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Neurons undergoing apoptosis can be rescued by trophic factors that simultaneously increase the activity of extracellular signal-regulated kinase (ERK) and decrease c-Jun N-terminal kinase (JNK) and p38. We identified a molecule, CEP-1347 (KT7515), that rescues motoneurons undergoing apoptosis and investigated its effect on ERK1 and JNK1 activity. Cultured(More)
Treatment of chick embryos in ovo with IGF-I during the period of normal, developmentally regulated neuronal death (embryonic days 5-10) resulted in a dose-dependent rescue of a significant number of lumbar motoneurons from degeneration and death. IGF-II and two variants of IGF-I with reduced affinity for IGF binding proteins, des(1-3) IGF-I and long R3(More)
The c-Jun N-terminal kinase signaling cascade appears to play a role in some cases of cell death, including neuronal apoptosis. CEP-1347 (KT7515), an indolocarbazole of the K252a family, blocks this stress signaling cascade and promotes survival. Here, we used CEP-1347 to probe whether neuronal death pathways activated by distinct insults also possess(More)
Advanced prostate cancer remains largely incurable, primarily because the very low growth fraction present in these tumors makes them generally resistant to treatment with standard chemotherapeutic agents that target cell division. Effective therapies should therefore induce death of prostate cancer cells, independent of their growth rate. trkA, the(More)
The present report describes the in vitro and in vivo profile of CEP-751, a novel receptor tyrosine kinase inhibitor. CEP-751 at 100 nM inhibits the receptor tyrosine kinase activity of the neurotrophin receptors trkA, trkB and trkC. CEP-751 has no effect on activity of receptors for EGF, IGF-I, insulin or on erbB2; inhibition of receptors for PDGF and bFGF(More)
A suspension of cells from embryonic day 21 fetal pig ventral mesencephalon was transplanted into the striatum of 20 immunosuppressed rats with 6-hydroxydopamine-induced lesions of the nigrostriatal dopamine pathway. Of these rats, 15 showed reduction of amphetamine-induced ipsilateral rotation by 9 weeks and complete reversal of rotation by 14–17 weeks.(More)
CEP-1347, also known as KT7515, a derivative of a natural product indolocarbazole, inhibited motor neuronal death in vitro, inhibited activation of the stress-activated kinase JNK1 (c-jun NH terminal kinase) in cultured spinal motor neurons, but had no effect on the mitogen-activated protein kinase ERK1 in these cells. Results reported here profile the(More)
We report the development and characterization of a rapid fluorometric microassay suitable for quantifying neuronal cell survival. The method can be used in two formats: (1) a time course analysis of survival response or (2) as a simple endpoint assay for the assessment of neuronal survival promoted by a variety of reagents. The assay uses calcein AM, a(More)
The protein kinase inhibitor K-252a has been shown to promote cholinergic activity in cultures of rat spinal cord and neuronal survival in chick dorsal root ganglion cultures. To determine the mechanism by which K-252a acts as a neurotrophic factor, we examined the effects of this molecule on a human neuroblastoma cell line, SH-SY5Y. K-252a induced neurite(More)
We have identified a class of small organic molecules, derived from the indolocarbazole K-252a, that promote the survival of cultured neurons. However, many of these indolocarbazoles inhibit protein kinase C and neurotrophin-activated tyrosine kinase receptors. These kinase inhibitory activities may limit the utility of these compounds for neurological(More)