Abstract
NS521 (1-(1-butyl)-4-(2-oxo-1-benzimidazolinyl)piperidine) belongs to a group of novel benzimidazolones, which exhibit neurotrophic-like activities. In vitro, NS521 rescued neuronal PC12 cells from death induced by serum and nerve growth factor deprivation. The survival effect of NS521 appeared to reflect a delay of the apoptotic process, because the extent of DNA fragmentation was attenuated transiently by NS521. NS521 did not preserve the neurites of the rescued cells, which, otherwise, appeared to be healthy and were able to regenerate when serum and nerve growth factor were added back to the culture. In vivo, NS521 provided significant protection against the delayed loss of hippocampal CA1 neurons in a gerbil model of transient global ischemia. A neuroprotective effect of NS521 in the peripheral nervous system also was observed in rats after transection of the sciatic nerve, where daily treatment with NS521 was found to inhibit retrograde degeneration of the transected nerve. The neuroprotective effect of NS521 is unlikely to be mediated through neurotrophin receptors, such as TrkA, because NS521 did not induce phosphorylation of the 44- and 42-kDa isoforms of mitogen-activated protein kinases (ERK1/2) in PC12 cells.
Footnotes
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Send reprint requests to: Mette Grønborg, Ph.D., NeuroSearch A/S, Smedeland 26B, DK-2600 Glostrup, Denmark. E-mail:mg{at}neurosearch.dk
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↵1 Supported by a grant from the Danish Research Council (9600277).
- Abbreviations:
- BDNF
- brain-derived neurotrophic factor
- ERK
- extracellular signal-regulated kinase
- GDNF
- glial cell line-derived neurotrophic factor
- ELISA
- enzyme-linked immunosorbent assay
- MAPK
- mitogen-activated protein kinase
- MTT
- 3-(4,5-dimethylethiazol-2-yl)-2,5-diphenyltetrazolium bromide
- NGF
- nerve growth factor
- Received November 3, 1998.
- Accepted March 18, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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