Systemic and intrathecal effects of a novel series of phospholipase A(2) inhibitors on hyperalgesia and spinal prostaglandin E-2 release
Yaksh, TL; Kokotos, G; Svensson, CI; Stephens, D; Kokotos, CG; Fitzsimmons, B; Hadjipavlou-Litina, D; Hua, XY; Dennis, EA
| HERO ID | 1461544 |
|---|---|
| In Press | No |
| Year | 2006 |
| Title | Systemic and intrathecal effects of a novel series of phospholipase A(2) inhibitors on hyperalgesia and spinal prostaglandin E-2 release |
| Authors | Yaksh, TL; Kokotos, G; Svensson, CI; Stephens, D; Kokotos, CG; Fitzsimmons, B; Hadjipavlou-Litina, D; Hua, XY; Dennis, EA |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 316 |
| Issue | 1 |
| Page Numbers | 466-475 |
| Abstract | 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. |
| Doi | 10.1124/jpet.105.091686 |
| Pmid | 16203828 |
| Wosid | WOS:000234140400055 |
| Is Certified Translation | No |
| Dupe Override | No |
| Comments | Source: Web of Science WOS:000234140400055 |
| Is Public | Yes |
| Language Text | English |