Indomethacin prevents increased catecholamine turnover in rat brain following systemic endotoxin challenge.
1. Key features of the acute phase response to infection are replicated by systemic administrations of lipopolysaccharide and may be mediated via the production of lymphokines and cytokines, including interleukin-1. Inhibition of prostaglandin synthesis may attenuate certain features of the acute phase response. 2. In the present study, the effects of systemic administration of the lipopolysaccharide (LPS, 250 micrograms/rat) and interleukin-1 (IL-1, 10 micrograms/rat) on catecholamine metabolism in different brain regions were compared and the effects of indomethacin, a cyclooxygenase inhibitor was determined. 3. The ratio of metabolite to parent amine was used as an index of turnover of catecholamines. 4. In hypothalamus, both epinephrine and norepinephrine concentrations were decreased and their major metabolite, 3-methoxy,4-hydroxyphenylglycol (MHPG), was elevated at 4, 8 and 24 hr following LPS. The major metabolite of dopamine (homovanillic acid, HVA) was increased at 8 hours in striatum, hypothalamus and medulla. LPS increased dopamine turnover at 8 and 24 hr and norepinephrine turnover at 4, 8 and 24 hr. 5. In all regions examined, IL-1 produced effects similar to LPS on amine and metabolite contents and norepinephrine and dopamine turnover. 6. Significantly, co-administration of a single dose of indomethacin (50 mg/kg) completely blocked LPS-induced changes in hypothalamic catecholamines and metabolites and the increase in turnover at 4 and 8 hr. Furthermore, the effects of IL-1 on hypothalamic MHPG content and norepinephrine turnover were also blocked by indomethacin, although the effects of IL-1 on regional catecholamines and HVA content and turnover were either not modified or partially antagonized by indomethacin. 7. The present results suggest that in the rat, activation of noradrenergic, dopaminergic and epinephrine-containing neurons in hypothalamus, as well as dopaminergic neurons in other regions is associated with the acute phase response to endotoxin and that synthesis of prostaglandins plays a pivotal role in catecholamine responses in all brain regions examined.
Masana
M I
MI
Section on Clinical Pharmacology, National Institute of Mental Health, Bethesda, Maryland.
Heyes
M P
MP
Mefford
I N
IN
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001933:Brain Stem / Q000187:drug effects / Q000201:enzymology; D002395:Catecholamines / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D004837:Epinephrine / Q000378:metabolism; D006719:Homovanillic Acid / Q000097:blood; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism; D008734:Methoxyhydroxyphenylglycol / Q000097:blood; D009638:Norepinephrine / Q000378:metabolism; D010625:Phenylethanolamine N-Methyltransferase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D002395:Catecholamines; D004731:Endotoxins; D008734:Methoxyhydroxyphenylglycol; D010625:Phenylethanolamine N-Methyltransferase; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid; D007213:Indomethacin; D004837:Epinephrine