p38 MAPK-IN-2

Mechanisms and functions of p38 MAPK signalling

The p38 MAPK (mitogen-activated protein kinase) signalling pathway allows cells to interpret a wide range of external signals and respond appropriately by generating a plethora of different biological effects. The diversity and specificity in cellular outcomes is achieved with an apparently simple linear architecture of the pathway, consisting of a core of three protein kinases acting sequentially. In the present review, we dissect the molecular mechanisms underlying p38 MAPK functions, with special emphasis on the activation and regulation of the core kinases, the interplay with other signalling pathways and the nature of p38 MAPK substrates as a source of functional diversity. Finally, we discuss how genetic mouse models are facilitating the identification of physiological functions for p38 MAPKs, which may impinge on their eventual use as therapeutic targets.

Involvement of p38 MAPK in Synaptic Function and Dysfunction

Many studies have revealed a central role of p38 MAPK in neuronal plasticity and the regulation of long-term changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). However, p38 MAPK is classically known as a responsive element to stress stimuli, including neuroinflammation. Specific to the pathophysiology of Alzheimer's disease (AD), several studies have shown that the p38 MAPK cascade is activated either in response to the Aβ peptide or in the presence of tauopathies. Here, we describe the role of p38 MAPK in the regulation of synaptic plasticity and its implication in an animal model of neurodegeneration. In particular, recent evidence suggests the p38 MAPK α isoform as a potential neurotherapeutic target, and specific inhibitors have been developed and have proven to be effective in ameliorating synaptic and memory deficits in AD mouse models.

p38(MAPK): stress responses from molecular mechanisms to therapeutics

The p38(MAPK) protein kinases affect a variety of intracellular responses, with well-recognized roles in inflammation, cell-cycle regulation, cell death, development, differentiation, senescence and tumorigenesis. In this review, we examine the regulatory and effector components of this pathway, focusing on their emerging roles in biological processes involved in different pathologies. We summarize how this pathway has been exploited for the development of therapeutics and discuss the potential obstacles of targeting this promiscuous protein kinase pathway for the treatment of different diseases. Furthermore, we discuss how the p38(MAPK) pathway might be best exploited for the development of more effective therapeutics with minimal side effects in a range of specific disease settings.

The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer

Background: The p38 mitogen-activated protein kinase (MAPK) is activated by various pro-inflammatory and stressful stimuli. Mounting evidence suggests that the p38 MAPK signaling cascade is involved in various biological responses other than inflammation such as cell proliferation, differentiation, apoptosis and invasion, suggesting that the p38 MAPK can serve as a potential therapeutic target for the treatment of not only inflammatory diseases but also cancer.
Methods: The unique characteristics of p38 MAPK are summarized with regard to activation and function of p38 MAPK signaling cascades. We then discuss the involvement of p38 MAPK in diseases and the implications of the possible therapeutic use of p38 MAPK inhibitors. The p38 MAPK inhibitors that have been used in the in vitro/in vivo systems as well as in the clinical trials are summarized.
Results/conclusion: The p38 MAPK plays an important role in key cellular processes related to inflammation and cancer. Understanding the signal transduction mechanisms and gene regulation by p38 MAPK provides useful information in the development of p38 MAPK inhibitors with therapeutic benefits with reduced side effects. In this review, we summarize and present the list of p38 MAPK inhibitors in in vitro/in vivo studies as well as in clinical trials.

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer's Disease

P38 mitogen-activated protein kinase (MAPK) is a crucial target for chronic inflammatory diseases. Alzheimer's disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain, as well as neurodegeneration, and there is no known cure. Recent studies on the underlying biology of AD in cellular and animal models have indicated that p38 MAPK is capable of orchestrating diverse events related to AD, such as tau phosphorylation, neurotoxicity, neuroinflammation and synaptic dysfunction. Thus, the inhibition of p38 MAPK is considered a promising strategy for the treatment of AD. In this review, we summarize recent advances in the targeting of p38 MAPK as a potential strategy for the treatment of AD and envision possibilities of p38 MAPK inhibitors as a fundamental therapeutics for AD.