CEP-1347/KT-7515, an inhibitor of c-jun N-terminal kinase activation, attenuates the 1-methyl-4-phenyl tetrahydropyridine-mediated loss of nigrostriatal dopaminergic neurons in vivo

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 surv ival properties of CEP-1347/KT-7515 may be related to its ability to inhibi t 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 neuron al apoptosis in culture and in adult mice. Thus, our studies were designed to determine if CEP-1347/KT-7515 could protect dopaminergic neurons from MP TP-mediated neurotoxicity. CEP-1347/KT-7515 was assessed for neuroprotectiv e activity in a low dose MPTP model (20 mg/kg) where there was a 50% loss o f striatal dopaminergic terminals in the absence of substantia nigra neuron al loss, and a high dose (40 mg/kg) MPTP model where there was a complete l oss 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 MP TP-mediated loss of striatal dopaminergic terminals by 50%. In the high dos e 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, sugg esting that the neuroprotective effects of CEP-1347/KT-7515 occur downstrea m of the metabolic conversion of MPTP to MPP+ and accumulation of MPP+ into dopaminergic neurons. These data implicate a c-jun N-terminal kinase signa ling system in MPTP-mediated dopaminergic degeneration and suggest that CEP -1347/KT-7515 may have potential as a treatment for Parkinson's disease.