Increased brain synthesis of prostaglandin E2 and F2-isoprostane in human and experimental transmissible spongiform encephalopathies.
The levels of 2 arachidonic acid metabolites formed either by enzymatic activity of cyclooxygenase, i.e. prostaglandin E2 (PGE2), or by free radical-catalyzed peroxidation, i.e. F2-isoprostane 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha), were measured in the CSF of subjects with sporadic and familial Creutzfeldt-Jakob disease (CJD) and in brain homogenates of scrapie-infected mice. The CSF levels of both metabolites were increased in sporadic CJD (n = 52) and familial CJD (n = 10) patients when compared with a group of patients with noninflammatory disorders. Similarly, PGE2 and 8-epi-PGF2alpha levels were higher in brain homogenates obtained from C57BL/6J mice infected with the ME7 scrapie strain than in brain homogenates from control animals. As PGE2 is 1 of the most abundant prostaglandins released during inflammation and 8-epi-PGF2alpha is a quantitative marker of lipid peroxidation, our results provide in vivo biochemical evidence for the occurrence of inflammation and oxidative stress in human and experimental transmissible spongiform encephalopathies (TSEs), a concept so far based mainly on histopathological and in vitro evidence. Interestingly, in sporadic CJD patients, high CSF levels of PGE2, but not 8-epi-PGF2alpha, correlated with short survival time, suggesting that the inflammatory response correlates with the clinical duration of disease.
Minghetti
L
L
Laboratory of Pathophysiology, Istituto Superiore di Sanità, Rome, Italy.
Greco
A
A
Cardone
F
F
Puopolo
M
M
Ladogana
A
A
Almonti
S
S
Cunningham
C
C
Perry
V H
VH
Pocchiari
M
M
Levi
G
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000378:metabolism*; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism* / Q000401:mortality; D051546:Cyclooxygenase 2; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis*; D028441:F2-Isoprostanes; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000201:enzymology; D008875:Middle Aged; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012608:Scrapie / Q000378:metabolism*; D016019:Survival Analysis
D028441:F2-Isoprostanes; D007527:Isoenzymes; D008565:Membrane Proteins; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone