31
Pharmacological Research, Vol . 25, Supplement 1, 1992 EFFECTS OF BACTERIAL ENDOTOXIN, INTERLEUKIN-1 AND PROSTAGLANDINS ON THERMOREGULATION AND CEREBROSPINAL FLUID-CALCIUM CONCENTRATION IN RABBITS Palmi M ., Frosini ._Mn and Sgaragli G .P . Istituto di Scienze Farmacologiche, UniversitA di Siena, Siena . Key words : Pyrogens-Brain Calcium Metabolism .
Studies on the pathogenesis of fever have established that interleukin-i (IL-1) is the primary host mediator of febrile response regardless of the origin of the disease . Bacterial endotoxins and other fever inducing agents are meant to stimulate release of IL-1, which, in turn, would activate the reaction cascade that leads to prostaglandin synthesis and fever (1) . Previous study carried out in our laboratory has shown that in febrile rabbits total calcium concentration ([Cal) of cerebrospinal fluid (CSF) is positively and significantly correlated to the extent of increase in rectal temperature (RT)
(2) . To gain more insight on the possible
relationship between brain calcium metabolism and fever we have performed a series of experiments which are reported here . The effects of E . Coli endotoxin (Ditco Laboratories, Detroit, MI) human IL-lB , nonapeptide (position 163-171) E2
(PGE1 and PGE2)
(Sclavo,
IL-1 derived
Siena Italy) prostaglandin El and
(Sigma Chem . Co ., S .Louis, USA) on RT and CSF [Cal were
assessed in New Zealand rabbits bearing chronically implanted cannulas into lateral ventricle and cisterna magna .
With the exception of endotoxin that
was injected i .v . all the other compounds were administered intracerebroventricularly (i .c .v .) in a volume of 10 pl through the cannula . In all animals CSF was drawn from
cisterna magna in 125 Ill
fractions collected at a rate of 5 pl/min, during the entire experimental session (4-8 hr) . Calcium was determined colorimetrically
. Body and skin
temperatures were monitored by using a 16 channel thermocouple thermometer
1043-6618/92/2510031-02/$03 .00/0
© 1992 The Italian Pharmacological Society
32
Pharmacological Research, Vol. 25, Supplement 1, 1992 coupled to a Personal Computer . Basal values for RT and [Cal were assessed during the first 1.00 minutes that preceded treatments . Both endotoxin (0 .15 uq/kq b .w .) and IL-1 above baseline
(25 ng) induced a rise of RT with mean peak value
(L1Tmax)
of 1 .8±0 .3 °C (SEM)
and 1 .5±0 .2 °C (n=3)
respectively, which was accompanied by a significant increase in CSF [Ca] The maximal calcium increase above baseline
was 14 .3±2 .3 and 16 .'1±1 .8
for endotoxin and for IL-l, respectively . Acetylsalicilic acid (80 mg/kg b .w .)
injected i .v .
immediately before endotoxin abolished fever and
antagonized endotoxin-induced [Ca]
increase in CSF . IL-1 derived
nonapeptide at the same dose of IL-1 was devoid of pyrogenic effect, is known, and did not modify CSF [Ca] .
as it
PGE2 at a single dose of 25 jig and
PGE1 at two different doses of 2 .5 and 25 pg, induced fever ./ Tmax was 1 .8±0 .3 °C for PGE2
(n=3) and 1 .0±0 .15 °C and 1 .8 ±0 .2 °C (n=3) at the
lowest and the highest dose of PGE 1 respectively . Both PGE1 and PGE2 tailed to enhance CSF[Ca] . These findings suggest that changes in brai
calcium metabolism participate
in the mechanisms involved in the pathogenesis of fever and that prostaglandins involvement takes place beyond the steps which modify calcium metabolism . References : H .A . Bernheim . Is Prostaglandin E2 Involved in the Pathogenesis of 1) Fever? Effects of Interleukin-1 on the Release of Prostaglandins . The Yale J . Biol . Med . 59 : 151-158, 1986 . 2) M . Palmi and G .P . Sqaraqli . Positive correlation of calcium concentration in cerebrospinal fluid and rectal temperature in rabbits . Acta Physiol . Hung . 75 : 229-230, 1990
Pharmacological Research, Vol . 25, Supplement 1, 1992 EFFECTS OF BACTERIAL ENDOTOXIN, INTERLEUKIN-1 AND PROSTAGLANDINS ON THERMOREGULATION AND CEREBROSPINAL FLUID-CALCIUM CONCENTRATION IN RABBITS Palmi M ., Frosini ._Mn and Sgaragli G .P . Istituto di Scienze Farmacologiche, UniversitA di Siena, Siena . Key words : Pyrogens-Brain Calcium Metabolism .
