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Vol. 288, Issue 2, 421-427, February 1999
Cephalon Inc., West Chester, Pennsylvania
We have identified a bis-ethylthiomethyl analog of K-252a,
CEP-1347/KT-7515, that promotes neuronal survival in culture and in
vivo. The neuronal survival properties of CEP-1347/KT-7515 may be
related to its ability to inhibit the activation of c-jun N-terminal kinase, a key kinase in some forms of stress-induced neuronal death and perhaps apoptosis. There is evidence that the selective nigrostriatal dopaminergic neurotoxin, MPTP, produces neuronal apoptosis in culture and in adult mice. Thus, our studies were
designed to determine if CEP-1347/KT-7515 could protect dopaminergic neurons from MPTP-mediated neurotoxicity. CEP-1347/KT-7515 was assessed
for neuroprotective activity in a low dose MPTP model (20 mg/kg) where
there was a 50% loss of striatal dopaminergic terminals in the absence
of substantia nigra neuronal loss, and a high dose (40 mg/kg) MPTP
model where there was a complete loss of dopaminergic terminals and
80% loss of dopaminergic cell bodies. In the low dose MPTP model,
CEP-1347/KT-7515 (0.3 mg/kg/day) attenuated the MPTP-mediated loss of
striatal dopaminergic terminals by 50%. In the high dose model,
CEP-1347/KT-7515 ameliorated the loss of dopaminergic cell bodies by
50% and partially preserved striatal dopaminergic terminals.
CEP-1347/KT-7515 did not inhibit monoamine oxidase B or the dopamine
transporter, suggesting that the neuroprotective effects of
CEP-1347/KT-7515 occur downstream of the metabolic conversion of MPTP
to MPP+ and accumulation of MPP+ into
dopaminergic neurons. These data implicate a c-jun
N-terminal kinase signaling system in MPTP-mediated dopaminergic
degeneration and suggest that CEP-1347/KT-7515 may have potential as a
treatment for Parkinson's disease.
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