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Inhibition of endogenous pyrogen-induced fever by a muramyl dipeptide derivative
Abstract:
N-acetylmuramyl-L-alanyl-D-isoglutamine, or muramyl dipeptide (MDP), is a synthetic immunoadjuvant analogue of a bacterial peptidoglycan subunit that has a definite pyrogenic effect in the rabbit. Some adjuvant-active derivatives such as murabutide [MDP(Gln)-OnBu] or murametide [MDP(Gln)-OMe] are not pyrogenic. Murabutide did not stimulate human or rabbit cells to release endogenous pyrogen (EP), but murametide induced EP production at the same dosage levels as MDP. Moreover, plasma from rabbits treated with murametide transferred into untreated recipients elicited a febrile response typical of EP fever and comparable with that induced by plasma from MDP-treated animals. Murametide not only inhibited the central effect of EP that is generated but also the effect of an extra dose of EP administered later by the intravenous route. Moreover, pretreatment of rabbits with murametide decreased fever responses induced by certain high-molecular-weight exogenous pyrogens as mediated through the production of EP.
Insights
Murametide, a muramyl dipeptide (MDP) derivative, induces fever by stimulating endogenous pyrogen (EP) release, unlike non-pyrogenic murabutide. This pyrogenic effect in rabbits highlights differences in MDP analogue activity.
Area of Science:
- Immunology
- Pharmacology
Background:
- N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) is a synthetic immunoadjuvant.
- MDP is an analogue of bacterial peptidoglycan subunits and exhibits pyrogenic effects.
- Some adjuvant-active MDP derivatives, like murabutide, are non-pyrogenic, while others, like murametide, retain pyrogenic properties.
Purpose of the Study:
- To investigate the pyrogenic effects of murametide, a derivative of muramyl dipeptide (MDP).
- To compare the pyrogenic activity of murametide with MDP and murabutide.
- To elucidate the mechanism of fever induction by murametide, specifically its role in endogenous pyrogen (EP) production.
Main Methods:
- Administration of MDP, murabutide, and murametide to rabbits.
- Measurement of pyrogenic responses and fever induction.
- Assay of endogenous pyrogen (EP) production in vitro and in vivo.
- Plasma transfer experiments from treated to untreated rabbits.
- Evaluation of fever responses to exogenous pyrogens after murametide pretreatment.
Main Results:
- Murametide induced endogenous pyrogen (EP) production in rabbit and human cells, similar to MDP.
- Murabutide did not stimulate EP release.
- Plasma from murametide-treated rabbits induced fever in recipients, comparable to MDP-treated animals.
- Murametide inhibited the central effects of EP and reduced fever responses to exogenous pyrogens.
Conclusions:
- Murametide possesses pyrogenic activity mediated by endogenous pyrogen (EP) release.
- Murametide's pyrogenic effects differ from the non-pyrogenic adjuvant murabutide.
- Murametide's ability to inhibit EP effects suggests potential therapeutic applications in managing fever and inflammation.