Arachidonic acid effects

The compound saikosaponin inhibited human platelet aggregation induced by ADP, with a potency of inhibition comparable to that of aspirin, and dose-dependently inhibited platelet thromboxane formation from exogenous and endogenous arachidonic acid. Effects were similar to that of epigallocatechin isolated from green tea (Chang and Hsu 1991). 

Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-called local hormones that (1) exert their effects at very low concentrations and (2) usually act near their sites of synthesis. These substances include the prostaglandins (PG) (Figure 25.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxBg is actually a hemiacetal see Figure 25.27) with a hydroxyl group at C-15. 

Palytoxin is hemolytic (4) and is an extremely potent toxin (7). We have shown that in rat liver cells palytoxin stimulates de-esterification of cellular lipids to liberate arachidonic acid (5). These rat liver cells metabolize this increased arachidonic acid via the cyclooxygenase pathway to produce prostaglandin (PG) I2 and lesser amounts of PGE2 and PGp2. Palytoxin acts on many cells in culture to stimulate the production of cyclooxygenase metabolites (Table I). Clearly, the myriad pharmacological effects of the arachidonic acid metabolites must be considered in any explanation of the many clinical manifestations of palytoxin s toxicity. 

Furthermore, we found that the two types of tumor promoters induced common biological effects, such as irritation of mouse ear, and stimulation of prostaglandin E2 production and of arachidonic acid metabolism in rat macrophages. These common effects seem to be the most essential biological activities in tumor promotion (6). 

The main problem with any study of prostaglandins (PGs) is that although brain concentrations can exceed 0.1 /rg/g, they appear to be formed on demand, rather than preformed and stored and they have very short half-lives (seconds). Also specific effective antagonists remain to be developed and PGs are widely and evenly distributed, unlike many NTs. Thus any analysis of their central effects rests heavily on either studying PG release, or their effects when applied directly (icv injection). Certainly the brain has the enzymatic ability to synthesise both prostaglandins (cycloxygenase) and leukotrienes (lypoxygenase) from arachidonic acid (AA) (see Fig. 13.8) and a number of central functions have been proposed for them (see Piomelli 1994). 

Interest in the PGs has recently reverted to their precursor arachidonic acid (AA), which seems to be able to act intracellulary as a second messenger, and also extra-cellularly. In this latter mode it may play a part in LTP. It is known that AA produces a long-lasting enhancement of synaptic transmission in the hippocampus that resembles LTP and in fact activation of NMDA receptors leads to the release of AA by phospholipase A2 (see Dumuis et al. 1988) and inhibition of this enzyme prevents the induction of LTP. AA has also been shown to block the uptake of glutamate (see Williams and Bliss 1989) which would potentiate its effects on NMDA receptors. This would not only prolong LTP but also cause neurotoxicity. 

Williams, JH and Bliss, TV (1989) An in vitro study of the effect of lipoxygenase and cyclooxygenase inhibitors of arachidonic acid on the induction and maintenance of long-term potentiation in the hippocampus. Neurosci. Lett. 107 301-309. 

Lipoxygenases catalyse the regio-specific and stereoselective oxygenation of unsaturated fatty acids. The mammalian enzymes have been detected in human platelets, lung, kidney, testes and white blood cells. The leukotrienes, derived from the enzymatic action of the enzyme on arachidonic acid, have effects on neutrophil migration and aggregation, release of lysosomal enzymes, capillary permeability, induction of pain and smooth muscle contraction (Salmon, 1986). 

AUgayer, H. and Stenson, W.F. (1988). A comparison of effects of sulfasalazine and its metabolites on the metabolism of endogenous vs. exogenous arachidonic acid. Immunophar-macology 15 39-45. 

Payne, A.N., Garland, L.G., Lees, I.W. and Salmon, J.A. (1988). Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids effects on bronchial anaphylaxis in anaesthetised guinea-pigs. Br. J. Pharmacol. 94, 540-546. 

A series of 4-arylpyrimidines that arc amine substituted at pyrimidine C-2 was prepared. FK360 was most effective from this group on both arachidonate-induced cerebral oedema in rats and as an in vitro inhibitor of lipid peroxidation. The authors link effects of FK360 to the arachidonic acid cascade (Kuno et al., 1992). This is an unusual structure. 

One of the conspicuous resorcinols is HU-308 (362), which is a CB2-specific agonist this compound does not bind to CBi (if > 10 uM), but has a significant affinity for CB2 ( i = 22.7 nM) [226]. HU-308 elicited analgesic activity in a formalin-induced peripheral pain model and an anti-infiam-matory effect on arachidonic acid-induced ear inflammation, though it showed no activity in a tetrad of behavioural tests, which are linked to CNS activity (Table 6.34). 

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