Evidence for a direct inhibitory effect of glucocorticoids on the activity of phospholipase A2 as a further possible liechanism of some actions of steroidal anti-inflammatory drugs

Mentz, P; Giessler, C; Förster, W

doi:10.1016/s0031-6989(80)80085-3

Cited by 20 publications

(6 citation statements)

References 32 publications

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“…Most studies have shown the absence of a direct inhibitory effect of glucocorticoids, such as dexamethasone, on soluble PLA2 [30,31]. Only those studies using the sodium phosphate salt of dexamethasone were able to show a direct inhibitory effect [33,34]. However, it is apparent from our study that the "direct" inhibition of PLA2 activity is factitious and attributable to removal of calcium by formation of calcium phosphate complexes.…”

Section: Discussioncontrasting

confidence: 58%

“…Corticosteroids are thought to be indirect inhibitors of PLA2 by induction of the synthesis and release of a family ofphospholipase-inhibitory proteins [32,33]. As well, steroids inhibit the extracellular secretion of PLA2 from activated macrophages in vitro [32,34] and in vivo [1] subsequent to endotoxin challenge. Most studies have shown the absence of a direct inhibitory effect of glucocorticoids, such as dexamethasone, on soluble PLA2 [30,31].…”

Section: Discussionmentioning

confidence: 99%

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Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

1986

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Soluble phospholipase A2 has been implicated in the pathogenesis of local and systemic inflammatory reactions. Elevated levels of circulating phospholipase A2 (PLA2) correlate with the severity of circulatory collapse and pulmonary dysfunction in gram-negative septic shock. Characterization of septic shock serum PLA2 revealed a calcium-dependent enzyme with absolute 2-acyl specificity with a pH optimum of 7.5. We tested a number of therapeutic agents for their ability to inhibit PLA2 from human septic shock serum. Chloroquine, chlorpromazine, dexamethasone base, dexamethasone sodium phosphate, indomethacin, lidocaine, oleic acid, palmitic acid, promethazine, trans-retinoic acid, rutin and dl-alpha-tocopherol were all studied over the range of 10(-2) to 10(-7) M. All agents, with the sole exception of dexamethasone base, inhibited PLA2 activity at concentrations greater than 10(-3) M. PLA2 inhibition by dexamethasone sodium phosphate was factitious, due to the formation of calcium-phosphate complexes. Of the 11 agents studied, chlorpromazine was the most effective, with an IC50 of 7.5 X 10(-5) M, a membrane concentration achievable within its therapeutic range. Inhibition was non-competitive with an apparent Ki of 5 nM. Since serum PLA2 levels correlate with mortality in both experimental endotoxemia and clinical gram-negative septic shock, and chlorpromazine was previously shown to improve survival in these conditions, we postulate that its therapeutic efficacy resides at least in part in its PLA2-inhibitory activity.

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Section: Discussioncontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

1986

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“…Methylprednisolone, a corticosteroid, was demonstrated in a pig model to reduce nucleus pulposus-induced effects on nerve root function dramatically if administered intravenously in high doses within 48 h [32]. The pharmacological mechanisms in high-dose steroid treatment are complex and not yet fully understood [16], but they include inhibition of phospholipase A2 activation [27], prostaglandin synthesis [7], and physical stabilization of membranes [2].…”

