P. Braquet

Is there a case for PAF antagonists in the treatment of ischemie states

It is becoming clear that PAF plays an important role in a variety of life-threatening pathologies including shock, asthma, graft rejection and ischemia-induced damage. Pierre Braquet and colleagues analyse recent reports on PAF and ischemia and propose a hypothesis based on the catastrophe theory to explain why PAF antagonists are effective in countering ischemic injury and many other disorders. PAF antagonists, perhaps in combination with other agents, may consequently prove to have extensive therapeutic potential.

Involvement of platelet-activating factor (PAF) in cerebral post-ischemic phase in Mongolian gerbils

Platelet-activating factor (PAF) is a potent mediator of anaphylaxis and shock. In addition, evidence for PAF participation in gastric, intestinal and heart post-ischemic phase has been recently demonstrated. Ginkgo biloba extracts improve cerebral metabolism and protect brain against hypoxic damage in various models of cerebral ischemia. Potent and specific antagonists of PAF have been found in Ginkgo biloba and termed Ginkgolides: BN 52020, BN 52021, BN 52022, BN 52024. We therefore undertook the investigation of the role of Ginkgolides in cerebral ischemia obtained by bilateral ligature of the common carotid for 10 min and 6 h of recirculation in male Mongolian adult gerbils. Given preventively (one week treatment 10 mg/kg/day orally) or at the time of clamping, BN 52021 and related Ginkgolides dose-dependently antagonize morbidity assessed by the stroke-index. Similarly the mitochondrial respiration evaluated by the respiratory control ratio is significantly improved. In both determinations, the range of activity: BN 52021 greater than, BN 52020 greater than BN 52022 greater than BN 52024 shows that the effect of Ginkgolides in cerebral ischemia are correlated with their PAF antagonistic properties. Given curatively, 1 h after declamping, BN 52021 is able to reverse the cerebral impairment trend. Kadsurenone and brotizolam, two other chemically unrelated PAF antagonists led to similar recovery. Therefore PAF appears to play an important role in the post-ischemic phase after bilateral carotid ligation in Mongolian gerbils.

Heterogenous effect of flavonoids on K+ loss and lipid peroxidation induced by oxygen-free radicals in human red cells

Abstract Treatment of fresh erythrocytes with phenazine methosulfate, an intracellular generator of oxygen-free radicals, and diethyldithiocarbamate an inhibitor of superoxide dismutase results in membrane damage consisting in lipid peroxidation and increase in passive K+ permeability. Various flavonoids which have previously been reported to act as oxygen-free radical scavengers were tested on this erythrocyte model. Surprisingly, flavonoids did not exhibit the same effect on the oxygen free radical-stimulated K+ permeability. It was possible to classify these agents into four groups: (i) protective (those decreasing the oxygen-free radical-stimulated K+ permeability): kaempferol, naringenin, apigenin, naringin; (ii) toxic (those increasing the deleterious effect of oxygen-free radicals): myricetin, delphinidin, quercetin; (iii) biphasic effective (characterized by opposite effects depending on the concentration): phloretin, cyanin, catechin, morin and (iv) inactive: rutin, phloridzin. In addition, a similar classification was observed when membrane lipid peroxidation was examined, i.e. kaempferol (i) decreased lipid peroxide formation whereas myricetin (ii) enhanced it, morin (iii) exhibited a biphasic effect and rutin (iv) has no effect. The previously reported metal chelating effect of flavonoids could not totally explain the protective effect of kaempferol as was demonstrated by the partial protective effect exhibited by desferrioxamine. Moreover, this study suggests that a generation of oxygen-free radicals in red cells induced a K+ loss which probably results from membrane lipid peroxidation.

