Resting and arecoline-stimulated brain metabolism and signaling involving arachidonic acid are altered in the cyclooxygenase-2 knockout mouse.
Abstract Studies were performed to determine if cyclooxygenase (COX)-2 regulates muscarinic receptor-initiated signaling involving brain phospholipase A2 (PLA2) activation and arachidonic acid (AA; 20 : 4n-6) release. AA incorporation coefficients, k* (brain [1-14C]AA radioactivity/integrated plasma radioactivity), representing this signaling, were measured following the intravenous injection of [1-14C]AA using quantitative autoradiography, in each of 81 brain regions in unanesthetized COX-2 knockout (COX-2(-/-)) and wild-type (COX-2(+/+)) mice. Mice were administered arecoline (30 mg/kg i.p.), a non-specific muscarinic receptor agonist, or saline i.p. (baseline control). At baseline, COX-2(-/-) compared with COX-2(+/+) mice had widespread and significant elevations of k*. Arecoline increased k* significantly in COX-2(+/+) mice compared with saline controls in 72 of 81 brain regions, but had no significant effect on k* in any region in COX-2(-/-) mice. These findings, when related to net incorporation rates of AA from brain into plasma, demonstrate enhanced baseline brain metabolic loss of AA in COX-2(-/-) compared with COX-2(+/+) mice, and an absence of a normal k* response to muscarinic receptor activation. This response likely reflects selective COX-2-mediated conversion of PLA2-released AA to prostanoids.
Basselin
Mireille
M
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda,MD 20892-0947, USA. mirvasln@mail.nih.gov
Villacreses
Nelly E
NE
Langenbach
Robert
R
Ma
Kaizong
K
Bell
Jane M
JM
Rapoport
Stanley I
SI
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001115:Arecoline / Q000494:pharmacology*; D001345:Autoradiography / Q000379:methods; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001931:Brain Mapping; D018679:Cholinergic Agonists / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D016192:Resting Phase, Cell Cycle / Q000502:physiology*
D018679:Cholinergic Agonists; D016718:Arachidonic Acid; D001115:Arecoline; D051546:Cyclooxygenase 2; D010741:Phospholipases A; D054467:Phospholipases A2