Inhibition of Phospholipase

Blackwell, G.J.; Flower, Roderick J.

doi:10.1093/oxfordjournals.bmb.a071830

Cited by 221 publications

(87 citation statements)

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“…Quinacrine is known to block PLA 2 activity by forming complexes with phospholipids that then cannot serve as PLA 2 substrates (19), and inhibits NMDA-mediated arachidonic acid release from neurons (20,21). Because dexamethasone can block PLA 2 either by inducing synthesis of PLA 2 -inhibiting compounds, annexins, or by direct inhibition of PLA 2 synthesis (22), our studies indicate that PLA 2 activation subsequently to NMDAreceptor stimulation increases COX-2 expression.…”

Section: Discussionmentioning

confidence: 72%

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Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N -methyl- d -aspartic acid-receptors and phospholipase A ₂

Miettinen

Fusco

Yrjänheikki

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

271

170

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Repetitive spreading depression (SD) waves, involving depolarization of neurons and astrocytes and upregulation of glucose consumption, is thought to lower the threshold of neuronal death during and immediately after ischemia. Using rat models for SD and focal ischemia we investigated the expression of cyclooxygenase-1 (COX-1), the constitutive form, and cyclooxygenase-2 (COX-2), the inducible form of a key enzyme in prostaglandin biosynthesis and the target enzymes for nonsteroidal anti-inf lammatory drugs. Whereas COX-1 mRNA levels were undetectable and uninducible, COX-2 mRNA and protein levels were rapidly increased in the cortex, especially in layers 2 and 3 after SD and transient focal ischemia. The cortical induction was reduced by MK-801, an N-methyl-D-aspartic acid-receptor antagonist, and by dexamethasone and quinacrine, phospholipase A 2 (PLA 2 ) inhibiting compounds. MK-801 acted by blocking SD whereas treatment with PLA 2 inhibitors preserved the wave propagation. NBQX, an ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid͞kainate-receptor antagonist, did not affect the SD-induced COX-2 expression, whereas COXinhibitors indomethacin and diclofenac, as well as a NO synthase-inhibitor, N G -nitro-L-arginine methyl ester, tended to enhance the COX-2 mRNA expression. In addition, ischemia induced COX-2 expression in the hippocampal and perifocal striatal neurons and in endothelial cells. Thus, COX-2 is transiently induced after SD and focal ischemia by activation of N-methyl-D-aspartic acid-receptors and PLA 2 , most prominently in cortical neurons that are at a high risk to die after focal brain ischemia.

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Section: Discussionmentioning

confidence: 72%

“…This hypothesis is supported by reports that COX (15,16) and phospholipase A 2 (PLA 2 ) inhibitors (17) reduce hippocampal damage in global ischemia. We studied the regulation of COX-2 mRNA and protein in the rat brain using a model of transient focal ischemia and a KCl model of SD.…”

mentioning

confidence: 66%

Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N -methyl- d -aspartic acid-receptors and phospholipase A ₂

Miettinen

Fusco

Yrjänheikki

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

271

170

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“…As shown in Fig. 1, the addition of 5 mm quinacrine (PLA 2 inhibitor) [26], 0´5 mm NMMA (NOS inhibitor) [27], or`1000 U/ml SOD 1 900 U/ml catalase' (scavengers of O 2 2 and H 2 O 2 , respectively), significantly accelerated the growth of the organisms in IFN-g-activated macrophages (P , 0´01; Student's ttest). The same result was obtained for unstimulated macrophages (data not shown).…”

Section: Resultsmentioning

confidence: 80%

Comparative roles of free fatty acids with reactive nitrogen intermediates and reactive oxygen intermediates in expression of the anti-microbial activity of macrophages againstMycobacterium tuberculosis

