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Title: Prenylated Quinolinecarboxylic Acid Derivative Prevents Neuronal Cell Death Through Inhibition of MKK4
Authors: Ogura, Masato
Kikuchi, Haruhisa
Shakespear, Norshalena
Suzuki, Toshiyuki
Yamaki, Junko
Homma, Miwako K
Oshima, Yoshiteru
Homma, Yoshimi
Affiliation: 生体物質研究部門
放射性同位元素研究施設
Source title: Biochemical pharmacology
Volume: 162
Start page: 109
End page: 122
Issue Date: Apr-2019
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 β1-42-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.
Publisher: Elsevier
language: eng
URI: http://ir.fmu.ac.jp/dspace/handle/123456789/1061
Full text URL: http://ir.fmu.ac.jp/dspace/bitstream/123456789/1061/1/BiochemPharmacol_162_p109.pdf
ISSN: 0006-2952
1873-2968
DOI: 10.1016/j.bcp.2018.10.008
PubMed ID: 30316820
Other version: https://doi.org/10.1016/j.bcp.2018.10.008
Rights: © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.
Rights: http://creativecommons.org/licenses/by-nc-nd/4.0/
Appears in Collections:a10 学術雑誌論文等 = Journal Article

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