Prenylated quinolinecarboxylic acid derivative prevents neuronal cell death through inhibition of MKK4.
Biochem Pharmacol
; 162: 109-122, 2019 04.
Article
em En
| MEDLINE
| ID: mdl-30316820
ABSTRACT
The development of neuroprotective agents is necessary for the treatment of neurodegenerative diseases. Here, we report PQA-11, a prenylated quinolinecarboxylic acid (PQA) derivative, as a potent neuroprotectant. PQA-11 inhibits glutamate-induced cell death and caspase-3 activation in hippocampal cultures, as well as inhibits N-Methyl-4-phenylpyridinium iodide- and amyloid ß1-42-induced cell death in SH-SY5Y cells. PQA-11 also suppresses mitogen-activated protein kinase kinase 4 (MKK4) and c-jun N-terminal kinase (JNK) signaling activated by these neurotoxins. Quartz crystal microbalance analysis and in vitro kinase assay reveal that PQA-11 interacts with MKK4, and inhibits its sphingosine-induced activation. The administration of PQA-11 by intraperitoneal injection alleviates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of nigrostriatal dopaminergic neurons in mice. These results suggest that PQA-11 is a unique MKK4 inhibitor with potent neuroprotective effects in vitro and in vivo. PQA-11 may be a valuable lead for the development of novel neuroprotectants.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Quinolinas
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Ácidos Carboxílicos
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Fármacos Neuroprotetores
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MAP Quinase Quinase 4
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Prenilação
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Neurônios
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Biochem Pharmacol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Japão