Presence of specific binding sites for platelet-activating factor (PAF) in brain

The existence of specific binding sites for [3H]-labelled PAF ([3H]PAF) was investigated on membrane preparations of gerbil brain. Binding assays of [3H]PAF showed a specific, saturable, reversible and time dependent binding. Scatchard analysis indicated the presence of two apparent populations of binding sites with Kd1 = 3.66 +/- 0.92 nM and Kd2 = 20.4 +/- 0.50 nM corresponding respectively to a maximum number of binding sites: Bmax1 = 0.83 +/- 0.23 pmol/mg protein Bmax2 = 1.1 +/- 0.32 pmol/mg protein. The binding of [3H]PAF was fully displaced by unlabelled PAF and partially inhibited by the PAF antagonist BN 52021 suggesting that BN 52021 interacts only with one site. Distribution of [3H]PAF specific binding revealed a maximum amount of binding in midbrain and hippocampus. These data suggest a biochemical and physiological role of PAF in brain.

In vivo inhibition of plasma protein leakage andSalmonella enteritidis—induced mortality in the rat by a specific paf-acether antagonist: BN 52021

The effects of BN 52021, a new specific paf-acether receptor antagonist and the total Ginkgo biloba extract (GBE 761) from which this product was isolated, were studied in the rat on paf-acether-induced permeability and cell number changes and on endotoxin-induced lethality.Their activities were compared to those of cycloxygenase, 5-lipoxygenase and phospholipase A2 inhibitors. BN 52021 given s.c. or orally exerted a dose-related inhibition of paf-acether deleterious effects as well as of endotoxin lethality whereas the other drugs tested were poorly effective. These results strongly suggest paf-acether involvement in endotoxic and septic shock.

Effect of BN 52063, a specific PAF-acether antagonist, on bronchial provocation test to allerens in asthmatic patients a preliminary study

Platelet Activating Factor, PAF-acether, elicits acute and more prolonged inflammatory responses in both experimental animals and man, and is recognised as a possible mediator of asthma. The effect of a specific PAF-acether antagonist, BN 52063, on the early asthmatic response to inhaled allergen was assessed in a randomised, double-blind, crossover study in eight atopic asthmatics, who received three days treatment with BN 52063 or placebo, separated by a one week washout. On the third day of treatment, subjects were challenged with nebulised house dust mite or pollen allergen. BN 52063 significantly antagonised early bronchoconstriction and showed a tendency to inhibit residual bronchial hyperreactivity, assessed six hours after allergen challenge by a provocation test to acetylcholine. No side effects were reported during active treatment. This is the first study in man demonstrating the efficacy of a specific PAF-acether antagonist on the immediate response to inhaled allergen challenge in asthmatics. The findings support the possible role of specific PAF-acether antagonists in the treatment of asthma.

Effect of endothelin-1 on blood pressure and bronchopulmonary system of the guinea pig.

Summary The bronchopulmonary and pressor effects of endothelin-1 (ET-1), a newly described vasoconstrictor peptide produced by endothelial cells, were investigated in the guinea pig. Intravenous injection of ET-1 (1 nmol/kg) induced an increase in pulmonary inflation pressure (PIP) as well as an important and sustained increase in arterial blood pressure (BP). Pretreatment of these animals with propranolol (1 mg/kg i.v.), provoked a significant enhancement of the ET-1-induced increase in PIP, accompanied by a dramatic and significant decrease of BP. When administered by aerosol for 1 min, ET-1 (1, 5, or 10

The effect of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (paf-acether) on the arterial wall.

mUg/ml) induced a dose-dependent increase in PIP that was maximal by 4–5 min, but no significant change of BP. Pretreatment of guinea pigs with propranolol (1 mg/kg), mepyramine (1mg/kg i.v.), nifedipine (50 mg/kg i.p.), or verapamil (0.3 mg/kg i.v.) did not inhibit the bronchopulmonary response evoked by aerosol administration of 10

Ginkgo biloba extract inhibits oxygen species production generated by phorbol myristate acetate stimulated human leukocytes.

mUg/ml of ET-1. In contrast, pretreatment of the animals with indomethacin (10 mg/kg i.v.) or BN 52021 (10 mg/kg i.v.) significantly reduced the bronchopulmonary response of ET-1 given by aerosol. Injection of ET-1 (0.1, 0.3, and 1

Effect of platelet-activating factor (PAF-acether) and its specific receptor antagonist, BN 52021, on interleukin 1 (IL1) release and synthesis by rat spleen adherent monocytes

mUg) into isolated guinea pig lungs caused significant increases in PIP that were accompanied by the release of T