Attenuation of lipopolysaccharide fever in rats by protein kinase C inhibitors

1997 ◽  
Vol 273 (3) ◽  
pp. R873-R879 ◽  
Author(s):  
W. Kozak ◽  
J. J. Klir ◽  
C. A. Conn ◽  
M. J. Kluger
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Inhibitory Effect ◽  
Limiting Factor ◽  
Antipyretic Effect ◽  
Pkc Inhibitor ◽  
Protein Kinase C Inhibitors ◽  
Kinase C ◽  
Freely Moving ◽  
Rate Limiting

The purpose of this study was to assess the effects of inhibitors of protein kinase C (PKC) on lipopolysaccharide (LPS)-induced fever and changes in circulating interleukin-6 (IL-6) levels in freely moving biotelemetered rats. We used PKC inhibitors with different inhibition constants (Ki): H-7 (Ki = 6 microM) and chelerythrine (Chel; Ki = 0.66 microM; a more potent PKC inhibitor). Rats were injected subcutaneously with either 3 or 15 microM/kg of these inhibitors and then 1 h later were injected intraperitoneally with LPS (50 micrograms/kg). Blood samples for IL-6 bioassay were collected 4 h after LPS injection. H-7 at lower doses did not significantly affect fever and LPS-induced elevation of circulating IL-6, whereas at a higher dose (15 microM/kg) H-7 reduced both fever and the increase of IL-6 (analysis of variance, Scheffe's test, P < 0.05). Chel (3 and 15 microM/kg) significantly reduced fever and almost completely inhibited the LPS-induced elevation of plasma IL-6. In separate experiments, we studied the effect of H-7 on antipyresis due to dexamethasone (Dex). Dex at a dose of 0.6 microM/kg given subcutaneously 1 h before LPS partially prevented fever (approximately 55% inhibition) and attenuated the increase of IL-6 (P < 0.05). Simultaneous pretreatment of the rats with Dex and H-7 (3 microM/kg; a dose that did not affect fever and IL-6 elevation) led to a potentiation of the antipyretic effect of Dex, resulting in no fever. H-7 did not potentiate, however, the inhibitory effect of Dex on LPS-induced elevation of circulating IL-6. We conclude that PKC is involved in the regulation of LPS fever and constitutes a rate-limiting factor in modulation of the fever by glucocorticoids.

scholarly journals Protein kinase C-dependent and -independent mechanisms regulating the parotid substance P receptor as revealed by differential effects of protein kinase C inhibitors

1988 ◽  
Vol 256 (2) ◽  
pp. 677-680 ◽  
Author(s):  
H Sugiya ◽  
J W Putney
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Substance P ◽  
Time Course ◽  
Phorbol Esters ◽  
Inhibitory Effect ◽  
Protein Kinase C Inhibitors ◽  
Kinase C ◽  
Substance P Receptor ◽  
Rat Parotid

Substance P-induced inositol trisphosphate (InsP3) formation was inhibited by 1 microM-4 beta-phorbol 12,13-dibutyrate (PDBu) in rat parotid acinar cells. The inhibitory effect of PDBu was reversed by the protein kinase C inhibitors H-7 or K252a. Substance P also elicits a persistent desensitization of subsequent substance P-stimulated InsP3 formation. However, this desensitization was not inhibited by H-7. In addition, H-7 had no effect on the time course of substance P-induced InsP3 formation. These results suggest that, although activation of protein kinase C by phorbol esters can inhibit the substance P receptor-linked phospholipase C pathway, this mechanism apparently plays little, if any, role in regulating this system after activation by substance P.

Arachidonate activation of protein kinase C may be involved in the stimulation of protein synthesis by insulin in L6 myoblasts

1993 ◽  
Vol 13 (6) ◽  
pp. 359-366 ◽  
Author(s):  
Michael G. Thompson ◽  
Fiona Acamovic ◽  
Steven C. Mackie ◽  
Kenneth S. Morrison ◽  
Robert M. Palmer
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Inhibitory Effect ◽  
Pkc Inhibitor ◽  
Lipase Inhibitor ◽  
Kinase C ◽  
Arachidonoyl Glycerol ◽  
Arachidonate Release ◽  
Stimulation Of

Insulin stimulated protein synthesis in L6 myoblasts but did not increase the labelling of DAG or the release of phosphocholine from phosphatidylcholine. The DAG lipase inhibitor, RHC 80267, more than doubled the amount of label appearing in DAG but did not stimulate protein synthesis. Even in the presence of the DAG lipase inhibitor insulin failed to have any effect on DAG labelling, and conversely RHC 80267 did not modify the insulin-induced increase in protein synthesis. These results suggest that endogenous DAG production is not involved in the stimulation of protein synthesis by insulin. However, exogenous diacylglycerols (1-oleoyl-2-acetyl glycerol and 1-stearoyl-2-arachidonoyl glycerol) both stimulated protein synthesis in L6 myoblasts. The efficacy of the former (arachidonatefree) DAG suggested that their action was by activation of protein kinase C rather than by arachidonate release and prostaglandin formation. Ibuprofen, an inhibitor of cyclo-oxygenase failed to block the effects of insulin whereas a second cyclo-oxygenase inhibitor, indomethacin had only a partial inhibitory effect. The protein kinase C (PKC) inhibitor, RO-31-8220, totally blocked the effect of insulin. Since indomethacin is also recognised to inhibit phospholipase A2, the data suggests that insulin acts on protein synthesis in myoblasts by arachidonate activation of PKC.

scholarly journals Lycopene depresses glutamate release through inhibition of voltage-dependent Ca2+ entry and protein kinase C in rat cerebrocortical nerve terminals

