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

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 A selective p38α/β MAPKs inhibitor alleviates neuropathology and cognitive impairment, and modulates 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 ◽  
Cognitive Impairment ◽  
In Vitro Studies ◽  
Therapeutic Effects ◽  
Mitogen Activated Protein ◽  
5Xfad Mice ◽  
Ad Therapy ◽  
P38 Mapks

Abstract Background: Chronic neuroinflammation, aggressive amyloid beta (Aβ) deposition, neuronal cell loss, and cognitive impairment are pathological presentations of Alzheimer’s disease (AD). Therefore, resolution of neuroinflammation and inhibition of Aβ-driven pathology have been suggested to be important strategies for AD therapy. Previous efforts to prevent AD progression have identified p38 mitogen-activated protein kinases (MAPKs) as a promising target for AD therapy. Recent studies showed pharmacological inhibition of p38α MAPK improved memory impairment in AD mouse models. Methods: In this study, we used an AD mouse model, 5XFAD, to explore the therapeutic potential of NJK14047 which is a novel, selective p38α/β MAPKs inhibitor. The mice were injected with 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, respectively. In vitro studies were conducted to measure the cytotoxicity of microglia- and astrocyte-conditioned medium on primary neurons using the MTT assay and TUNEL assay. Results: NJK14047 treatment downregulated phospho-p38 MAPK levels, decreased the amount of Aβ deposits, and reduced spatial learning memory loss in 9-month-old 5XFAD mice. While the pro-inflammatory conditions were decreased, the expression of alternatively activated microglial markers and microglial phagocytic receptors was increased. Furthermore, NJK14047 treatment reduced the number of degenerating neurons labeled with Fluoro-jade B in the brains of 5XFAD mice. The neuroprotective effect of NJK14047 was further confirmed by in vitro studies. Conclusion: Taken together, a selective p38α/β MAPKs inhibitor NJK14047 successfully showed therapeutic effects for AD in 5XFAD mice. Based on our data, p38 MAPKs inhibition is a potential strategy for AD therapy, suggesting NJK14047 as one of the promising candidates for AD therapeutics targeting p38 MAPKs. Keywords : Alzheimer’s disease, Amyloid-β, P38 mitogen-activated protein kinase, Kinase inhibitor, Microglia

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.

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.

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 The Proto-oncoprotein Brx Activates Estrogen Receptor β by a p38 Mitogen-activated Protein Kinase Pathway

2001 ◽  
Vol 276 (50) ◽  
pp. 46792-46797 ◽  
Author(s):  
Paul H. Driggers ◽  
James H. Segars ◽  
Domenica M. Rubino
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Active Form ◽  
Mitogen Activated Protein Kinase ◽  
The Novel ◽  
Mapk Activity ◽  
Dependent Activity ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

The estrogen receptors (ERs) are ligand-inducible transcription factors that play key roles in the control of growth and differentiation in reproductive tissues. We showed that the novel Dbl family proto-oncoprotein Brx enhances ligand-dependent activity of ERα via a Cdc42-dependent pathway. Brx also significantly enhances ligand-dependent activity of ERβ. This enhancement is not affected by inhibition of p44/42 mitogen-activated protein kinase (MAPK) activation by PD98059. However, addition of the p38 MAPK inhibitor SB202190 abrogates the enhancement of ERβ activity by Brx, showing that p38 MAPK activity is required for the enhancement of ERβ function by Brx. In COS-7 cells, transfection of Brx leads to activation of endogenous p38 MAPK activity. Co-expression of the β2 isoform of human p38 MAPK and a constitutively active form of the p38 MAPK kinase MKK6 (MKK6-EE) synergistically augments ligand-dependent activity of ERβ. Our findings suggest that p38 MAPKs may be important regulators of ERβ activity.

Role of p38/MAPKs in Alzheimer’s disease: implications for amyloid beta toxicity targeted therapy

2018 ◽  
Vol 30 (1) ◽  
pp. 9-30 ◽  
Author(s):  
Ghazaleh Kheiri ◽  
Mahsa Dolatshahi ◽  
Farzaneh Rahmani ◽  
Nima Rezaei
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
P38 Mapk ◽  
Amyloid Beta ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Green Tea Polyphenols ◽  
Glutamate Excitotoxicity

AbstractA myriad of environmental and genetic factors, as well as the physiologic process of aging, contribute to Alzheimer’s disease (AD) pathology. Neuroinflammation is and has been a focus of interest, as a common gateway for initiation of many of the underlying pathologies of AD. Amyloid beta (Aβ) toxicity, increasing RAGE expression, tau hyperphosphorylation, induction of apoptosis, and deregulated autophagy are among other mechanisms, partly entangled and being explained by activation of mitogen-activated protein kinase (MAPK) and MAPK signaling. p38 MAPK is the most essential regulator of Aβ induced toxicity from this family. p38 induces NF-κB activation, glutamate excitotoxicity, and disruption of synaptic plasticity, which are other implications of all justifying the p38 MAPK as a potential target to break the vicious Aβ toxicity cycle. Until recently, manyin vivoandin vitrostudies have investigated the effects of p38 MAPK inhibitors in AD. The pyridinyl imidazole compoundsSB202190andSB203580have shown promising anti-apoptotic resultsin vivo. MW108inhibits activation of p38 and is able to postpone cognitive decline in animal models. ThePD169316, with anti-inflammatory, anti-oxidative, and anti-apoptotic features, has improved spatial memoryin vivo. Natural compounds fromCamellia sinensis(green tea), polyphenols from olive oil, pinocembrin from propolis, and the puerarine extract isoflavones, have shown strong anti-apoptotic features, mediated by p38 MAPK inhibition. Use of these drug targets is limited due to central nervous system side effects or cross-reactivity with other kinases, predicting the low efficacy of these drugs in clinical trials.

scholarly journals A selective p38α/β MAPKs 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 ◽  
Cognitive Impairment ◽  
Conditioned Medium ◽  
In Vitro Studies ◽  
Therapeutic Effects ◽  
5Xfad Mice ◽  
Ad Therapy ◽  
P38 Mapks

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 one of the important strategies for AD therapy. Previous efforts to prevent AD progression have identified that p38 mitogen-activated protein kinase (MAPK) is a promising target for AD therapy. Especially, recent studies showed that pharmacological p38α MAPK inhibition improved memory impairment in AD mouse models. Methods: In this study, we explored the therapeutic potential of NJK14047, a selective p38α/β MAPKs 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 respectively. 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 prevented spatial learning memory loss in 9-month-old 5XFAD mice. Interestingly, we found the decreased pro-inflammatory conditions and increased expression of alternatively activated microglial markers and microglial phagocytic receptors. 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 was further confirmed by in vitro studies. Conclusion: Taken together, a selective p38α/β MAPKs inhibitor NJK14047 successfully showed therapeutic effects in 5XFAD mice. Our data support that p38 MAPKs inhibition is a potential strategy for AD therapy and NJK14047 might be one of the promising candidates for AD therapeutics targeting p38 MAPKs.

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