Abstract A8: LY2228820 dimesylate, a p38-MAPK inhibitor, modulates angiogenic endothelial cord formation in vitro and in vivo.

Background Local anesthetic-induced direct neurotoxicity (paresthesia, failure to regain normal sensory and motor function) is a potentially devastating complication of regional anesthesia. Local anesthetics activate the p38 mitogen-activated protein kinase (MAPK) system, which is involved in apoptotic cell death. The authors therefore investigated in vitro (cultured primary sensory neurons) and in vivo (sciatic nerve block model) the potential neuroprotective effect of the p38 MAPK inhibitor SB203580 administered together with a clinical (lidocaine) or investigational (amitriptyline) local anesthetic. Methods Cell survival and mitochondrial depolarization as marker of apoptotic cell death was assessed in rat dorsal root ganglia incubated with lidocaine or amitriptyline either with or without the addition of SB203580. Similarly, in a sciatic nerve block model, the authors assessed wallerian degeneration by light microscopy to detect a potential mitigating effect of MAPK inhibition. Results Lidocaine at 40 mm/approximately 1% and amitriptyline at 100 microm reduce neuron count, but coincubation with the p38 MAPK inhibitor SB203580 at 10 mum significantly reduces cytotoxicity and the number of neurons exhibiting mitochondrial depolarization. Also, wallerian degeneration and demyelination induced by lidocaine (600 mm/approximately 15%) and amitriptyline (10 mm/approximately 0.3%) seem to be mitigated by SB203580. Conclusions The cytotoxic effect of lidocaine and amitriptyline in cultured dorsal root ganglia cells and the nerve degeneration in the rat sciatic nerve model seem, at least in part, to be mediated by apoptosis but seem efficiently blocked by an inhibitor of p38 MAPK, making it conceivable that coinjection might be useful in preventing local anesthetic-induced neurotoxicity.

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Inhibition of p38 MAPK in the brain through nasal administration of p38 inhibitor loaded in chitosan nanocapsules

Nanomedicine ◽

10.2217/nnm-2018-0496 ◽

2019 ◽

Vol 14 (18) ◽

pp. 2409-2422 ◽

Cited By ~ 1

Author(s):

Álvaro Casadomé-Perales ◽

Laura De Matteis ◽

Maria Alleva ◽

Cristina Infantes-Rodríguez ◽

Irene Palomares-Pérez ◽

...

Keyword(s):

P38 Mapk ◽

Ex Vivo ◽

Competitive Inhibitor ◽

Nasal Administration ◽

Model Of Alzheimer’S Disease ◽

P38 Mapk Inhibitor ◽

The Brain ◽

Mapk Inhibitor

Aim: To determine whether a p38 MAPK inhibitor incorporated into nanoemulsion-based chitosan nanocapsules can reduce the activity of this kinase in the brain through their nasal administration in mice. Materials & methods: We selected the p38 MAPK inhibitor PH797804, an ATP-competitive inhibitor of p38α encapsulated in nanoemulsion-based chitosan nanocapsules. Biological effect was evaluated in microglial and neuronal cells in vitro and in ex vivo and in vivo systems, in a mouse model of Alzheimer’s disease. Results: Encapsulated inhibitor retains enzymatic inhibitory activity and tissue penetration capacity in vitro, ex vivo and in vivo. Conclusion: Nasal administration of chitosan nanocapsules can be an effective approach for brain-restricted reduction of p38 MAPK activity, thus reducing the side effects of systemic administration.

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The p38 MAPK Inhibitor SB203580 Blocks Adenosine A1 Receptor-Induced Attenuation of In Vivo Myocardial Stunning

Cardiovascular Drugs and Therapy ◽

10.1007/s10557-004-6220-4 ◽

2004 ◽

Vol 18 (6) ◽

pp. 433-440 ◽

Cited By ~ 10

Author(s):

Yukihiro Yoshimura ◽

Gentian Kristo ◽

Byron J. Keith ◽

Salik A. Jahania ◽

Robert M. Mentzer ◽

...

Keyword(s):

P38 Mapk ◽

Myocardial Stunning ◽

Adenosine A1 Receptor ◽

Adenosine A1 ◽

A1 Receptor ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

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P0143OPPOSING EFFECTS OF P38 MAPK IN PODOCYTES ON ALDOSTERONE-INDUCED GLOMERULAR INJURY IN POD-GC-A CKO MICE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0143 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

SAYAKA SUGIOKA ◽

Yukiko Kato ◽

Akira Ishii ◽

Keita Mori ◽

Keisuke Osaki ◽

...

Keyword(s):

P38 Mapk ◽

Renal Injury ◽

High Salt ◽

Glomerular Injury ◽

Podocyte Damage ◽

Foot Process ◽

Genetic Deletion ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

Abstract Background and Aims Previously, we demonstrated that uninephrectomized aldosterone-infused, high salt-fed podocyte-specific guanylyl cyclase-A (natriuretic peptide receptor 1) conditional KO (pod-GC-A cKO) mice exhibited glomerular injury and that pharmacological inhibition of p38 MAPK ameliorates podocyte damage. However, the effects of genetic deletion of p38 MAPK in podocytes of pod-GC-A cKO mice have been unclarified. Method We generated p38 MAPK(fl/fl);Nephrin-Cre (pod-p38 MAPK cKO) mice and p38 MAPK(fl/fl);GC-A(fl/fl);Nephrin-Cre (pod-p38MAPK/GC-A DKO) mice. For induction of glomerular injury, we treated them with aldosterone and high salt at 2 months of age for 3 weeks without nephrectomy (B-ALDO). In vitro, we examined the effect of p38 MAPK inhibitor in cultured human podocytes transfected with GC-A siRNA. Results B-ALDO-treated pod-p38 MAPK/GC-A DKO mice resulted in significant elevation of serum Cr (0.29 ± 0.04 mg/dl), massive albuminuria (42,660 ± 20,200 μg/mgCr) and severe foot process effacement in addition to intracapillary fibrin thrombi which indicated endothelial damage. Vehicle-treated DKO mice, B-ALDO-treated pod-GC-A cKO mice, and B-ALDO-treated pod-p38 MAPK cKO showed normal serum Cr levels (0.14 ± 0.01, 0.18 ± 0.02, 0.20 ± 0.01 mg/dl, respectively), mild increase of albuminuria (223 ± 6.5, 1,496 ± 592, 649 ± 303 μg/mgCr, respectively) and only segmental foot process effacement. Blood pressure was not elevated in either mutant mice compared with that of B-ALDO control mice. Furthermore, glomerular mRNA expressions of MCP-1, PAI-1, and FN were upregulated and that of VEGF-A was downregulated in DKO mice. In vitro, suppression of GC-A mRNA by siRNA in combination with p38 MAPK inhibitor downregulated VEGF mRNA in human cultured podocytes. Our previous works showed that pharmacological inhibition of p38 MAPK in the whole body ameliorated podocyte damage, whereas our current result showed that genetic deletion of p38 MAPK in podocytes aggravated renal injury. In order to explain the discrepancy in these results, we added an analysis of podocyte specific GC-A fl/fl p38 fl/+ cKO mice. Pod GC-A fl/fl p38 fl/+ cKO mice exhibited considerably milder renal damage than pod GC-A fl/fl p38 fl/fl double cKO mice. Conclusion Genetic complete p38 MAPK deletion in GC-A-nul podocytes exacerbated aldosterone-induced glomerular endothelial cell injury as well as podocytes, and resulted in renal dysfunction, probably through VEGF downregulation, whereas partial p38 MAPK inhibition in podocytes ameliorated aldosterone-induced glomerular injury in pod-GC-A cKO mice. These results suggest a certain level of p38 MAPK in podocytes is necessary to protect endothelial and epithelial cells from aldosterone-induced renal injury.

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Pharmacological Inhibition of p38 Mitogen-Activated Protein Kinases Affects KC/CXCL1-Induced Intraluminal Crawling, Transendothelial Migration, and Chemotaxis of NeutrophilsIn Vivo

Mediators of Inflammation ◽

10.1155/2013/290565 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Najia Xu ◽

Mokarram Hossain ◽

Lixin Liu

Keyword(s):

P38 Mapk ◽

Neutrophil Recruitment ◽

Mitogen Activated Protein Kinase ◽

Dependent Manner ◽

Mitogen Activated Protein ◽

Multistep Process ◽

Inflammatory Processes ◽

P38 Mapk Inhibitor

p38 mitogen-activated protein kinase (MAPK) signalling is critical in the pathophysiology of a variety of inflammatory processes. Leukocyte recruitment to the site of inflammation is a multistep process governed by specific signalling cascades. After adhesion in the lumen, many leukocytes crawl to optimal sites at endothelial junctions and transmigrate to extravascular tissue in a Mac-1-dependent manner. The signalling mechanisms that regulate postadhesion steps of intraluminal crawling, transmigration, and chemotaxis in tissue remain incompletely understood. The present study explored the effect of p38 MAPK inhibitor SB203580 on various parameters of neutrophil recruitment triggered by chemokine KC (CXCL1) gradient. Neutrophil-endothelial interactions in microvasculature of murine cremaster muscle were determined using intravital microscopy and time-lapsed video analysis. SB203580 (100 nM) did not change leukocyte rolling but significantly attenuated neutrophil adhesion, emigration, and transmigration and impaired the initiation of neutrophil crawling and transmigration. In response to KC chemotactic gradient, SB203580 significantly reduced the velocity of migration and chemotaxis index of neutrophils in tissue. The upregulation of Mac-1 expression in neutrophils stimulated by KC was significantly blunted by SB203580in vitro. Collectively, our findings demonstrate that pharmacological suppression of p38 MAPK significantly impairs multiple steps of neutrophil recruitmentin vivo.

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In vivo suppression of SIV-mediated immune activation by a p38 MAPK inhibitor combined with ART

Journal of Virus Eradication ◽

10.1016/s2055-6640(20)31279-6 ◽

2015 ◽

Vol 1 ◽

pp. 2

Author(s):

A. Aldovini ◽

O. Chaudhary ◽

V. Narayan ◽

R. Veazey

Keyword(s):

P38 Mapk ◽

Immune Activation ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

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IL-17A acts via p38 MAPK to increase stability of TNF-α-induced IL-8 mRNA in human ASM

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00367.2005 ◽

2006 ◽

Vol 290 (6) ◽

pp. L1283-L1290 ◽

Cited By ~ 66

Author(s):

Sheridan Henness ◽

Eveline van Thoor ◽

Qi Ge ◽

Carol L. Armour ◽

J. Margaret Hughes ◽

...

Keyword(s):

Gene Expression ◽

P38 Mapk ◽

In Vitro Study ◽

Dependent Manner ◽

Tnf Α ◽

Synthetic Function ◽

P38 Mapk Inhibitor ◽

Dependent Pathway ◽

Mapk Inhibitor

Human airway smooth muscle (ASM) plays an immunomodulatory role in asthma. Recently, IL-17A has become of increasing interest in asthma, being found at elevated levels in asthmatic airways and emerging as playing an important role in airway neutrophilia. IL-17A predominantly exerts its neutrophil orchestrating role indirectly via the induction of cytokines by resident airway structural cells. Here, we perform an in vitro study to show that although IL-17A did not induce secretion of the CXC chemokine IL-8 from ASM cells, IL-17A significantly potentiates TNF-α-induced IL-8 protein secretion and gene expression in a concentration- and time-dependent manner ( P < 0.05). Levels of IL-8 protein produced after 24 h of incubation with TNF-α were enhanced 2.7-fold in the presence of IL-17A, and conditioned media significantly enhanced neutrophil chemotaxis in vitro. As IL-17A had no effect on the activity of NF-κB, a key transcriptional regulator of IL-8 gene expression, we then examined whether IL-17A acts at the posttranscriptional level. We found that IL-17A significantly augmented TNF-α-induced IL-8 mRNA stability. Interestingly, this enhanced stability occurred via a p38 MAPK-dependent pathway. The decay of IL-8 mRNA transcripts proceeded at a significantly faster rate when cells were pretreated with the p38 MAPK inhibitor SB-203580 (−0.05763 ± 0.01964, t1/2 = 12.0 h), compared with vehicle (−0.01030 ± 0.007963, t1/2 = 67.3 h) [results are expressed as decay constant (means ± SE) and half-life ( t1/2 in h): P < 0.05]. Collectively, these results demonstrate that IL-17A amplifies the synthetic function of ASM cells, acting via a p38 MAPK-dependent posttranscriptional pathway to augment TNF-α-induced secretion of the potent neutrophil chemoattractant IL-8 from ASM cells.

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In vitro activity of P38 MAPK inhibitor-loaded particles for the long term intra-articular treatment of osteoarthritis

Annals of the Rheumatic Diseases ◽

10.1136/ard.2010.149013.26 ◽

2011 ◽

Vol 70 (Suppl 2) ◽

pp. A78-A79 ◽

Cited By ~ 1

Author(s):

J. Pradal ◽

O. Jordan ◽

C. Gabay ◽

P. A. Guerne ◽

M. C. Bagley ◽

...

Keyword(s):

P38 Mapk ◽

Vitro Activity ◽

In Vitro Activity ◽

P38 Mapk Inhibitor ◽

Mapk Inhibitor

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Mineralocorticoid Receptor Blockade Improves Insulin Sensitivity in the Rat Heart and a Possible Molecular Mechanism

Cellular Physiology and Biochemistry ◽

10.1159/000447796 ◽

2016 ◽

Vol 39 (3) ◽

pp. 860-870 ◽

Cited By ~ 4

Author(s):

Mei Wang ◽

Yongjun Li ◽

Kun Zhou ◽

Guoru Zhang ◽

Yaling Wang ◽

...

Keyword(s):

Insulin Resistance ◽

P38 Mapk ◽

Mineralocorticoid Receptor ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Mapk Inhibitor

Background/Aims: Extensive research has explored the role of aldosterone in insulin resistance. Recent evidence suggests that the mineralocorticoid receptor (MR) mediates aldosterone-induced dysregulation of cytokines, and most of this research has focused on adjustments in fat tissue and adipocytes. However, the direct effect of MR blockade on insulin resistance in cardiomyocytes remains largely unknown. In the present study, we investigated whether MR blockade improves insulin-sensitizing factors in insulin-resistant rats and attenuates the dysregulation of the aldosterone-related transport of adiponectin and glucose in cardiomyocytes and examined the underlying mechanisms. Methods: The effects of aldosterone, MR inhibitors (e.g., eplerenone), a peroxisome proliferator-activated receptor (PPAR) α agonist, and a p38 mitogen-activated protein kinase (MAPK) inhibitor on adiponectin and glucose transport were studied at the mRNA and protein levels in vitro and in vivo. Results: Our data revealed that aldosterone reduced the expression of adiponectin and inhibited the transport of glucose in cardiomyocytes and that MR blockade reversed these affects. In vivo, MR blockade improved insulin-sensitive parameters and increased adiponectin expression in the myocardia of high-fat diet rats. Furthermore, aldosterone promoted p38MAPK expression but negatively affected PPARα expression, and the downregulation of adiponectin by aldosterone was reversed by MR blockade, a PPARα agonist, and a p38 MAPK inhibitor. Conclusion: The above results suggested that aldosterone promoted insulin resistance in the heart and that this effect could be partly reversed by MR blockade through signal transduction in the P38 MAPK pathway and PPARα.

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