| Summary: | The objective of the study was to investigate the possibility that the synthetic glucocorticoid analogue, dexamethasone was antipyretic. In addition, the possible involvement of peripheral PGE<SUB>2</SUB> during fever and the mechanism by which ketoprofen, dexamethasone and the neuropeptide ACTH<SUB>1-24</SUB> interact with fever in response to pyrogenic immunomodulators such as Poly I:C, LPS and IL-1/EP and their effect on PGE<SUB>2</SUB> biosynthesis both <i>in vivo</i> and <i>in vitro</i> in the rabbit was also investigated. The febrile response was measured as changes in rectal temperatures and CSF levels of PGE<SUB>2</SUB> were estimated by collecting samples from the third cerebral ventricle by using a push-pull perfusion system. PGE<SUB>2</SUB> release was also measured <i>in vitro</i> from rabbit monocytes prepared by Percoll density gradient centrifugation. PGE<SUB>2</SUB> was estimated by RIA. Ketoprofen (3 mg/Kg s.c.) administered prior to or after the onset of fever completely inhibited the febrile response to all pyrogens. Dexamethasone (1 mg/kg i.v.) attenuated the febrile response to Poly I:C (5 μ g/Kg i.v.) but only if administered between 0.5 - 2 hours before Poly I:C and a maximum effect was observed with 3 mg/Kg. Fever in response to LPS (50 - 200 ng/Kg i.v.), IL-1/EP (50 μl/animal = 5 x 10<SUP>8</SUP> cell equivalents i.v.), TNF (15 μg/animal i.v.) or Poly I:C (5 μg i.c.v.) was also attenuated by pretreatment for 1 hour with dexamethasone. ACTH<SUB>1-24</SUB> (1 - 10 μg/Kg i.v.) produced a dose-related hypothermia at an ambient temperature of 22 ± 2<SUP>o</SUP>C. A non-hypothermic dose of ACTH<SUB>1-24</SUB> (5 μg/Kg i.v.) significantly reduced the febrile response to Poly I:C (5 μg/Kg i.v.) or IL-1/EP (50 μl/animal i.v.). Poly I:C, LPS and IL-1/EP administered i.v. were found to produce a significant increase in the plasma PGE_2 level (in order of 6 - 8 fold) which occurred simultaneously with the rise in body temperature. Ketoprofen (3 mg/Kg s.c.) abolished both the rise in body temperature and the increase in plasma PGE_2 level. Dexamethasone (3 mg/Kg i.v.) pretreatment (1 hour) attenuated the pyrogen-stimulated increase in both parameters. If dexamethasone was administered after the onset of fever in response to Poly I:C, it potentiated both the increase in body temperature and plasma PGE_2. ACTH_1-24 (5 μg/Kg i.v.) significantly reduced the febrile response to Poly I:C and IL-1/EP but had no effect on plasma PGE<SUB>2</SUB> levels. Poly I:C and IL-1/EP increased the amount of PGE<SUB>2</SUB> detected in the perfusate collected from the third cerebral ventricle. The increase was in the order of 2 - 4 fold compared with control levels which parallelled the increase in body temperature. Ketoprofen abolished the fever and the increase in CSF PGE<SUB>2</SUB> level. Dexamethasone also significantly attenuated the febrile response and reduced the amount of PGE<SUB>2</SUB> in the CSF perfusate. Experiments were also carried out on rabbit monocytes <i>in vitro</i>. Poly I:C, LPS and IL-1/EP all increased the concentration of PGE<SUB>2</SUB> in culture supernatants. Ketoprofen and dexamethasone significantly reduced pyrogen-stimulated release of PGE<SUB>2</SUB>, but ACTH<SUB>1-24</SUB> had no effect. The protein synthesis inhibitor anisomycin reduced Poly I:C and LPS-stimulated release of PGE<SUB>2</SUB> but had no effect on IL-1/EP-stimulated release of PGE<SUB>2</SUB>. In addition, anisomycin antagonised the inhibitory effect of dexamethasone on the PGE<SUB>2</SUB> released from monocytes in the presence of IL-1/EP. These results suggest that the increase in plasma PGE<SUB>2</SUB> levels in response to the pyrogenic agents may contribute to their pyrogenicity. In addition, the antipyretic actions of dexamethasone and ketoprofen may involve a reduction in circulating levels of PGE<SUB>2</SUB> and this action of dexamethasone may occur via the induction of a protein intermediate possibly the PLA<SUB>2</SUB> inhibitory protein, lipocortin.
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