Differential gene expression patterns in cyclooxygenase-1 and cyclooxygenase-2 deficient mouse brain.
BACKGROUND
Cyclooxygenase (COX)-1 and COX-2 produce prostanoids from arachidonic acid and are thought to have important yet distinct roles in normal brain function. Deletion of COX-1 or COX-2 results in profound differences both in brain levels of prostaglandin E2 and in activation of the transcription factor nuclear factor-kappaB, suggesting that COX-1 and COX-2 play distinct roles in brain arachidonic acid metabolism and regulation of gene expression. To further elucidate the role of COX isoforms in the regulation of the brain transcriptome, microarray analysis of gene expression in the cerebral cortex and hippocampus of mice deficient in COX-1 (COX-1-/-) or COX-2 (COX-2-/-) was performed.


RESULTS
A majority (>93%) of the differentially expressed genes in both the cortex and hippocampus were altered in one COX isoform knockout mouse but not the other. The major gene function affected in all genotype comparisons was 'transcriptional regulation'. Distinct biologic and metabolic pathways that were altered in COX-/- mice included beta oxidation, methionine metabolism, janus kinase signaling, and GABAergic neurotransmission.


CONCLUSIONS
Our findings suggest that COX-1 and COX-2 differentially modulate brain gene expression. Because certain anti-inflammatory and analgesic treatments are based on inhibition of COX activity, the specific alterations observed in this study further our understanding of the relationship of COX-1 and COX-2 with signaling pathways in brain and of the therapeutic and toxicologic consequences of COX inhibition.
Toscano
Christopher D
CD
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. toscanoc@mail.nih.gov
Prabhu
Vinaykumar V
VV
Langenbach
Robert
R
Becker
Kevin G
KG
Bosetti
Francesca
F
D000818:Animals; D002540:Cerebral Cortex / Q000201:enzymology*; D051545:Cyclooxygenase 1 / Q000172:deficiency*; D051546:Cyclooxygenase 2 / Q000172:deficiency*; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D006624:Hippocampus / Q000201:enzymology*; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D050485:GABA Plasma Membrane Transport Proteins; D018079:Receptors, GABA; D008715:Methionine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D053612:Janus Kinases