of exogenous nerve growth factor on rat striatal cholinergic neurons: comparison between intraparenchymal and intraventricular administration. Mol. Pharmacol. 49:303–310.
Emerich, D. F., Winn, S. R., Harper, J., Hammang, J. P., Baetge, E. E., and Kordower, J. H. 1994. Implants of polymerencapsulated human NGF-secreting cells in the nonhuman primate: rescue and sprouting of degenerating cholinergic basal forebrain neurons. J. Comp. Neurol. 349:148–164.
Björklund, A., Kirik, D., Rosenblad, C., Georgievska, B., Lundberg, C., Mandel, R. J. 2000. Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model. Brain Res. 886:82–98.
Grønborg, M., Johansen, T. E., Peters, D., Ahring, P. K., Drejer, J., Møller, A., and Jensen, L. H. 1999. Neuroprotection by a novel compound, NS521. J. Pharmacol Exp. Ther. 90:348–353.
Rønn, L. C., Ralets, I., Hartz, B. P., Bech, M., Berezin, A., Berezin, V., Møller, A., and Bock, E. 2000. A simple procedure for quantification of neurite outgrowth based on stereological principles. J. Neurosci. Methods 100:25–32.
Chao, M. V. 1992. Growth factor signaling: where is the specificity? Cell 68:995–997.
Nguyen, T. T., Scimeca, J. C., Filloux, C., Peraldi, P., Carpentier, J. L., and Van Obberghen, E. 1993. Co-regulation of the mitogen-activated protein kinase, extracellular signal-regulated kinase 1, and the 90–kDa ribosomal S6 kinase in PC12 cells. Distinct effects of the neurotrophic factor, nerve growth factor, and the mitogenic factor, epidermal growth factor. J. Biol. Chem. 268:9803–9810.
Traverse, S., Seedorf, K., Paterson, H., Marshall, C. J., Cohen, P., and Ullrich, A. 1994. EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr. Biol. 4:694–701.
Nakafuki, M. and Kaziro, Y. 1993. Epidermal growth factor and transforming growth factor-alpha can induce neuronal differentiation of rat pheochromocytoma PC12 cells under particular culture conditions. FEBS Lett. 315:227–232.
Gotoh, Y., Nishida, E., Yamashita, T., Hoshi, M., Kawakami, M., and Sakai, H. 1990. Microtubule-associated-protein (MAP) kinase activated by nerve growth factor and epidermal growth factor in PC12 cells. Identity with the mitogen-activated MAP kinase of fibroblastic cells. Eur. J. Biochem. 193:661–669.
Peraldi, P., Scimeca, J. C., Filloux, C., and Van Obberghen, E. 1993. Regulation of extracellular signal-regulated protein kinase-1 (ERK-1; pp44/mitogen-activated protein kinase) by epidermal growth factor and nerve growth factor in PC12 cells: implication of ERK1 inhibitory activities. Endocrinology 132: 2578–2585.
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Dagø, L., Peters, D., Meyer, M. et al. NS-417, a Novel Compound with Neurotrophic-Like Effects. Neurochem Res 27, 107–111 (2002). https://doi.org/10.1023/A:1014810824056
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DOI: https://doi.org/10.1023/A:1014810824056