Neuroprotection by a novel compound, NS521.
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.
Grønborg
M
M
NeuroSearch A/S, Glostrup, Denmark. mg@neurosearch.dk
Johansen
T E
TE
Peters
D
D
Ahring
P K
PK
Drejer
J
J
Møller
A
A
Jensen
L H
LH
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003470:Culture Media; D053938:DNA Fragmentation; D005849:Gerbillinae; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000517:prevention & control; D008297:Male; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control; D009414:Nerve Growth Factors / Q000172:deficiency; D009416:Nerve Regeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
C120154:1-(1-butyl)-4-(2-oxo-1-benzimidazolinyl)piperidine; D001562:Benzimidazoles; D003470:Culture Media; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D010880:Piperidines; D017871:Calcium-Calmodulin-Dependent Protein Kinases