Akaki

Tomioka²,

Shimizu³

et al. 2000

Clinical and Experimental Immunology

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SUMMARYWe assessed the role of free fatty acids (FFA) in the expression of the activity of macrophages against Mycobacterium tuberculosis in relation to the roles of two major anti-microbial effectors, reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI). Intracellular growth of M. tuberculosis residing inside macrophages was accelerated by treatments of macrophages with either quinacrine (phospholipase A 2 (PLA 2 ) inhibitor), arachidonyl trifuloromethylketone (type IV cytosolic PLA 2 inhibitor), N G -monomethyl-l-arginine (nitric oxide synthase inhibitor), and superoxide dismutase plus catalase (ROI scavengers). In addition, M. tuberculosis-infected macrophages produced and/or secreted these effectors sequentially in the order ROI (0±3 h), FFA (0±48 h), and RNI (3 to at least 72 h). Notably, membranous FFA (arachidonic acid) of macrophages translocated to M. tuberculosis residing in the phagosomes of macrophages in phagocytic ability-and PLA 2 -dependent fashions during cultivation after M. tuberculosis infection. FFA, RNI and H 2 O 2 -mediated halogenation system (H 2 O 2 -halogenation system) displayed strong activity against M. tuberculosis in cell-free systems, while ROI alone exerted no such effects. Combinations of`FFA 1 RNI' and`RNI 1 H 2 O 2 -halogenation system' exhibited synergistic and additive effects against M. tuberculosis, respectively, while`FFA 1 H 2 O 2 -halogenation system' had an antagonistic effect. Moreover, a sequential attack of FFA followed by RNI exerted synergistic activity against M. tuberculosis. Since M. tuberculosis-infected macrophages showed simultaneous production of RNI with FFA secretion for relatively long periods (approx. 45 h) and prolonged RNI production was seen thereafter, RNI in combination with FFA appear to play critical roles in the manifestation of the activity of macrophages against M. tuberculosis.

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“…Arachidonic acid similarly mimics the effect of FMRFamide on the presynaptic sensory neurons, modulating three different K+ conductances (Piomelli et al, 1987;Critz et al, 1991). However, the present evidence for a second messenger function for arachidonic acid in the LFS neurons is only suggestive since, in addition to its inhibitory effects on phospholipase A,, 4-bromophenacyl bromide has been demonstrated to have nonspecific effects in a variety of systems (see Blackwell and Flower, 1983, for review).…”

Section: Discussionmentioning

confidence: 80%

FMRFamide produces biphasic modulation of the LFS motor neurons in the neural circuit of the siphon withdrawal reflex of Aplysia by activating Na+ and K+ currents

Belkin

Abrams

1993

J. Neurosci.

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The molluscan neuropeptide FMRFamide has an inhibitory effect on transmitter release from the presynaptic sensory neurons in the neural circuit for the siphon withdrawal reflex. We have explored whether FMRFamide also acts postsynaptically in motor neurons in this circuit, focusing on the LFS motor neurons. FMRFamide typically produces a biphasic response in LFS neurons: a fast excitatory response followed by a prolonged inhibitory response. We have analyzed these postsynaptic actions and compared them with the mechanism of FMRFamide's inhibition of the presynaptic sensory neurons. The transient excitatory effect of FMRFamide, which desensitizes rapidly, is due to activation of a TTX- insensitive, Na(+)-dependent inward current. The late hyperpolarizing phase of the FMRFamide response results from activation of at least two K+ currents. One component of the hyperpolarizing response is active at rest and at more hyperpolarized membrane potentials, and is blocked by 5 mM 4-aminopyridine, suggesting that it differs from the previously described FMRFamide-modulated K+ currents in the presynaptic sensory neurons. In addition, FMRFamide increases a 4-aminopyridine-insensitive K+ current. Presynaptically, FMRFamide increases K+ conductance, acting via release of arachidonic acid. In the LFS motor neurons, application of arachidonic acid mimicked the prolonged, hyperpolarizing phase of the FMRFamide response; 4-bromophenacyl bromide, an inhibitor of phospholipase A2, selectively blocked this component of the FMRFamide response. Thus, FMRFamide may act in parallel pre- and post- synaptically to inhibit the output of the siphon withdrawal reflex circuit, producing this inhibitory effect via the same second messenger in the sensory neurons and motor neurons, though a number of the K+ currents modulated in these two types of neurons are different.

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Inhibition of Phospholipase

Cited by 221 publications

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Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N -methyl- d -aspartic acid-receptors and phospholipase A ₂

Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N -methyl- d -aspartic acid-receptors and phospholipase A ₂

Comparative roles of free fatty acids with reactive nitrogen intermediates and reactive oxygen intermediates in expression of the anti-microbial activity of macrophages againstMycobacterium tuberculosis

FMRFamide produces biphasic modulation of the LFS motor neurons in the neural circuit of the siphon withdrawal reflex of Aplysia by activating Na+ and K+ currents

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Inhibition of Phospholipase

Cited by 221 publications

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Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N -methyl- d -aspartic acid-receptors and phospholipase A 2

Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N -methyl- d -aspartic acid-receptors and phospholipase A 2

Comparative roles of free fatty acids with reactive nitrogen intermediates and reactive oxygen intermediates in expression of the anti-microbial activity of macrophages againstMycobacterium tuberculosis

FMRFamide produces biphasic modulation of the LFS motor neurons in the neural circuit of the siphon withdrawal reflex of Aplysia by activating Na+ and K+ currents

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Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N -methyl- d -aspartic acid-receptors and phospholipase A ₂

Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N -methyl- d -aspartic acid-receptors and phospholipase A ₂