Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus

J Cereb Blood Flow Metab

White

et al. 2006

In rat brain, dopaminergic D 2 -like but not D 1 -like receptors can be coupled to phospholipase A 2 (PLA 2 ) activation, to release the second messenger, arachidonic acid (AA, 20:4n-6), from membrane phospholipids. In this study, we hypothesized that D-amphetamine, a dopamine-releasing agent, could initiate such AA signaling. The incorporation coefficient, k* (brain radioactivity/integrated plasma radioactivity) for AA, a marker of the signal, was determined in 62 brain regions of unanesthetized rats that were administered i.p. saline, D-amphetamine (2.5 or 0.5 mg/kg i.p.), or the D 2 -like receptor antagonist raclopride (6 mg/kg, i.v.) before saline or 2.5 mg/kg D-amphetamine. After injecting [1-14 C]AA intravenously, k* was measured by quantitative autoradiography. Compared to saline-treated controls, D-amphetamine 2.5 mg/kg i.p. increased k* significantly in 27 brain areas rich in D 2 -like receptors. Significant increases were evident in neocortical, extrapyramidal, and limbic regions. Pretreatment with raclopride blocked the increments, but raclopride alone did not alter baseline values of k*. In independent experiments, D-amphetamine 0.5 mg/kg i.p. increased k* significantly in only seven regions, including the nucleus accumbens and layer IV neocortical regions. These results indicate that D-amphetamine can indirectly activate brain PLA 2 in the unanesthetized rat, and that activation is initiated entirely at D 2 -like receptors. D-Amphetamine's lowdose effects are consistent with other evidence that the nucleus accumbens, considered a reward center, is particularly sensitive to the drug.

Section: Discussionsupporting

confidence: 77%

D-Amphetamine Stimulates D₂Dopamine Receptor-Mediated Brain Signaling Involving Arachidonic Acid in Unanesthetized Rats

Bhattacharjee

J Cereb Blood Flow Metab

White

et al. 2006

“…The AA release could be blocked by the nonspecific PLA 2 inhibitor, mepracrine, or in the rat hippocampus by bilobalide, a constituent of Ginkgo biloba, and by a specific inhibitor of cPLA 2 (cytosolic PLA 2 ) (see below) (Sanfeliu et al, 1990;Tapia-Arancibia et al, 1992;Tencé et al, 1994;Weichel et al, 1999). In contrast, NMDA did not stimulate AA release in hippocampal astroglia (Sanfeliu et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

“…Release of NMDARs from the endoplasmic reticulum requires phosphorylation of NR1 and NR2 by protein kinases A and C (PKA and PKC), or by serine or tyrosine kinases (Scott et al, 2003;Wenthold et al, 2003). Binding of glutamate or NMDA to synaptic NMDARs allows Ca 2 + into the cell to activate Ca 2 + -dependent enzymes such as calcium/calmodulindependent protein kinase II (CaMKII), PKC, phospholipase Cg, and phospholipase A 2 (PLA 2 ) (Colbran, 2004;Fukunaga et al, 1992;Gurd and Bissoon, 1997;Weichel et al, 1999;Wenthold et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Exposure of neurons from different brain regions to NMDA is reported to activate PLA 2 through the Ca 2 + mechanism, to release the second messenger, arachidonic acid (AA, 20 : 4 n-6), from membrane phospholipid (Dumuis et al, 1988;Kim et al, 1995;Kolko et al, 1999Kolko et al, , 2003Lazarewicz et al, 1990;Pellerin and Wolfe, 1991;Sanfeliu et al, 1990;Tapia-Arancibia et al, 1992;Tencé et al, 1994;Weichel et al, 1999). The AA release could be blocked by the nonspecific PLA 2 inhibitor, mepracrine, or in the rat hippocampus by bilobalide, a constituent of Ginkgo biloba, and by a specific inhibitor of cPLA 2 (cytosolic PLA 2 ) (see below) (Sanfeliu et al, 1990;Tapia-Arancibia et al, 1992;Tencé et al, 1994;Weichel et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Chronic Lithium Chloride Administration Attenuates Brain NMDA Receptor-Initiated Signaling via Arachidonic Acid in Unanesthetized Rats

