The p38α mitogen-activated protein kinase as a central nervous system drug discovery target

Borders, Aaron S.; Almeida, Lúcia de; Eldik, Linda J. Van; Watterson, D. Martin

doi:10.1186/1471-2202-9-s2-s12

Cited by 38 publications

(22 citation statements)

References 67 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3A). Similarly, p38α and p38β, human orthologs of Accp38b, were abundantly expressed in brain tissues, and p38α plays an important role in the central nervous system (20,21). Additionally, the expression analysis revealed that Accp38b was responsive to light (Fig.…”

Section: Discussionmentioning

confidence: 91%

Molecular characterization and immunohistochemical localization of a mitogen-activated protein kinase, Accp38b, from Apis cerana cerana

Zhang

Meng²,

Li³

et al. 2012

BMB Reports

View full text Add to dashboard Cite

The p38 mitogen-activated protein kinase (MAPK) is involved in various processes, including stress responses, development, and differentiation. However, little information on p38 MAPK in insects is available. In this study, a p38 MAPK gene, Accp38b, was isolated from Apis cerana cerana and characterized. The quantitative real-time PCR (Q-PCR) analysis revealed that Accp38b was induced by multiple stressors. Notably, the expression of Accp38b was relatively higher in the pupae phase than in other developmental phases. During the pupae phase, Accp38b expression was higher in the thorax than in the head and abdomen and higher in the fat body than in the muscle and midgut. Immunohistochemisty

show abstract

Section: Discussionmentioning

confidence: 91%

Molecular characterization and immunohistochemical localization of a mitogen-activated protein kinase, Accp38b, from Apis cerana cerana

Zhang

Meng²,

Li³

et al. 2012

BMB Reports

View full text Add to dashboard Cite

show abstract

“…Insights into the mechanisms by which p38α MAPK contributes to proinflammatory cytokine overproduction in the CNS suggest that this kinase could also be a valid target for neurological disorders (reviewed in REF. 3). For example, the p38 MAPK pathway is activated in neurons and glia in the brains of patients with early-stage Alzheimer’s disease and in rodent models of neurodegenerative disease, as assessed by staining for phosphorylated (activated) p38 MAPK.…”

Section: Examples Of Cns Protein Kinase Targetsmentioning

confidence: 99%

“…Half of the oncology pipeline are kinase inhibitors, but none of the disclosed CNS candidates seems to target protein kinases. Nevertheless, there is increasing interest in the development of kinase-targeted therapeutics for CNS indications3-11, and the established success in other disease indications provides encouragement for the development of small-molecule kinase modulators for CNS disorders.…”

mentioning

confidence: 99%

Targeting protein kinases in central nervous system disorders

Chico

Eldik

Watterson

2009

Nat Rev Drug Discov

255

198

View full text Add to dashboard Cite

Protein kinases are a growing drug target class in disorders in peripheral tissues, but the development of kinase-targeted therapies for central nervous system (CNS) diseases remains a challenge, largely owing to issues associated specifically with CNS drug discovery. However, several candidate therapeutics that target CNS protein kinases are now in various stages of preclinical and clinical development. We review candidate compounds and discuss selected CNS protein kinases that are emerging as important therapeutic targets. In addition, we analyse trends in small-molecule properties that correlate with key challenges in CNS drug discovery, such as blood-brain barrier penetrance and cytochrome P450-mediated metabolism, and discuss the potential of future approaches that will integrate molecular-fragment expansion with pharmacoinformatics to address these challenges.Protein kinases regulate diverse cellular functions through the orchestrated propagation and amplification of cellular stimuli into distinct biological responses through coordinated signal transduction cascades. With several hundred kinases encoded in the human genome, almost every signal transduction process is influenced by interconnected phosphorylation events. Deregulation of kinase activity has been implicated in various diseases, ranging from vascular disorders and inflammatory diseases to neurological disorders and cancer 1,2 . This has generated intense interest in the pursuit of protein kinases as drug targets.However, most kinase-targeted drugs and potential kinase targets that have been investigated are for non-central nervous system (CNS) disorders. CNS disease indications for kinasetargeted drugs seem to be lagging behind those for other disease areas, such as cancer (FIG. 1), and ~25% of publications related to CNS disorders are for CNS cancers. This pattern is also seen in pharmaceutical industry pipelines that are publicly disclosed. For example, Novartis, the manufacturer of the kinase inhibitor cancer therapeutics imatinib (Gleevec) and nilotinib (Tasigna), has various oncology candidates and CNS-targeted therapies in clinical development. Half of the oncology pipeline are kinase inhibitors, but none of the disclosed CNS candidates seems to target protein kinases. Nevertheless, there is increasing interest in the development of kinase-targeted therapeutics for CNS indications [3][4][5][6][7][8][9][10][11] , and the established success in other disease indications provides encouragement for the development of smallmolecule kinase modulators for CNS disorders. NIH Public Access Author ManuscriptNat Rev Drug Discov. Author manuscript; available in PMC 2010 February 19. Published in final edited form as:Nat Rev Drug Discov. 2009 November ; 8(11): 892-909. doi:10.1038/nrd2999. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThis Review focuses on the special challenge of targeting protein kinases for CNS disease indications. A recent review 2 provides an up-to-date overview of targeting protein kinases i...

