(1) Altered arachidonic acid release and metabolism by the enzymes cPLA2 and COX-2 is thought to be involved in the pathophysiology of a number of neurological and psychiatric disorders. Thus, a better understanding of the mechanisms that control the expression of cPLA2 and COX-2 may provide therapeutic targets to enhance neuroprotection. We used cPLA2 deficient mice to study compensatory mechanisms and coupling between cPLA2 and downstream enzymes in the eicosanoid biosynthetic pathway. We found a significant 50-60% decrease in mRNA, protein, and enzyme activity levels of COX-2, but no change in COX-1, prostaglandin E synthase (PGES), or other arachidonic acid oxygenating enzymes. Enzyme activities and protein levels of Ca2+-independent iPLA2 and secretory sPLA2 were not significantly changed. These results show that other brain PLA2 enzymes do not compensate for the cPLA2 deficiency and that cPLA2 is critical for COX-2-derived eicosanoid production in mouse brain. (2) To further investigate the interaction between upstream and downstream enzymes involved in brain prostaglandin synthesis, we examined expression and activity of COX-1, of different PLA2 enzymes, and of PGES enzymes in COX-2 deficient mice. The PGE2 level was decreased by 52% in the COX-2 knockout mice brain, indicating a significant role of COX-2 in formation of PGE2. However, when we added exogenous arachidonic acid to brain homogenates, COX activity was increased in the COX-2 deficient mice, suggesting a compensatory increase in COX-1 expression and an intracellular compartmentalization of the COX isozymes. Activity and expression of cPLA2 and sPLA2 enzymes, supplying AA to COX, were significantly increased. Our results indicate that compensatory mechanisms exist in COX-2 deficient mice and that microsomal PGES-2 is functionally coupled with COX-2. Thus, this pathway might represent a novel target for anti-inflammatory and neuroprotective drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000423-01
Application #
6969270
Study Section
(BPM)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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