The anti-inflammatory prostaglandin 15d-PGJ2 decreases oxidative/nitrosative mediators in brain after acute stress in rats.
BACKGROUND
Immobilisation stress is followed by accumulation of oxidative/nitrosative mediators in brain after the release of tumour necrosis factor-alpha (TNFalpha) and other cytokines, nuclear factor kappa B (NFkappaB) activation, nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) expression in the brain.


OBJECTIVE
This study was conducted to assess if some of the anti-inflammatory products of COX can modify the accumulation of oxidative/nitrosative species seen in brain after stress and to study the mechanisms by which this effect is achieved.


METHODS
Young-adult male Wistar rats were subjected to a single session of immobilisation during 6 h.


RESULTS
In stressed animals, brain levels of the anti-inflammatory 15d-PGJ2 increases concomitantly with COX-2 expression. Inhibition of COX-2 with NS-398 prevents stress-induced 15d-PGJ2 increase. Injection of supraphysiological doses of 15d-PGJ2 (80-120 microg/kg) decreases stress-induced increase in NOS-2 activity as well as the stress-induced increase in NO metabolites. On the other hand, 15d-PGJ2 decreases stress-induced malondialdehyde (an indicator of lipid peroxidation) accumulation in cortex and prevents oxidation of the main anti-oxidant glutathione. The mechanisms involved in the anti-oxidative properties of 15d-PGJ2 in stress involve NFkappaB blockade (by preventing stress-induced IkappaBalpha decrease) as well as inhibition of TNFalpha release in stressed animals. At the doses tested, 15d-PGJ2 decreases COX-2 expression and PGE2 release during stress, suggesting an alternative mechanism for this endogenous compound.


CONCLUSIONS
These findings demonstrate a role for this anti-inflammatory pathway in the brain response to stress and open the possibility for preventing accumulation of oxidative/nitrosative species and subsequent brain damage.
García-Bueno
Borja
B
Department of Pharmacology, Faculty of Medicine, Universidad Complutense Madrid, 28040, Madrid, Spain.
Madrigal
José L M
JL
Lizasoain
Ignacio
I
Moro
María A
MA
Lorenzo
Pedro
P
Leza
Juan C
JC
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D015538:Nitrosation / Q000187:drug effects; D010084:Oxidation-Reduction / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical / Q000009:adverse effects; D013312:Stress, Physiological / Q000209:etiology / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
C477819:15-deoxyprostaglandin J2; D016861:Cyclooxygenase Inhibitors; D018836:Inflammation Mediators; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015230:Prostaglandin D2
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