Studies on the pathogenesis of fever have established that interleukin-i (IL-1) is the primary host mediator of febrile response regardless of the origin of the disease . Bacterial endotoxins and other fever inducing agents are meant to stimulate release of IL-1, which, in turn, would activate the reaction cascade that leads to prostaglandin synthesis and fever (1) . Previous study carried out in our laboratory has shown that in febrile rabbits total calcium concentration ([Cal) of cerebrospinal fluid (CSF) is positively and significantly correlated to the extent of increase in rectal temperature (RT)
(2) . To gain more insight on the possible
relationship between brain calcium metabolism and fever we have performed a series of experiments which are reported here . The effects of E . Coli endotoxin (Ditco Laboratories, Detroit, MI) human IL-lB , nonapeptide (position 163-171) E2
(PGE1 and PGE2)
(Sclavo,
IL-1 derived
Siena Italy) prostaglandin El and
(Sigma Chem . Co ., S .Louis, USA) on RT and CSF [Cal were
assessed in New Zealand rabbits bearing chronically implanted cannulas into lateral ventricle and cisterna magna .
With the exception of endotoxin that
was injected i .v . all the other compounds were administered intracerebroventricularly (i .c .v .) in a volume of 10 pl through the cannula . In all animals CSF was drawn from
cisterna magna in 125 Ill
fractions collected at a rate of 5 pl/min, during the entire experimental session (4-8 hr) . Calcium was determined colorimetrically
. Body and skin
temperatures were monitored by using a 16 channel thermocouple thermometer
1043-6618/92/2510031-02/$03 .00/0
© 1992 The Italian Pharmacological Society
32
Pharmacological Research, Vol. 25, Supplement 1, 1992 coupled to a Personal Computer . Basal values for RT and [Cal were assessed during the first 1.00 minutes that preceded treatments . Both endotoxin (0 .15 uq/kq b .w .) and IL-1 above baseline
(25 ng) induced a rise of RT with mean peak value
(L1Tmax)
of 1 .8±0 .3 °C (SEM)
and 1 .5±0 .2 °C (n=3)
respectively, which was accompanied by a significant increase in CSF [Ca] The maximal calcium increase above baseline
was 14 .3±2 .3 and 16 .'1±1 .8
for endotoxin and for IL-l, respectively . Acetylsalicilic acid (80 mg/kg b .w .)
injected i .v .
immediately before endotoxin abolished fever and
antagonized endotoxin-induced [Ca]
increase in CSF . IL-1 derived
nonapeptide at the same dose of IL-1 was devoid of pyrogenic effect, is known, and did not modify CSF [Ca] .
as it
PGE2 at a single dose of 25 jig and
PGE1 at two different doses of 2 .5 and 25 pg, induced fever ./ Tmax was 1 .8±0 .3 °C for PGE2
(n=3) and 1 .0±0 .15 °C and 1 .8 ±0 .2 °C (n=3) at the
lowest and the highest dose of PGE 1 respectively . Both PGE1 and PGE2 tailed to enhance CSF[Ca] . These findings suggest that changes in brai
calcium metabolism participate
in the mechanisms involved in the pathogenesis of fever and that prostaglandins involvement takes place beyond the steps which modify calcium metabolism . References : H .A . Bernheim . Is Prostaglandin E2 Involved in the Pathogenesis of 1) Fever? Effects of Interleukin-1 on the Release of Prostaglandins . The Yale J . Biol . Med . 59 : 151-158, 1986 . 2) M . Palmi and G .P . Sqaraqli . Positive correlation of calcium concentration in cerebrospinal fluid and rectal temperature in rabbits . Acta Physiol . Hung . 75 : 229-230, 1990
