Group-Specific Assays That Distinguish between the Four Major Types of Mammalian Phospholipase A2

Yang, Hsiu‐Chiung; Mosior, Marian; Johnson, Chris A.; Chen, Yijun; Dennis, Edward A.

doi:10.1006/abio.1999.4053

Cited by 146 publications

(111 citation statements)

References 31 publications

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“…50,51 In the brain, these enzymes may include AA-selective calcium-dependent cytosolic PLA 2 (cPLA 2 ), calcium-dependent secretory PLA 2 (sPLA 2 ), or calcium-independent PLA 2 (iPLA 2 ). 52,53 The majority of released AA is reincorporated into brain phospholipids via one of several long-chain acyl-CoA synthetases (Acsls) 54 and an acyl transferase, 55,56 but a small portion of the released AA is b-oxidized or converted to eicosanoids via cyclooxygenase (COX)-1, COX-2, lipoxygenase, cytochrome P450 or epoxygenase. [57][58][59] Like AA, docosahexaenoic acid (DHA; 22:6nÀ3; Figure 2) is esterified in the sn-2 position of brain phospholipids.…”

Section: Overview Of the Aa Cascadementioning

confidence: 99%

“…Lithium decreases brain inositol levels, 24 but this occurs more rapidly than changes in mood, 149,150 thus a prolonged decreased inositol signaling and PLC activity may be needed to decrease cPLA 2 activity (which requires 4,5 bisphosphatidylinositol and calcium) and the turnover of AA. 52 Because PKC activity can be increased by AA, 81,83 decreased AA turnover could explain how mood stabilizers decrease PKC activity. 27 Thus far it appears that other suggested targets for lithium, carbamazepine and valproate overlap at the level of the AA cascade in the rat brain, and the hypothesis that drugs effective in bipolar disorder target the brain AA cascade is likely not exclusive of other hypothesized targets.…”

Section: Observations Related To Aa In Bipolar Disorder Patientsmentioning

confidence: 99%

“…A large number of potential compounds could be screened that selectively inhibit cPLA 2 or arachidonoyl-CoA formation in in vitro assays. 52,95,156,157 Compounds demonstrating selectivity can then be further tested by administering them to rats and measuring brain PLA 2 or Acsl activities. Candidate drugs could be tested in the unanesthetized rat turnover model for efficacy prior to clinical studies.…”

Section: Observations Related To Aa In Bipolar Disorder Patientsmentioning

confidence: 99%

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Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

et al. 2008

Mol Psychiatry

108

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Bipolar disorder is a major medical, social and economic burden worldwide. However, the mechanisms of action of effective antibipolar disorder drugs remain elusive. In this paper, we review studies using a neuropharmacological approach in unanesthetized rats, combined with kinetic, biochemical and molecular biology techniques, showing that chronic administration of three Food and Drug Administration-approved mood stabilizers (lithium, valproate and carbamazepine) at therapeutically relevant doses, selectively target the brain arachidonic acid (AA) cascade. Whereas chronic lithium and carbamazepine decrease the binding activity of activator protein-2 and in turn the transcription, translation and activity of its AA-selective calcium-dependent phospholipase A 2 gene product, valproate appears to be a non-competitive inhibitor of long-chain acyl-CoA synthetase. The net overlapping effects of the three drugs are decreased turnover of AA but not of docosahexaenoic acid in rat brain phospholipids, and decreased brain cyclooxygenase-2 and prostaglandin E 2 . Although these observations support the hypothesis proposed by Rapoport and colleagues that the AA cascade is a common target of mood stabilizers, this hypothesis is not necessarily exclusive of other targets. Targeting the AA cascade with drugs or diet may be a useful therapeutic approach in bipolar disorder, and examining the AA cascade in patients might help in better understanding the disease.

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Section: Overview Of the Aa Cascadementioning

confidence: 99%

Section: Observations Related To Aa In Bipolar Disorder Patientsmentioning

confidence: 99%

Section: Observations Related To Aa In Bipolar Disorder Patientsmentioning

confidence: 99%

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Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

et al. 2008

Mol Psychiatry

108

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“…All have been identified in neurons (Kishimoto et al, 1999;Strokin et al, 2004;Yang et al, 1999;Yegin et al, 2002). cPLA 2 has been localized at postsynaptic neuronal membranes in the brain (Basavarajappa et al, 1998;Ong et al, 1999;Pardue et al, 2003) and is activated by 300 nM to 1 mM Ca 2 + (Clark et al, 1995), in the physiological range of intracellular Ca 2 + during neuronal activation (Ismailov et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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

Basselin

Chang

Bell

et al. 2005

Neuropsychopharmacol

103

132

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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.

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“…iPLA2 exhibits no substrate specificity for AA-containing phospholipids and no Ca 2ϩ requirement for activity. Coexpression of different forms of PLA2 has been found within the same cell or tissue (1,2). The physiological functions of individual PLA2s in the hepatocyte are currently unknown (3).…”

mentioning

confidence: 99%

Role of Phospholipase A2 Activation and Calcium in CYP2E1-dependent Toxicity in HepG2 Cells

Andrés

Cederbaum

2003

Journal of Biological Chemistry

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Previous studies suggested a role for calcium in CYP2E1-dependent toxicity. The possible role of phospholipase A 2 (PLA2) activation in this toxicity was investigated. HepG2 cells that overexpress CYP2E1 (E47 cells) exposed to arachidonic acid (AA) ؉Fe-NTA showed higher toxicity than control HepG2 cells not expressing CYP2E1 (C34 cells). This toxicity was inhibited by the PLA2 inhibitors aristolochic acid, quinacrine, and PTK. PLA2 activity assessed by release of preloaded [ 3 H]AA after treatment with AA؉Fe was higher in the CYP2E1 expressing HepG2 cells. This [ 3 H]AA release was inhibited by PLA2 inhibitors, ␣-tocopherol, and by depleting Ca 2؉ from the cells (intracellular ؉ extracellular sources), but not by removal of extracellular calcium alone. Toxicity was preceded by an increase in intracellular calcium caused by influx from the extracellular space, and this was prevented by PLA2 inhibitors. PLA2 inhibitors also blocked mitochondrial damage in the CYP2E1-expressing HepG2 cells exposed to AA؉Fe. Ca 2؉ depletion and removal of extracellular calcium inhibited toxicity at early time periods, although a delayed toxicity was evident at later times in Ca 2؉ -free medium. This later toxicity was also inhibited by PLA2 inhibitors. Analogous to PLA2 activity, Ca 2؉ depletion but not removal of extracellular calcium alone prevented the activation of calpain activity by AA؉Fe. These results suggest that release of stored calcium by AA؉Fe, induced by lipid peroxidation, can initially activate calpain and PLA2 activity, that PLA2 activation is critical for a subsequent increased influx of extracellular Ca 2؉ , and that the combination of increased PLA2 and calpain activity, increased calcium and oxidative stress cause mitochondrial damage, that ultimately produces the rapid toxicity of AA؉Fe in CYP2E1-expressing HepG2 cells.Phospholipase A 2 (PLA2) 1 comprises a set of extracellular and intracellular enzymes that catalyze the hydrolysis of the sn-2

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Group-Specific Assays That Distinguish between the Four Major Types of Mammalian Phospholipase A2

Cited by 146 publications

References 31 publications

Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

Mode of action of mood stabilizers: is the arachidonic acid cascade a common target?

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

Role of Phospholipase A2 Activation and Calcium in CYP2E1-dependent Toxicity in HepG2 Cells

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