CEP-1347/KT7515 prevents motor neuronal programmed cell death and injury-induced dedifferentiation in vivo.
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 functional activity of CEP-1347/KT7515 in vivo in models of motor neuronal death or dedifferentiation. Application of CEP-1347/KT7515 to the chorioallantoic membrane of embryonic chicks rescued 40% of the lumbar motor neurons that normally die during the developmental period assessed. Peripheral administration of low doses (0.5 and 1 mg/kg daily) of CEP-1347/KT7515 reduced death of motor neurons of the spinal nucleus of the bulbocavernosus in postnatal female rats, with efficacy comparable to testosterone. Strikingly, daily administration of CEP-1347/KT7515 during the 4-day postnatal window of motor neuronal death resulted in persistent long-term motor neuronal survival in adult animals that received no additional CEP-1347/KT7515. In a model of adult motor neuronal dedifferentiation following axotomy, local application of CEP-1347/KT7515 to the transected hypoglossal nerve substantially reduced the loss of choline acetyl transferase immunoreactivity observed 7 days postaxotomy compared to untreated animals. Results from these experiments demonstrate that a small organic molecule that inhibits a signaling pathway associated with stress and injury also reduces neuronal death and degeneration in vivo.
Glicksman
M A
MA
Division of Neuroscience, Beckman Research Institute, City of Hope Medical Center, Duarte, California 91010, USA.
Chiu
A Y
AY
Dionne
C A
CA
Harty
M
M
Kaneko
M
M
Murakata
C
C
Oppenheim
R W
RW
Prevette
D
D
Sengelaub
D R
DR
Vaught
J L
JL
Neff
N T
NT
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects*; D019771:Axotomy; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002227:Carbazoles / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002642:Chick Embryo; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007002:Hypoglossal Nerve / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; C106592:3,9-bis((ethylthio)methyl)-K-252a; D002795:Choline O-Acetyltransferase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases