Is p38 MAPK Associated to Drugs of Abuse-Induced Abnormal Behaviors?

The family members of the mitogen-activated protein kinases (MAPK) mediate a wide variety of cellular behaviors in response to extracellular stimuli. p38 MAPKs are key signaling molecules in cellular responses to external stresses and regulation of pro-inflammatory cytokines. Some studies have suggested that p38 MAPK in the region of the nucleus accumbens is involved in abnormal behavioral responses induced by drugs of abuse. In this review, we discuss the role of the p38 MAPK in the rewarding effects of drugs of abuse. We also summarize the implication of p38 MAPK in stress, anxiety, and depression. We opine that p38 MAPK activation is more closely associated to stress-induced aversive responses rather than drug effects per se, in particular cocaine. p38 MAPK is only involved in cocaine reward, predominantly when promoted by stress. Downstream substrates of p38 that may contribute to the p38 MAPK associated-behavioral responses are proposed. Finally, we suggest p38 MAPK inhibitors as possible therapeutic interventions against stress-related disorders by potentially increasing resilience against stress and addiction relapse induced by adverse experiences.

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The Expanding Role of p38 Mitogen-Activated Protein Kinase in Programmed Host Cell Death

Microbiology Insights ◽

10.1177/1178636119864594 ◽

2019 ◽

Vol 12 ◽

pp. 117863611986459 ◽

Cited By ~ 4

Author(s):

Jessica Gräb ◽

Jan Rybniker

Keyword(s):

Protein Kinase ◽

Host Cell ◽

P38 Mapk ◽

Bacterial Infections ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Host Cell Apoptosis ◽

Mitogen Activated Protein ◽

P38 Mapk Inhibitors ◽

Mapk Inhibitors

The p38 mitogen-activated protein kinase (MAPK) is involved in a multitude of essential cellular processes. The kinase is activated in response to environmental stresses, including bacterial infections and inflammation, to regulate the immune response of the host. However, recent studies have demonstrated that pathogens can manipulate p38 MAPK signaling for their own benefit to either prevent or induce host cell apoptosis. In addition, there is evidence demonstrating that p38 MAPK is a potent trigger of pathogen-induced necrosis driven by mitochondrial membrane disruption. Given the large number of p38 MAPK inhibitors that have been tested in clinical trials, these findings provide an opportunity to repurpose these drugs for improved control of infectious diseases.

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Peripheral Injection of SB203580 Inhibits the Inflammatory-Dependent Synthesis of Proinflammatory Cytokines in the Hypothalamus

BioMed Research International ◽

10.1155/2014/475152 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 19

Author(s):

Andrzej P. Herman ◽

Agata Krawczyńska ◽

Joanna Bochenek ◽

Hanna Antushevich ◽

Anna Herman ◽

...

Keyword(s):

Gene Expression ◽

P38 Mapk ◽

Proinflammatory Cytokines ◽

Inflammatory Diseases ◽

Competitive Inhibitor ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

P38 Mapk Inhibitors ◽

Mapk Inhibitors ◽

P38 Mapk Inhibitor

The study was designed to determine the effects of peripheral injection of SB203580 on the synthesis of interleukin- (IL-) 1β, IL-6, and tumor necrosis factor (TNF)αin the hypothalamus of ewes during prolonged inflammation. Inflammation was induced by the administration of lipopolysaccharide (LPS) (400 ng/kg) over 7 days. SB203580 is a selective ATP-competitive inhibitor of the p38 mitogen-activated protein kinase (MAPK), which is involved in the regulation of proinflammatory cytokines IL-1β, IL-6 and TNFαsynthesis. Intravenous injection of SB203580 successfully inhibited (P<0.01) synthesis of IL-1βand reduced (P<0.01) the production of IL-6 in the hypothalamus. The p38 MAPK inhibitor decreased (P<0.01) gene expression of TNFαbut its effect was not observed at the level of TNFαprotein synthesis. SB203580 also reduced (P<0.01) LPS-stimulated IL-1 receptor type 1 gene expression. The conclusion that inhibition of p38 MAPK blocks LPS-induced proinflammatory cytokine synthesis seems to initiate new perspectives in the treatment of chronic inflammatory diseases also within the central nervous system. However, potential proinflammatory effects of SB203580 treatment suggest that all therapies using p38 MAPK inhibitors should be introduced very carefully with analysis of all expected and unexpected consequences of treatment.

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Characterization and inhibition of a p38-like mitogen-activated protein kinase (MAPK) from Echinococcus multilocularis: Antiparasitic activities of p38 MAPK inhibitors

Biochemical Pharmacology ◽

10.1016/j.bcp.2008.08.020 ◽

2008 ◽

Vol 76 (9) ◽

pp. 1068-1081 ◽

Cited By ~ 51

Author(s):

Verena Gelmedin ◽

Rocio Caballero-Gamiz ◽

Klaus Brehm

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Echinococcus Multilocularis ◽

Mitogen Activated Protein Kinase ◽

Mitogen Activated Protein ◽

P38 Mapk Inhibitors ◽

Mapk Inhibitors

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p38 mitogen-activated protein kinase mediates adenosine-induced alterations in myocardial glucose utilization via 5′-AMP-activated protein kinase

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01121.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. H1978-H1985 ◽

Cited By ~ 26

Author(s):

Jagdip S. Jaswal ◽

Manoj Gandhi ◽

Barry A. Finegan ◽

Jason R. B. Dyck ◽

Alexander S. Clanachan

Keyword(s):

