Leukotrienes in brain : natural occurrence and induced changes

Abstract Peptidoleukotrienes (SP-LTs) (both total product and individual LTC 4 and LTE 4 ) and LTB 4 were measured by radioimmunoassay in cerebrospinal fluid (CSF) collected from the third ventricle of conscious cats. Total SP-LT was expressed as LTE 4 after treating samples with crude γ-glutamyltranspeptidase. Prostaglandin (PG) E 2 and throm☐ane (TX) B 2 , the stable metabolite of TXA 2 , were also assayed in part of the experiments. Under basal conditions, SP-LT and LTC 4 were consistently measurable (respectively, 327 ± 14and244 ± 41pg/ml), while native LTE 4 was below the threshold of the assay (60–280 pg/ml) in most cases. LTB 4 was barely detectable (30 ± 2pg/ml) or not detectable at all. PGE 2 was normally less abundant than TXB 2 (31 ± 4vs281 ± 47pg/ml). Intracerebroventricular (i.c.v.) administration of arachidonic acid (40 μg) caused a 4-fold increase in SP-LT levels which was relatively small and transient compared to PGE 2 (76-fold) and TXB 2 (23-fold) while there was no change in either native LTE 4 or LTB 4 . A similar response was obtained with platelet-activating factor (PAF, 1 μg 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 μg i.c.v.), whereas PAF effect was reversed by pretreatment with either the PAF antagonist, BN52021 (1 μg i.c.v.), or the 5-lipoxygenase inhibitors, U-60, 257 (75 μg i.c.v.) and L-651, 392 (10 mg/kg p.o.). PAF was also effective in causing a 3-fold rise in LTC 4 . 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, LTC 4 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.