Leukotrienes in brain: natural occurrence and induced changes.
Peptidoleukotrienes (SP-LTs) (both total product and individual LTC4 and LTE4 and LTB4 were measured by radioimmunoassay in cerebrospinal fluid (CSF) collected from the third ventricle of conscious cats. Total SP-LT was expressed as LTE4 after treating samples with crude gamma-glutamyltranspeptidase. Prostaglandin (PG) E2 and thromboxane (TX) B2, the stable metabolite of TXA2, were also assayed in part of the experiments. Under basal conditions, SP-LT and LTC4 were consistently measurable (respectively, 327 +/- 14 and 244 +/- 41 pg/ml), while native LTE4 was below the threshold of the assay (60-280 pg/ml) in most cases. LTB4 was barely detectable (30 +/- 2 pg/ml) or not detectable at all. PGE2 was normally less abundant than TXB2 (31 +/- 4 vs 281 +/- 47 pg/ml). Intracerebroventricular (i.c.v.) administration of arachidonic acid (40 microgram) caused a 4-fold increase in SP-LT levels which was relatively small and transient compared to PGE2 (76-fold) and TXB2 (23-fold), while there was no change in either native LTE4 or LTB4. A similar response was obtained with platelet-activating factor (PAF, 1 microgram i.c.v.), though SP-LT elevation (4-fold) was more persistent. A further rise in SP-LT (9-fold) was noted when PAF administration was preceded by indomethacin (500 microgram i.c.v.), whereas PAF effect was reversed by pretreatment with either the PAF antagonist, BN52021 (1 microgram i.c.v.), or the 5-lipoxygenase inhibitors, U-60,257 (75 micrograms i.c.v.) and L-651,392 (10 mg/kg p.o.). PAF was also effective in causing a 3-fold rise in LTC4. Unlike PAF, pyrogens (endotoxin i.c.v. or i.v.; interleukin-1 i.v.) at doses above threshold for fever had no effect on LT levels in CSF, both in the absence and presence of indomethacin pretreatment. We conclude that SP-LTs are a normal constituent of CSF, LTC4, being the major species. The response to PAF accords with a pathogenetic role of the compounds in inflammatory processes and the reactive changes to injury. No evidence was obtained for the involvement of SP-LTs in the central mechanism of fever.
Research Institute, Hospital for Sick Children, Toronto, Ont, Canada.
N
N
Hynes
I
I
Bishai
J
J
Lees
F
F
Coceani
D000284:Administration, Oral; D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D002415:Cats; D002555:Cerebrospinal Fluid / Q000166:cytology; D002556:Cerebrospinal Fluid Proteins / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D015289:Leukotrienes / Q000134:cerebrospinal fluid / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000494:pharmacology; D011749:Pyrogens / Q000494:pharmacology; D011863:Radioimmunoassay; D013929:Thromboxane B2 / Q000378:metabolism
D002556:Cerebrospinal Fluid Proteins; D016861:Cyclooxygenase Inhibitors; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D011749:Pyrogens; D016718:Arachidonic Acid; D013929:Thromboxane B2; D015232:Dinoprostone