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Antagonism of PAF-induced death in mice
A K Myers1, T Nakanishi, P Ramwell
1Department of Physiology and Biophysics, Georgetown University Medical Center Washington, D.C. 20007.
Abstract:
The ability of three platelet activating factor (PAF) antagonists, BN52021, L652,731 and 48740RP, and the leukotriene antagonist FPL55712 to block iv PAF-induced death was tested in mice. PAF-induced sudden death has been previously characterized as a model of systemic anaphylaxis and circulatory shock related its hypotensive actions. Of the drugs, BN5201 and L652,731 provided dose-dependent protection against PAF toxicity, whereas the others had no effect. 48740RP was, however active against PAF-induced rabbit platelet aggregation. BN52021 was inactive in three other mouse sudden death models in which arachidonic acid, U46619 or collagen combined with epinephrine is injected iv to provoke a thrombotic/ischemic sudden death. In contrast, the TXA2 antagonist SQ29548 inhibited the acute toxicity of two of these latter challenges (arachidonic acid and thromboxane agonist U46619), but was inactive against PAF lethality. These results suggest that PAF toxicity in mice is a specific model for PAF agonism, and is not mediated by TXA2 or peptido-leukotrienes. Further, PAF-induced mortality should be a simple and useful technique for testing potential PAF antagonists for in vivo activity by various routes of administration.
Insights
Platelet activating factor (PAF) antagonists BN52021 and L652,731 effectively protected mice against PAF-induced death. This indicates PAF toxicity is a specific model for testing PAF antagonists in vivo.
Area of Science:
- Pharmacology
- Immunology
- Toxicology
Background:
- Platelet-activating factor (PAF) is implicated in systemic anaphylaxis and circulatory shock.
- PAF-induced sudden death in mice serves as a model for these conditions.
- Understanding PAF's role is crucial for developing targeted therapies.
Purpose of the Study:
- To evaluate the efficacy of specific platelet activating factor (PAF) antagonists in blocking PAF-induced mortality in mice.
- To determine if PAF toxicity is mediated by thromboxane A2 (TXA2) or leukotrienes.
- To establish a reliable in vivo model for screening potential PAF antagonists.
Main Methods:
- Testing three PAF antagonists (BN52021, L652,731, 48740RP) and a leukotriene antagonist (FPL55712) in mice challenged with intravenous PAF.
- Assessing dose-dependent protection against PAF-induced death.
- Evaluating antagonist activity in other mouse sudden death models (arachidonic acid, U46619, collagen/epinephrine) and PAF-induced rabbit platelet aggregation.
- Comparing results with a TXA2 antagonist (SQ29548).
Main Results:
- BN52021 and L652,731 demonstrated dose-dependent protection against PAF-induced death in mice.
- The antagonist 48740RP showed activity against PAF-induced rabbit platelet aggregation but not PAF lethality in mice.
- Neither FPL55712 nor SQ29548 affected PAF lethality, suggesting PAF toxicity is not mediated by TXA2 or leukotrienes.
Conclusions:
- PAF-induced mortality in mice is a specific and effective model for evaluating the in vivo activity of PAF antagonists.
- The tested PAF antagonists, BN52021 and L652,731, show promise for therapeutic development.
- This model provides a simple and useful method for screening potential PAF antagonists via various administration routes.