Prenylated quinolinecarboxylic acid derivative prevents neuronal cell death through inhibition of MKK4

Masato Ogura, Haruhisa Kikuchi, Norshalena Shakespear, Toshiyuki Suzuki, Junko Yamaki, Miwako K. Homma, Yoshiteru Oshima, Yoshimi Homma

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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 β 1-42 -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.

Original languageEnglish
Pages (from-to)109-122
Number of pages14
JournalBiochemical Pharmacology
Volume162
DOIs
Publication statusPublished - 2019 Apr
Externally publishedYes

Keywords

  • MAPK
  • Neurodegeneration
  • Neuronal cell death
  • Neurotoxin
  • Ppc-1 (PubChem CID: 46910769)
  • PQA-11 (PubChem CID: 74223691)
  • PQA-18 (PubChem CID: 73602831)
  • Small molecule

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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