RGD Reference Report - Systemic and intrathecal effects of a novel series of phospholipase A2 inhibitors on hyperalgesia and spinal prostaglandin E2 release. - Rat Genome Database

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Systemic and intrathecal effects of a novel series of phospholipase A2 inhibitors on hyperalgesia and spinal prostaglandin E2 release.

Authors: Yaksh, TL  Kokotos, G  Svensson, CI  Stephens, D  Kokotos, CG  Fitzsimmons, B  Hadjipavlou-Litina, D  Hua, XY  Dennis, EA 
Citation: Yaksh TL, etal., J Pharmacol Exp Ther. 2006 Jan;316(1):466-75. Epub 2005 Oct 3.
RGD ID: 1642461
Pubmed: (View Article at PubMed) PMID:16203828
DOI: Full-text: DOI:10.1124/jpet.105.091686

Phospholipase A(2) (PLA(2)) forms are expressed in spinal cord, and inhibiting spinal PLA(2) induces a potent antihyperalgesia. Here, we examined the antihyperalgesic effects after systemic and i.t. delivery of four compounds constructed with a common motif consisting of a 2-oxoamide with a hydrocarbon tail and a four-carbon tether. These molecules were characterized for their ability to block group IVA calcium-dependent PLA(2) (cPLA(2)) and group VIA calcium-independent PLA(2) (iPLA(2)) in inhibition assays using human recombinant enzyme. The rank ordering of potency in blocking group IVA cPLA(2) was AX048 (ethyl 4-[(2-oxohexadecanoyl)amino]butanoate), AX006 (4-[(2-oxohexadecanoyl)amino]butanoic acid), and AX057 (tert-butyl 4-[(2-oxohexadecanoyl)amino]butanoate) > AX010 (methyl 4-[(2-oxohexadecanoyl)amino]butanoate) and for inhibiting group VIA iPLA(2) was AX048, AX057 > AX006, and AX010. No agent altered recombinant cyclooxygenase activity. In vivo, i.t. (30 mug) and systemic (0.2-3 mg/kg i.p.) AX048 blocked carrageenan hyperalgesia and after systemic delivery in a model of spinally mediated hyperalgesia induced by i.t. substance P (SP). The other agents were without activity. In rats prepared with lumbar i.t. loop dialysis catheters, SP evoked spinal prostaglandin E(2) (PGE(2)) release. AX048 alone inhibited PGE(2) release. Intrathecal SR141617, a cannabinoid CB1 inhibitor at doses that blocked the effects of i.t. anandamide had no effect upon i.t. AX048. These results suggest that AX048 is the first systemically bioavailable compound with a significant affinity for group IVA cPLA(2), which produces a potent antihyperalgesia. The other agents, although demonstrating enzymatic activity in cell-free assays, appear unable to gain access to the intracellular PLA(2) toward which their action is targeted.


Disease Annotations    
Hyperalgesia  (IMP,ISO)

Gene Ontology Annotations    

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Pla2g4a  (phospholipase A2 group IVA)

Genes (Mus musculus)
Pla2g4a  (phospholipase A2, group IVA (cytosolic, calcium-dependent))

Genes (Homo sapiens)
PLA2G4A  (phospholipase A2 group IVA)

Additional Information