MAPK inhibitors

Cytokines Corticosteroid MAPK inhibitors Humanized antibodies Antisense oligonucleotides Soluble receptors... 

FIGURE 3.13 Decrease in the volume of the cerebral infarct induced by middle cerebral artery occlusion in the rat following oral administration of a mitogen-activated protein kinase (MAPK) inhibitor. Source Redrawn from Barone et p < 0.05 p < 0.01)... 

Fig. 2 (continued) (g) reverse transcriptase inhibitors (160 compounds) (h) serine protease inhibitors (531 compounds) (i) p38 MAPK inhibitors (100 compounds) (j) histamine receptor antagonists (168 compounds) (k) lipoxygenase inhibitors (114 compounds) (I) serine/threonine kinase inhibitors (120 compounds). 

FIGURE 31.6 Effect of different MAPK inhibitors on the palytoxin-induced calcium influx in cultured neurons. Cerebellar granule cells were exposed to 10 nM palytoxin in the presence or absence of different MAPK inhibitors and the cytosolic calcium concentration was monitored with the fluorescent calcium indicator Fura-2 AM. 

Several studies have shown that PMN production of cytokines during microbial stimulation requires activation of MAPK. Using specific MAPK inhibitors, neutrophil IL-8 production in response to LPS, Mycoplasma fermentans membrane lipoproteins, type III group B streptococci, as well as TNF-a and GM-CSF was found to be dependent upon p38 MAPK [22-24,33]. The ERKl/2 and p38 MAPK are also involved in LPS andM. fermentans membrane lipoprotein-stimulated IL-8 production, as determined by inhibitor studies with PD98059 and SB203580 [22]. 

The MAPK-Dependent Mechanisms. The MAPK-depen-dent mechanisms can be activated by PKC which phosphory-lates the Raf protein, an important kinase of the MARK cascade (1). PLC and PKC can stimulate PGF release by bovine endometrial cells (3), rabbit amnion cells, and hamster ovary cells (9) via the MAPK-dependent pathway. In porcine granulosa cells, the MAPK blocker PD98059 did not affect basal PGF and PGE secretion. Nevertheless, GH, a stimulator of both PGF and PGE, increased the accumulation of MAPK (ERK1,2) in porcine granulosa cells, whereas the MAPK inhibitor PD98059 prevented a stimulatory action of GH on the release of these PG (12). Thus, MAPK can be a mediator of GH action on PG release, but the involvement of MAPK in basal PG secretion should not be excluded. 

The modulation of neutrophil recruitment might also be targeted indirectly, for the chemotactic responses of these cells are relatively sensitive to alterations within the stress-induced p38 mitogen-activated protein (MAP) kinase cascade (49). A number of recent publications have highlighted a potential therapeutic role for inhibitors of this pathway in airway disease (49-51). Preadministration of the p38 MAPK inhibitors before LPS intratracheal challenge in mice reduced the numbers of neutrophils in the airway. This effect was not due to a reduction in the levels of these chemokines following p38 MAPK inhibition. Nick and... 

Underwood DC, Osborn RR, Bochnowicz S, Webb EF, Rieman DJ, Lee JC, Romanic AM, Adams JL, Hay DW, Griswold DE. SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung. Am J Physiol Lung Cell Mol Physiol 2000 279 L895-902. 

Koch L, Hofer S, Weigand MA, Frommhold D, Poeschl J, Ruef P. Inhibition of LPS-induced activation of coagulation by p38 MAPK inhibitor. ISRN Hematol. 2012 762614. doi 10.5402/2012/76614. 

It was demonstrated that mitogen-activated protein kinases (MAPKs) were critically involved in the cytotoxicity of CA-4 [50]. CA-4 stimulated both extracellular signal-regulated kinases (ERKl/2) and p38 MAPK in the BEL-7402 hepatocellular carcinoma cell line in a time- and dose-dependent manner. This stimulation was a result of CA-4-induced microtubule disassembly, a reversible process. In authors opinion, these data indicated that p38 MAPK is a potential anticancer target and that the combination of CA-4 with p38 MAPK inhibitors may be a novel and promising strategy for cancer therapy. 

The discovery of the novel p38 MAPK inhibitor is the first at that time, at least within the realm of published journals. It is worth noting that the spatial encoding method is conceptually similar to Harbury s DNA routing, despite in which the DNA encoding by DNA happens before the spatial separation and chemical reaction. 

---