Flurbiprofen, A Cyclooxygenase Inhibitor, Reduces the Brain Arachidonic Acid Signal in Response to the Cholinergic Muscarinic Agonist, Arecoline, in Awake Rats

Abstract

Cholinergic muscarinic receptors, when stimulated by arecoline, can activate cytosolic phospholipase A(2) (cPLA(2)) to release arachidonic acid (AA) from membrane phospholipid. This signal can be imaged in the brain in vivo using quantitative autoradiography following the intravenous injection of radiolabeled AA, as an increment in a regional brain AA incorporation coefficient k*. Arecoline increases k* significantly in brain regions having muscarinic M(1,3,5) receptors in wild-type but not in cyclooxygenase (COX)-2 knockout mice. To further clarify the roles of COX enzymes in the AA signal, in this paper we imaged k* following arecoline (5 mg/kg i.p.) or saline in each of 81 brain regions of unanesthetized rats pretreated 6 h earlier with the non-selective COX inhibitor flurbiprofen (FB, 60 mg/kg s.c.) or with vehicle. Baseline values of k* were unaffected by FB treatment, which however reduced by 80% baseline brain concentrations of prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)), eicosanoids preferentially derived from AA via COX-2 and COX-1, respectively. In vehicle-pretreated rats, arecoline increased the brain PGE(2) but not TXB(2) concentration, as well as values for k* in 77 of the 81 brain regions. FB-pretreatment prevented these arecoline-provoked changes. These results and those reported in COX-2 knockout mice suggest that the AA released in brain following muscarinic receptor-mediated activation is lost via COX-2 to PGE(2) but not via COX-1 to TXB(2), and that increments in k* following arecoline largely represent replacement by unesterified plasma AA of this loss.

Chronic Carbamazepine Administration Attenuates Dopamine D2-like Receptor-Initiated Signaling via Arachidonic Acid in Rat Brain

“…Furthermore, regional baseline values of J in in vehicle-treated rats, 4.5-36.1 fmol/s/g, agree with a published global value of 6.57 fmol/s/g [11]. Given that J in represents the regional rate of metabolic AA loss from brain [10,44], our data on J in indicate comparable baseline rates of AA loss in vehicle-and CBZtreated rats.…”

“…The baseline values of k* for AA in vehicle-treated rats, which ranged from 2.65 to 20.9 × 10 −4 ml/s/g brain, are similar to previously reported values [5,6,8,10,15]. Quinpirole significantly increased k* in 35 regions, many of which belong to dopaminergic circuits containing D 2 receptors (e.g.…”

“…PGE 2 and TXB 2 are converted preferentially from AA by COX-2 and COX-1, respectively. When these enzymes are pharmacologically inhibited or knocked out in rodent models, k* responses to drugs acting at cPLA 2 -coupled neuroreceptors are reduced or lost, as are the increments in brain PGE 2 and/or TXB 2 concentrations [9,10]. Our finding that quinpirole elevated brain PGE 2 in vehicle-treated rats agrees with prior in vitro and in vivo observations [23].…”

“…The signaling process can be imaged in unanesthetized rats by injecting intravenously [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]AA and measuring tracer AA uptake into brain using quantitative autoradiography. Regional brain AA incorporation coefficients k* (brain radioactivity/integrated plasma radioactivity) are calculated and, if multiplied by unlabeled unesterified plasma AA concentrations, are converted to regional incorporation rates J in that represent regional brain AA consumption.…”

“…Increments in k* caused by drug reflect the quantity of unesterified AA released and then metabolized to eicosanoids (e.g. prostaglandin E 2 (PGE 2 ), thromboxane B 2 (TXB 2 )) and other products [9,10]. Unesterified AA as well as its eicosanoid metabolites are bioactive and can influence many physiological processes, including membrane excitability, gene transcription, apoptosis, sleep, brain blood flow and behavior [49].…”