A New Generation of Arachidonic Acid Analogues as Potential Neurological Agent Targeting Cytosolic Phospholipase A2

Cytosolic phospholipase A 2 (cPLA 2 ) is an enzyme that releases arachidonic acid (AA) for the synthesis of eicosanoids and lysophospholipids which play critical roles in the initiation and modulation of oxidative stress and neuroinflammation. In the central nervous system, cPLA 2 activation is impl...

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Bibliographic Details
Published in:Scientific reports 2017-10, Vol.7 (1), p.1-12, Article 13683
Main Authors: Ng, Cheng Yang, Kannan, Srinivasaraghavan, Chen, Yong Jun, Tan, Francis Chee Kuan, Ong, Wee Yong, Go, Mei Lin, Verma, Chandra S., Low, Chian-Ming, Lam, Yulin
Format: Article
Language:English
Subjects:
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Arachidonic acid
Central nervous system
Computational neuroscience
Cytotoxicity
Eicosanoids
Humanities and Social Sciences
Inflammation
Microglia
multidisciplinary
Neurodegenerative diseases
Nitric oxide
Oxidative stress
Phospholipase A2
Reactive oxygen species
Science
Science (multidisciplinary)
Vitamin E
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Summary:Cytosolic phospholipase A 2 (cPLA 2 ) is an enzyme that releases arachidonic acid (AA) for the synthesis of eicosanoids and lysophospholipids which play critical roles in the initiation and modulation of oxidative stress and neuroinflammation. In the central nervous system, cPLA 2 activation is implicated in the pathogenesis of various neurodegenerative diseases that involves neuroinflammation, thus making it an important pharmacological target. In this paper, a new class of arachidonic acid (AA) analogues was synthesized and evaluated for their ability to inhibit cPLA 2 . Several compounds were found to inhibit cPLA 2 more strongly than arachidonyl trifluoromethyl ketone (AACOCF 3 ), an inhibitor that is commonly used in the study of cPLA 2 -related neurodegenerative diseases. Subsequent experiments concluded that one of the inhibitors was found to be cPLA 2 -selective, non-cytotoxic, cell and brain penetrant and capable of reducing reactive oxygen species (ROS) and nitric oxide (NO) production in stimulated microglial cells. Computational studies were employed to understand how the compound interacts with cPLA 2 .
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-13996-8