Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation.
OBJECTIVE
Cerebral edema is responsible for significant morbidity and mortality in patients harboring malignant gliomas. To examine the role of inflammatory cells in brain edema formation, we studied the expression cyclooxygenase (COX)-2, a key enzyme in arachidonic acid metabolism, by microglia in the C6 rodent glioma model.


METHODS
The expression of COX-2 in primary microglia cultures obtained from intracranial rat C6 gliomas was examined using reverse transcription-PCR, Western analysis, and prostaglandin E(2) (PGE(2)) enzyme immunoassay. Blood-tumor barrier permeability was studied in the same tumor model using magnetic resonance imaging.


RESULTS
In contrast to C6 glioma cells, microglia isolated from intracranial C6 tumors produced high levels of PGE(2) through a COX-2-dependent pathway. To test whether the observed microglia COX-2 activity played a role in brain edema formation in gliomas, tumor-bearing rats were treated with rofecoxib, a selective COX-2 inhibitor. Rofecoxib was as effective as dexamethasone in decreasing the diffusion of contrast material into the brain parenchyma (P = 0.01, rofecoxib versus control animals), suggesting a reduction in blood-tumor barrier permeability.


CONCLUSIONS
These findings suggest that glioma-infiltrating microglia are a major source of PGE(2) production through the COX-2 pathway and support the use of COX-2 inhibitors as possible alternatives to glucocorticoids in the treatment of peritumoral edema in patients with malignant brain tumors.
Badie
Behnam
B
Department of Neurological Surgery, University of Wisconsin School of Medicine, Madison, Wisconsin 53792, USA. badie@neurosurg.wisc.edu
Schartner
Jill M
JM
Hagar
Aaron R
AR
Prabakaran
Sakthivel
S
Peebles
Todd R
TR
Bartley
Becky
B
Lapsiwala
Samir
S
Resnick
Daniel K
DK
Vorpahl
Jessica
J
D000818:Animals; D015153:Blotting, Western; D001929:Brain Edema / Q000209:etiology*; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D005910:Glioma / Q000201:enzymology* / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D017628:Microglia / Q000201:enzymology* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone