Mitigation of Direct Neurotoxic Effects of Lidocaine and Amitriptyline by Inhibition of p38 Mitogen-activated Protein Kinase In Vitro  and In Vivo 

2006 ◽  
Vol 104 (6) ◽  
pp. 1266-1273 ◽  
Author(s):  
Philipp Lirk ◽  
Ingrid Haller ◽  
Robert R. Myers ◽  
Lars Klimaschewski ◽  
Yi-Chuan Kau ◽  
...  
Keyword(s):  
Sciatic Nerve ◽  
P38 Mapk ◽  
Local Anesthetic ◽  
Apoptotic Cell ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

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.

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

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
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.

scholarly journals A selective p38 MAPK inhibitor alleviates neuropathology and cognitive impairment by modulating microglia function in 5XFAD mouse

2020 ◽  
Author(s):  
Min Sung Gee ◽  
Seung Hwan Son ◽  
Seung Ho Jeon ◽  
Jimin Do ◽  
Namkwon Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
5Xfad Mice ◽  
Ad Therapy ◽  
Mapk Inhibitor

Abstract Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss and cognitive impairment are pathological symptoms of Alzheimer’s disease (AD). Regarding these symptoms, resolution of neuroinflammation and inhibition of Aβ-driven pathology might be a novel strategy for AD therapy. Efforts to prevent AD progression have identified that p38 mitogen-activated protein kinase (MAPK) is a promising target for AD therapy. However, the actual therapeutic effect of selective p38 MAPK inhibition in AD has not been ascertained yet. Methods: In this study, we explored the therapeutic potential of NJK14047, a selective p38 MAPK inhibitor, using an Alzheimer’s disease mouse model, 5XFAD. The mice were injected 2.5 mg/kg NJK14047 or vehicle every other day for 3 months. Morris water maze task and histological imaging analysis were performed. Protein and mRNA expression levels were measured using immunoblotting and qRT-PCR. In in vitro studies, the cytotoxicity of microglial conditioned medium and astrocyte conditioned medium on primary neurons were measured using MTT assay and TUNEL assay. Results: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and improved spatial learning memory in 5XFAD mice. Interestingly, these effects were associated with the decrease of inflammatory responses and the elevation of alternatively activated M2 markers. Furthermore, NJK14047 treatment reduced the number of Fluoro-jade B positive cells, a class of degenerating neurons, in the brains of 5XFAD mice. The neuroprotective effect of NJK14047, achieved via the restoration of microglia function, was further confirmed by in vitro studies. Conclusion: Taken together, our results reveal that inhibition of p38 MAPK in the brain alleviates AD pathology and represents a potential strategy for AD therapy. It also suggests that NJK14047 is a promising candidate for AD treatment. Keywords : Alzheimer’s disease, Amyloid-β, P38 mitogen-activated protein kinase, Kinase inhibitor, Microglia

Phosphorylation of Argonaute 2 at serine-387 facilitates its localization to processing bodies

2008 ◽  
Vol 413 (3) ◽  
pp. 429-436 ◽  
Author(s):  
Yan Zeng ◽  
Heidi Sankala ◽  
Xiaoxiao Zhang ◽  
Paul R. Graves
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Processing Bodies ◽  
Mitogen Activated Protein

Ago (Argonaute) proteins are essential effectors of RNA-mediated gene silencing. To explore potential regulatory mechanisms for Ago proteins, we examined the phosphorylation of human Ago2. We identified serine-387 as the major Ago2 phosphorylation site in vivo. Phosphorylation of Ago2 at serine-387 was significantly induced by treatment with sodium arsenite or anisomycin, and arsenite-induced phosphorylation was inhibited by a p38 MAPK (mitogen-activated protein kinase) inhibitor, but not by inhibitors of JNK (c-Jun N-terminal kinase) or MEK [MAPK/ERK (extracellular-signal-regulated kinase) kinase]. MAPKAPK2 (MAPK-activated protein kinase-2) phosphorylated bacterially expressed full-length human Ago2 at serine-387 in vitro, but not the S387A mutant. Finally, mutation of serine-387 to an alanine residue or treatment of cells with a p38 MAPK inhibitor reduced the localization of Ago2 to processing bodies. These results suggest a potential regulatory mechanism for RNA silencing acting through Ago2 serine-387 phosphorylation mediated by the p38 MAPK pathway.

scholarly journals Inhibition of LPS-Induced Activation of Coagulation by p38 MAPK Inhibitor

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Lutz Koch ◽  
Stefan Hofer ◽  
Markus A. Weigand ◽  
David Frommhold ◽  
Johannes Poeschl ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Sandwich Elisa ◽  
Mitogen Activated Protein Kinase ◽  
Toll Like Receptor ◽  
Inhibitory Effects ◽  
Coagulation Activation ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

During Gram-negative sepsis, lipopolysaccharide (LPS) activates toll-like receptor (TLR) 4 and induces complex responses of immune system and coagulation. However, the underlying LPS signalling mechanism on coagulation activation remains complex. To determine the role of the intracellular signalling factors p38 mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), and c-Jun N-terminal kinase (JNK) in the procoagulant response to LPS, coagulation process of human whole blood exposed to specific inhibitors was measured by thrombelastography. Samples were stimulated with LPS (100 μg/mL) after preincubation with BAY117082 (specific NF-κB inhibitor), SP600125 (specific JNK inhibitor), SB203580 (specific p38 MAPK inhibitor), or vehicle. SB203580 strongly inhibited LPS-induced coagulation activation, whereas BAY117082 and SP600125 showed no significant effect. Activation of p38 MAPK, NF-κB, and JNK and respective inhibitory effects were confirmed by Multi-Target Sandwich ELISA. In conclusion, activation of p38 MAPK is crucial for early LPS-induced activation of coagulation.

BIRB796 Inhibits p38 MAPK/Hsp27 Pathway and Enhances Cytotoxicity Triggered by Bortezomib, Hsp90 Inhibitor, and Dexamethasone in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3440-3440
Author(s):  
Hiroshi Yasui ◽  
Teru Hideshima ◽  
Hiroshi Ikeda ◽  
Janice Jin ◽  
Enrique M. Ocio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
P38 Mapk ◽  
Inhibitory Effect ◽  
Hsp90 Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Hsp27 Phosphorylation ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

Abstract We have previously shown that heat shock protein (Hsp) 27 or its upstream molecule p38 mitogen-activated protein kinase (MAPK) confers resistance to bortezomib and dexamethasone (Dex) in multiple myeloma (MM). In this study, we evaluate the anti-tumor activity of combination treatment with novel p38 MAPK inhibitor BIRB796 and other therapeutics agents in MM. Although BIRB796 alone triggers a marginal growth inhibitory effect in MM cells, it blocked baseline and bortezomib-triggered upregulated phosphorylation of p38 MAPK and Hsp27, associated with enhanced cytotoxicity in combination with bortezomib. BIRB796 augmented bortezomib- triggered cleavage of caspase-8, caspase-9, and poly(ADP)-ribose polymerase (PARP). We next examined the combination of BIRB796 with Hsp90 inhibitor 17-AAG. Surprisingly, 17-AAG up-regulates protein expression and phosphorylation of Hsp27; conversely, BIRB796 inhibits this phosphorylation and enhances 17-AAG-induced cytotoxicity. Importantly, BIRB796 enhances cytotoxicity induced by 17-AAG plus bortezomib. BIRB796 also augments cytotoxicity of Dex in MM cells, associated with inhibition of Hsp27 phosphorylation. In bone marrow stromal cells (BMSCs), BIRB796 inhibited phosphorylation of p38 MAPK and secretion of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) triggered by either tumor necrosis factor-α or tumor growth factor-β 1. BIRB796 also inhibits IL-6 secretion in BMSCs triggered by adherence to MM cells, thereby inhibiting MM cell proliferation. These studies therefore suggest that BIRB796 overcomes drug-resistance in the BM microenvironment, providing the framework for clinical trials of a p38 MAPK inhibitor alone, and in combination with bortezomib, Hep90 inhibitor, or Dex, to improve patient outcome in MM.

scholarly journals Flumequine-Mediated Upregulation of p38 MAPK and JNK Results in Melanogenesis in B16F10 Cells and Zebrafish Larvae

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 596 ◽  
Author(s):  
Wisurumuni Arachchilage Hasitha Maduranga Karunarathne ◽  
Ilandarage Menu Neelaka Molagoda ◽  
Myung Sook Kim ◽  
Yung Hyun Choi ◽  
Matan Oren ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Melanin Content ◽  
Melanin Pigmentation ◽  
Zebrafish Larvae ◽  
B16f10 Cells ◽  
Mitogen Activated Protein

Flumequine is a well-known second generation quinolone antibiotic that induces phototoxicity. However, the effect of flumequine on skin melanogenesis is unclear. Therefore, we, for the first time, investigated whether flumequine regulates melanogenesis. The present study showed that flumequine slightly inhibited in vitro mushroom tyrosinase activity but significantly increased extracellular and intracellular melanin content in B16F10 cells and promoted the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. Additionally, flumequine remarkably increased melanin pigmentation in zebrafish larvae without any toxicity. We also found that flumequine stimulated p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation; inhibition of p38 MAPK and JNK resulted in significant downregulation of extracellular and intracellular melanin content in B16F10 cells and pigmentation of zebrafish larvae accompanied with suppression of MITF and tyrosinase expression, indicating that flumequine-mediated p38 and JNK promote melanogenesis in vitro and in vivo. According to the molecular docking prediction, flumequine targeted dual-specificity MAPK phosphatase 16 (DUSP16), which is a major negative regulator of p38 MAPK and JNK. Our findings demonstrate that flumequine induces an increase in melanin content in B16F10 cells and zebrafish larvae by activating p38 MAPK and JNK. These data show the potential of flumequine for use as an anti-vitiligo agent.

An Inhibitor of p38 Mitogen-Activated Protein Kinase Abrogates Procoagulant and Proinflammatory Effects of Antiphospholipid Antibodies In Vivo.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 136-136
Author(s):  
Silvia S. Pierangeli ◽  
Mariano E. Vega-Ostertag ◽  
Xiaowei Liu
Keyword(s):  
Protein Kinase ◽  
Carotid Artery ◽  
P38 Mapk ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Peritoneal Cells ◽  
Mitogen Activated Protein ◽  
Pre Treatment

Abstract Background: Activation of p38 mitogen-activated protein kinase (p38 MAPK) has been shown to play a fundamental role in antiphospholipid-induced up regulation of tissue factor (TF) expression and function in monocytes and in endothelial cells (ECs) and increased expression of intercellular adhesion molecule -1 (ICAM-1) in vitro. Those effects correlate with the thrombogenic and pro-inflammatory effects of aPL in vivo. However, It is not clear whether aPL-induceTF in vivo. Methods: To examine this question, we treated CD1 male mice, in groups of 4, with IgG from 3 patients with Antiphospholipid Syndrome (IgG-APS) or with control IgG from healthy controls (IgG-NHS), twice. Seventy-two hours after the first injection, the adhesion of leukocytes per capillary venule (#WBC) to EC in cremaster muscle (as an indication of EC activation in vivo), as well the size of an induced thrombus in the femoral vein of the mice were examined. Some mice were infused i.p. with 25 mg/kg of SB203580 (a p38 MAPK-specific inhibitor) 30 minutes prior to the each IgG-APS injection. TF activity was determined using a chromogenic assay that measures the conversion of factor X into Factor Xa, in homogenates of carotid artery, and in peritoneal cells of mice treated with IgG-APS or with IgG-NHS. Expression of TF and ICAM-1 was determined by cyto-ELISA on cultured HUVECs after treatment of the cells with IgG-APS or with IgG-NHS. Results: At the time of the surgical procedures, the mean aCL titer in the sera of the mice injected with IgG-APS was 73 ± 34 GPL. In vivo, IgG-APS increased significantly the #WBC adhering to EC, when compared to control mice (5.25 ± 0.96 vs 1.85 ± 0.72) and these effects were significantly reduced (2.1 ± 0.74), when mice were pre-treated with SB203580. IgG-APS increased significantly the thrombus size when compared to IgG-NHS-treated mice (3189 ± 558 μm2 vs 1468 ± 401 μm2) and SB203580 inhibited this effect by 65%. Treatment of the mice with IgG-APS also induced significantly increased TF function in peritoneal cells and in homogenates of carotid artery when compared to IgG-NHS-treated mice (17.5 ±11.1 pM vs. 0.8 ±0.2 pM and 8.31 ± 1.59 vs 0.69 ± 0.03, respectively). Pre-treatment of the mice with SB203580 abrogated completely those effects (0.61 ± 0.06 pM in peritoneal cells and 0.75 ± 0.28 pM in carotid artery preparations of mice treated with IgG-APS). Significant expression of TF and ICAM-1 was observed in vitro when HUVECs were treated with any of the three IgG-APS. TF upregulation and ICAM-1 expression were significantly reduced by pre-treatment of the cells with SB203580 (49–97% for TF and 25–69% for ICAM-1). Conclusions: The data show that IgG-APS up regulates TF function in vivo, and this correlates with an in vivo pro-inflammatory and pro-thrombotic effect. Importantly, those effects were abrogated in vivo by a p38 MAPK specific inhibitor. These findings may be important in designing new modalities of targeted therapies to treat thrombosis in patients with APS.

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

Nanomedicine ◽  
2019 ◽  
Vol 14 (18) ◽  
pp. 2409-2422 ◽  
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.

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

2016 ◽  
Vol 39 (3) ◽  
pp. 860-870 ◽  
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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