show abstract

“…Taken together, our results showing the inhibition of mast cell degranulation by PGD 2 through the DP1 receptor may potentially be attributed to the activation of adenyl cyclase by the G s protein, leading to the increased production of cAMP. The p38 MAPK is known to have a role in proinflammatory cytokine production in response to various external stimuli (Saklatvala, 2004;Borders et al, 2008). We have also shown that activation of this kinase by STZ in keratinocytes can lead to nonclassical anti-inflammatory effects by the production of PGE 2 (Sur et al, 2008a).…”

Section: Discussionmentioning

confidence: 93%

Induction of Prostaglandin D2 through the p38 MAPK Pathway Is Responsible for the Antipruritic Activity of Sertaconazole Nitrate

Kaur

Sur

Liebel

et al. 2010

Journal of Investigative Dermatology

View full text Add to dashboard Cite

Prostaglandin D(2) (PGD(2)) is known to have antipruritic activity by suppressing histamine release. However, agents that can topically induce PGD(2) for itch relief are not well established. The antimycotic sertaconazole nitrate (STZ) has been shown to exhibit anti-itch properties; however, the mechanism for this activity has not been elucidated. STZ mitigated degranulation of RBL-2H3 (rat basophilic leukemia) mast cells induced by compound 48/80, a pruritogenic agent known to promote the release of histamine, and augmented PGD(2) production in mast cells and macrophages. Addition of exogenous PGD(2) abrogated compound 48/80-induced degranulation by acting through the prostanoid D receptor 1 (DP1). STZ induced p38 mitogen-activated protein kinase (MAPK) phosphorylation in mast cells and a pharmacological inhibitor of p38 MAPK, SB203580, resulted in the attenuation of PGD(2) levels. Finally, in a murine model of pruritus, the scratching behavior induced by compound 48/80 was mitigated by topical application of STZ. This effect was reversed by the addition of the cyclooxygenase inhibitor, ibuprofen, or a DP1 receptor antagonist (MK0524). Collectively, these results suggest that STZ mediates its anti-itch effects by boosting the antipruritic agent, PGD(2), by the activation of the p38-MAPK pathway. This is the first report to demonstrate a promising approach to topically induce PGD(2) for improving pruritus.

show abstract

The p38α mitogen-activated protein kinase as a central nervous system drug discovery target

Cited by 38 publications

References 67 publications

Molecular characterization and immunohistochemical localization of a mitogen-activated protein kinase, Accp38b, from Apis cerana cerana

Molecular characterization and immunohistochemical localization of a mitogen-activated protein kinase, Accp38b, from Apis cerana cerana

Targeting protein kinases in central nervous system disorders

Induction of Prostaglandin D2 through the p38 MAPK Pathway Is Responsible for the Antipruritic Activity of Sertaconazole Nitrate

Contact Info

Product

Resources

About