2018 ◽  
Vol 96 (5) ◽  
pp. 479-484 ◽  
Author(s):  
Cheng-Wei Lu ◽  
Chi-Feng Hung ◽  
Wei-Horng Jean ◽  
Tzu-Yu Lin ◽  
Shu-Kuei Huang ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Glutamate Release ◽  
Inhibitory Effect ◽  
Nerve Terminals ◽  
Protein Kinase C Inhibitors ◽  
Kinase C ◽  
Protein Kinase C Activity ◽  
Voltage Dependent ◽  
Intracellular Ca

Lycopene is a natural dietary carotenoid that was reported to exhibit a neuroprotective profile. Considering that excitotoxicity and cell death induced by glutamate are involved in many brain disorders, the effect of lycopene on glutamate release in rat cerebrocortical nerve terminals and the possible mechanism involved in such effect was investigated. We observed here that lycopene inhibited 4-aminopyridine (4-AP)-evoked glutamate release and intrasynaptosomal Ca2+ concentration elevation. The inhibitory effect of lycopene on 4-AP-evoked glutamate release was markedly reduced in the presence of the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was insensitive to the intracellular Ca2+-release inhibitors dantrolene and CGP37157. Furthermore, in the presence of the protein kinase C inhibitors GF109203X and Go6976, the action of lycopene on evoked glutamate release was prevented. These results are the first to suggest that lycopene inhibits glutamate release from rat cortical synaptosomes by suppressing presynaptic Ca2+ entry and protein kinase C activity.

Duality of plasmin effect on cytosolic free calcium in human platelets

1995 ◽  
Vol 268 (4) ◽  
pp. C958-C967 ◽  
Author(s):  
K. Nakamura ◽  
M. Kimura ◽  
J. W. Fenton ◽  
T. T. Andersen ◽  
A. Aviv
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Free Calcium ◽  
Protein Kinase C Inhibitors ◽  
Kinase C ◽  
Small Rise

Plasmin caused a modest and gradual increase in platelet cytosolic Ca2+, mediated through both Ca2+ mobilization and external Ca2+ entry. This response was associated with accelerated Ca2+ extrusion and protein tyrosine phosphorylation. Plasmin-enhanced external Ca2+ entry and Ca2+ extrusion (but not Ca2+ mobilization) were attenuated by the tyrosine kinase inhibitor, genistein. Plasmin inhibited the thrombin-evoked increase in cytosolic Ca2+ and also inhibited the Ca2+ response to the tethered peptide TRAP-6 of the thrombin receptor. Furthermore, plasmin inhibited the binding of 125I-labeled alpha-thrombin to platelets. The inhibitory effect of plasmin on the thrombin response shared some characteristics with the effect of protein kinase C stimulators but was not reversed by protein kinase C inhibitors. Plasmin did not change platelet cyclic nucleotides. These results suggest a dual effect of plasmin. Plasmin produces a small rise in platelet cytosolic Ca2+ and a tyrosine kinase-dependent enhancement of Ca2+ turnover (external Ca2+ influx and Ca2+ efflux). However, it also attenuates the thrombin-evoked cytosolic Ca2+ response by blocking Ca2+ mobilization and slowing the rate of external Ca2+ influx. The latter feature would result in a plasmin-induced inhibition of thrombogenesis.

scholarly journals N-Acetylcysteine and α-cyano-4-hydroxycinnamic acid alter protein kinase C (PKC)-δ and PKC-ζ and diminish dysmorphogenesis in rat embryos cultured with high glucose in vitro

2007 ◽  
Vol 192 (1) ◽  
pp. 207-214 ◽  
Author(s):  
Mattias Gäreskog ◽  
Parri Wentzel
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
High Glucose ◽  
Culture Medium ◽  
Hydroxycinnamic Acid ◽  
Oxygen Species ◽  
Rat Embryos ◽  
Protein Kinase C Inhibitors ◽  
Kinase C

Malformations and growth disturbances are two- to threefold more common in infants of diabetic mothers than in offspring of non-diabetic pregnancy. Several suggestions have emerged to explain the reasons for diabetic embryopathy, including enhanced mitochondrial production of reactive oxygen species leading to altered activation of protein kinase C. This study aimed to evaluate the effect of α-cyano-4-hydroxycinnamic acid (CHC) and N-acetylcysteine (NAC) addition on morphology and activity of protein kinase C-δ and protein kinase C-ζ in rat embryos exposed to a high glucose concentration in vitro. Day 9 embryos from normal rats were cultured in 10 or 30 mM glucose concentrations with or without supplementation of CHC, NAC, or protein kinase C inhibitors specific for protein kinase C-δ and protein kinase C-ζ. Embryos were evaluated for malformations, crown rump length, and somite number. Protein kinase C-δ and protein kinase C-ζ activities were estimated by western blot by separating membranous and cytosolic fractions of the embryo. We found increased malformations and growth retardation in embryos cultured in high versus low glucose concentrations. These abnormalities were diminished when CHC and NAC or specific protein kinase C-inhibitors were added to the culture medium. The activities of embryonic protein kinase C-δ and protein kinase C-ζ were increased in the high glucose environment after 24-h culture, but were normalized by the addition of CHC and NAC as well as respective inhibitor to the culture medium. These findings suggest that mitochondrial overproduction of reactive oxygen species is involved in diabetic embryopathy. Furthermore, such overproduction may affect embryonic development, at least partly, by enhancing the activities of protein kinase C-δ and protein kinase C-ζ.

scholarly journals Protein kinase C inhibitors for immune disorders

2014 ◽  
Vol 19 (8) ◽  
pp. 1217-1221 ◽  
Author(s):  
Amnon Altman ◽  
Kok-Fai Kong
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Immune Disorders ◽  
Protein Kinase C Inhibitors ◽  
Kinase C
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