Basselin

Bell

et al. 2005

Neuropsychopharmacol

103

132

It has been proposed that lithium is effective in bipolar disorder (BD) by inhibiting glutamatergic neurotransmission, particularly via N-methyl-D-aspartate receptors (NMDARs). To test this hypothesis and to see if the neurotransmission could involve the NMDARmediated activation of phospholipase A 2 (PLA 2 ), to release arachidonic acid (AA) from membrane phospholipid, we administered subconvulsant doses of NMDA to unanesthetized rats fed a chronic control or LiCl diet. We used quantitative autoradiography following the intravenous injection of radiolabeled AA to measure regional brain incorporation coefficients k* for AA, which reflect receptormediated activation of PLA 2 . In control diet rats, NMDA (25 and 50 mg/kg i.p.) compared with i.p. saline increased k* significantly in 49 and 67 regions, respectively, of the 83 brain regions examined. The regions affected were those with reported NMDARs, including the neocortex, hippocampus, caudate-putamen, thalamus, substantia nigra, and nucleus accumbens. The increases could be blocked by pretreatment with the specific noncompetitive NMDA antagonist MK-801 ((5R,10S)-( + )-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine hydrogen maleate) (0.3 mg/kg i.p.), as well by a 6-week LiCl diet sufficient to produce plasma and brain lithium concentrations known to be effective in BD. MK-801 alone reduced baseline values for k* in many brain regions. The results show that it is possible to image NMDA signaling via PLA 2 activation and AA release in vivo, and that chronic lithium blocks this signaling, consistent with its suggested mechanism of action in BD.

“…Receptors that are coupled to PLA 2 via Gproteins include muscarinic M 1,3,5 receptors, dopaminergic D 2 receptors, and 5-HT 2A/2C receptors (Axelrod, 1995;Bayon et al, 1997;Felder et al, 1990;Vial and Piomelli, 1995), whereas NMDA receptors are coupled by allowing Ca 2 þ into the cell (Lazarewicz et al, 1990;Weichel et al, 1999). The released AA and its bioactive eicosanoid metabolites can influence many physiological processes, including membrane excitability, gene transcription, apoptosis, sleep, and behavior (Fitzpatrick and Soberman, 2001;Shimizu and Wolfe, 1990).…”

Section: Introductionmentioning

confidence: 99%

Chronic Lithium Administration to Rats Selectively Modifies 5-HT2A/2C Receptor-Mediated Brain Signaling Via Arachidonic Acid

Basselin

Seemann

et al. 2004

Neuropsychopharmacol

The effects of chronic lithium administration on regional brain incorporation coefficients k* of arachidonic acid (AA), a marker of phospholipase A 2 (PLA 2 ) activation, were determined in unanesthetized rats administered i.p. saline or 1 mg/kg i.p. (7)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT 2A/2C receptor agonist. After injecting [1-14 C]AA intravenously, k* (brain radioactivity/integrated plasma radioactivity) was measured in each of 94 brain regions by quantitative autoradiography. Studies were performed in rats fed a LiCl or a control diet for 6 weeks. In the control diet rats, DOI significantly increased k* in widespread brain areas containing 5-HT 2A/2C receptors. In the LiCl-fed rats, the significant positive k* response to DOI did not differ from that in control diet rats in most brain regions, except in auditory and visual areas, where the response was absent. LiCl did not change the head turning response to DOI seen in control rats. In summary, LiCl feeding blocked PLA 2 -mediated signal involving AA in response to DOI in visual and auditory regions, but not generally elsewhere. These selective effects may be related to lithium's therapeutic efficacy in patients with bipolar disorder, particularly its ability to ameliorate hallucinations in that disease.