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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.
J Pharmacol Exp Ther. 1999 Feb; 288(2):421-7.JP

Abstract

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.

Authors+Show Affiliations

Cephalon Inc., West Chester, Pennsylvania, USA. msaporiti@cephalon.comNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9918541

Citation

Saporito, M S., et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 288, no. 2, 1999, pp. 421-7.
Saporito MS, Brown EM, Miller MS, et al. 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. J Pharmacol Exp Ther. 1999;288(2):421-7.
Saporito, M. S., Brown, E. M., Miller, M. S., & Carswell, S. (1999). 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. The Journal of Pharmacology and Experimental Therapeutics, 288(2), 421-7.
Saporito MS, et al. 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. J Pharmacol Exp Ther. 1999;288(2):421-7. PubMed PMID: 9918541.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Saporito,M S, AU - Brown,E M, AU - Miller,M S, AU - Carswell,S, PY - 1999/1/26/pubmed PY - 1999/1/26/medline PY - 1999/1/26/entrez SP - 421 EP - 7 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 288 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9918541/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_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9918541 DB - PRIME DP - Unbound Medicine ER -