Cyclooxygenase inhibitors, NSAID - PAF (Platelet Activating Factor)
PAF, Platelet Activating Factor, is an acetylated derivative of glycerophosphorylcholine, so called as one of its main effects is to induce platelet aggregation.
PAF is not stored in cells, it is synthesized, in response to various stimulations, by platelets, leukocytes, endothelial cells and mast cells.
The inactive precursor is 1-O-alkyl-2-acyl-glycerophosphocholine which, under the influence of A2 phospholipase, is hydrolyzed into an acid which is generally arachidonic acid and in lyso-PAF. The lyso-PAF is then acetylated by an acetyltransferase in active PAF. PAF is inactivated by desacetylation by an acetylhydrolase which transforms it into lyso-PAF, itself transformed by an acyltransferase into the inactive precursor, 1-O-alkyl-2-acyl-glycérophosphcholine. The inhibition of acetylhydrolase increases the tissue concentration of PAF.
Effects of PAF
PAF stimulates receptors coupled to G proteins which activate phospholipases C and A2, inducing the formation of diacylglycerol, inositolphosphate and arachidonic acid (A2).
- It elicits platelet aggregation. An intravenous injection in animals elicits the formation of a platelet clot, accompanied by thrombocytopenia.
- It induces leukocytes aggregation and is involved in chemotaxis of eosinophils, neutrophils and monocytes.
- It is a powerful vasodilator able to cause an important arterial hypotension, it increases vascular permeability and movement of liquid out of the vasculature.
- It constricts directly, or indirectly by release of autacoids, the majority of smooth muscles, except vascular fibers. It constricts digestive, uterine, bronchial fibers. Moreover it increases for a long duration the reactivity of bronchi to other bronchoconstrictors. PAF induces gastric ulcerations.
- It decreases renal blood flow rate, diuresis and sodium excretion.
- It probably is involved in ovulation and egg: implantation could be inhibited by PAFantagonists.
- It could induce uterine contractions during labor and its antagonists could delay parturition.
- It increases vascular permeability, edema and cellular chemotaxis and takes part in inflammatory reactions.
Drugs and PAF
Most of the effects of PAF are regarded as adverse but . One could try to reduce them by:
- inhibition of bio synthesis and release of PAF: but there does not exist at present of specific drug exerting these effects.
- inhibition of PAF receptors: compounds which could have antagonist effects on PAF receptors are terpenes, isolated from Ginkgo biloba such as ginkgolide B. Extracts of Ginkgo biloba were largely prescribed for preventive and curative treatment of cognitive and vasomotor disturbances.
On the whole, one does not have drugs today able to inhibit specifically PAF biosynthesis or effects.