Section: Discussionmentioning

confidence: 99%

Nucleus pulposus-induced nerve root injury: effects of diclofenac and ketoprofen

et al. 2001

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IntroductionSpinal nerve root injury can be induced by chronic compression and/or the presence of nucleus pulposus [1, 3, 4, 5,20,21,22,26,31,32,33,34,35,36,37,38,39,46,52]. It has been demonstrated experimentally that epidurally applied autologous nucleus pulposus, without any compression, can induce significant changes in nerve root morphology and function in animal models [4, 5,21,22,31,34,35]. Nucleus pulposus has been demonstrated to have inflammatogenic properties [33] and abundant macrophages and interleukin-1β immunoreactive cells have been demonstrated in human disc hernias, suggesting an active inflammation [11, 13]. Inflammatory mechanisms have been suggested to be of pathogenetic significance in sciatAbstract Main problem. Nucleus pulposus and/or chronic compression can induce spinal nerve root injury. Inflammation has been proposed as having major importance in the pathophysiologic mechanisms involved in the induction of such injuries. Corticosteroids, potent anti-inflammatory drugs, have been demonstrated to reduce nucleus pulposusinduced spinal nerve root injury. The aim of the present study was to assess the effects of two potent nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac and ketoprofen, in experimental nucleus pulposus-induced spinal nerve root injury in a pig model. Methods. Eighteen pigs were included in the study. Autologous nucleus pulposus was harvested from a lumbar disc and applied locally around the first sacral nerve root after a partial laminectomy of the first and second sacral vertebrae. Six pigs were treated with daily intramuscular injections of diclofenac, 3 mg/kg body weight, for 7 days. Six other pigs were treated with daily intramuscular injections of ketoprofen, 4 mg/kg body weight, for 7 days. As controls, six pigs received injections with physiologic saline. After 7 days, the pigs were reanesthetized and the nerve conduction velocity over the exposed nerve root area was determined. Results. The nerve conduction velocity was significantly higher in pigs treated with diclofenac than in the salinetreated controls, (57±6 m/s vs 38± 18 m/s, P<0.05, Student's t-test). The velocity in pigs treated with ketoprofen, 42±24 m/s, did not differ significantly from that of controls. Conclusions. This study of two potent NSAIDs indicates that nucleus pulposus-induced nerve root dysfunction may be reduced by diclofenac but not by ketoprofen. The reason for this difference is not known, but it might be related to the fact that ketoprofen and diclofenac belong to different NSAID subgroups and have a different selectivity for the two cyclo-oxygenases COX-1 and COX-2.

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“…The glucocorticoids are also capable of affecting cell-free enzyme activities, e.g. phospholipase A 2 [49] and cyclic AMP phosphodiesterase 150, 51]. The ability to inhibit the latter enzyme may explain the augmentation by hydrocortisone of re sponses to adenylate cyclase agonists of human polymorphonuclear leukocytes [22], rat mast cells [52,53], and guinea pig lung [91.…”

Section: Discussionmentioning

confidence: 99%

Influence of glucocorticoids on histamine release and45Calcium uptake by isolated rat mast cells

Grosman

Jensen

1984

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Hydrocortisone and prednisolone inhibited the histamine release from isolated rat mast cells induced by antigen, the ionophore A23187, and compound 48/80 in the absence and in the presence of calcium. Hydrocortisone reduced the response to the different releasing agents by 50% in the concentration range 2-6 X 10(-4) M, whereas prednisolone was about 1.5 times more potent. The inhibitory effect of hydrocortisone had a rapid onset of action and maximal inhibition was observed after preincubation for 20 minutes. The effect of hydrocortisone was reversed by including 2 mM glucose in the medium. The reversal was only partial with antigen and the ionophore A23187, indicating a greater energy requirement of these releasing agents compared with compound 48/80. The inhibition of the histamine release was accompanied by a concentration-related inhibition of the 45Ca uptake, except with the ionophore. The inhibition of the 45Ca uptake was also reversed by glucose, but differences were noted concerning the influence of preincubation time. The observations are explained by an association of 45Ca to cellular material, e.g. granules, secondary to the release process. The effects of hydrocortisone and prednisolone were qualitatively identical and were not observed with estriol. The glucocorticoid inhibition of histamine release does not seem to be caused by effects on phospholipase activity or cyclic AMP metabolism. The present observations are fully consistent with an impaired mitochondrial function as the mechanism for the mast cell effects of the glucocorticoids.

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Evidence for a direct inhibitory effect of glucocorticoids on the activity of phospholipase A2 as a further possible liechanism of some actions of steroidal anti-inflammatory drugs

Cited by 20 publications

References 32 publications

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock

Nucleus pulposus-induced nerve root injury: effects of diclofenac and ketoprofen

Influence of glucocorticoids on histamine release and45Calcium uptake by isolated rat mast cells

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