Protein Kinase ◽

P38 Mapk ◽

Glucose Utilization ◽

Glycogen Synthesis ◽

Mitogen Activated Protein Kinase ◽

Transient Ischemia ◽

Mitogen Activated Protein ◽

P38 Mapk Inhibitors ◽

Ampk Activity ◽

Mapk Inhibitors

Adenosine-induced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis and by increases in activity of adenosine 5′-monophosphate-activated protein kinase (AMPK). Because p38 mitogen-activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors SB202190 and SB203580 on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2 × 10-min ischemia followed by 5-min reperfusion). Phosphorylation of AMPK and p38 MAPK each were increased fourfold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580 occurred independently of any change in tissue ATP-to-AMP ratio and did not alter glucose uptake, but it was accompanied by an increase in glycogen synthesis and glycogen content and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.

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Drugs Designed To Inhibit Human p38 Mitogen-Activated Protein Kinase Activation Treat Toxoplasma gondii and Encephalitozoon cuniculi Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00680-07 ◽

2007 ◽

Vol 51 (12) ◽

pp. 4324-4328 ◽

Cited By ~ 20

Author(s):

Shuang Wei ◽

Benjamin J. Daniel ◽

Michael J. Brumlik ◽

Matthew E. Burow ◽

Weiping Zou ◽

...

Keyword(s):

Protein Kinase ◽

Toxoplasma Gondii ◽

P38 Mapk ◽

Human Fibroblasts ◽

Mitogen Activated Protein Kinase ◽

Encephalitozoon Cuniculi ◽

Mapk Activation ◽

Mitogen Activated Protein ◽

P38 Mapk Inhibitors ◽

Mapk Inhibitors

ABSTRACT We recently showed that the pyridinylimidazoles SB203580 and SB202190, drugs designed to block human p38 mitogen-activated protein kinase (MAPK) activation, also inhibited replication of the medically important intracellular parasite Toxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellular T. gondii replication in vitro and protect mice against fatal T. gondii infection. Mice surviving infection following treatment with p38 MAPK inhibitors were resistant to subsequent T. gondii challenge, demonstrating induction of protective immunity. Thus, drugs originally developed to block human p38 MAPK activation are useful for treating T. gondii infection without inducing significant immunosuppression. MAPK inhibitors combined with either of the approved anti-Toxoplasma drugs sulfadiazine and pyrimethamine resulted in improved survival among mice challenged with a fatal T. gondii inoculum. A MAPK inhibitor also treated mice infected with the Microsporidium parasite Encephalitozoon cuniculi, suggesting that MAPK inhibitors represent a novel class of agents that may have a broad spectrum of antiparasitic activity. Preliminary studies implicate a T. gondii MAPK homologue as the target of drug action, suggesting possibilities for more-selective agents.

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Neurotoxicity of Lidocaine Involves Specific Activation of the p38 Mitogen-activated Protein Kinase, but Not Extracellular Signal–regulated or c-jun N-Terminal Kinases, and Is Mediated by Arachidonic Acid Metabolites

Anesthesiology ◽

10.1097/00000542-200611000-00025 ◽

2006 ◽

Vol 105 (5) ◽

pp. 1024-1033 ◽

Cited By ~ 34

Author(s):

Ingrid Haller ◽

Barbara Hausott ◽

Bettina Tomaselli ◽

Christian Keller ◽

Lars Klimaschewski ◽

...

Keyword(s):

Arachidonic Acid ◽

P38 Mapk ◽

Ganglion Cells ◽

Time Dependent ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

P38 Mapk Inhibitors ◽

Mapk Inhibitors

Background Pharmacologic inhibition of the p38 mitogen-activated protein kinase (MAPK) leads to a reduction in lidocaine neurotoxicity in vitro and in vivo. The current study investigated in vitro the hypotheses that lidocaine neurotoxicity is specific for dorsal root ganglion cells of different size or phenotype, involves time-dependent and specific activation of the p38 MAPK, that p38 MAPK inhibitors are only effective if applied with local anesthetic, and that p38 MAPK activation triggers activation of lipoxygenase pathways. Methods The authors used primary sensory neuron cultures and pheochromocytoma cell line cultures to detect time-dependent activation of the p38 MAPK or related pathways such as extracellular signal-regulated kinases and c-jun N-terminal kinases. Cells were divided by size or by immunoreactivity for calcitonin gene-related peptide or isolectin B4, indicative of nociceptive phenotype. The authors also investigated whether arachidonic acid pathways represent a downstream effector of the p38 MAPK in local anesthetic-induced neurotoxicity. Results All types of dorsal root ganglion cells were subject to neurotoxic effects of lidocaine, which were mediated by specific activation of the p38 MAPK but not extracellular signal-regulated kinases or c-jun N-terminal kinases. Neuroprotective efficacy of p38 MAPK inhibitors declined significantly when administered more than 1 h after lidocaine exposure. Activation of p38 MAPK preceded activation of arachidonic acid pathways. Neurotoxicity of lidocaine, specific activation of p38 MAPK, and neuroprotective effects of a p38 MAPK inhibitor were further confirmed in pheochromocytoma cell line cultures. Conclusions Specific and time-dependent activation of the p38 MAPK is involved in lidocaine-induced neurotoxicity, most likely followed by activation of lipoxygenase pathways.

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