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Published on: September 27, 2020
p38 MAP kinase inhibitors as potential therapeutic drugs for neural diseases
S Yasuda1, H Sugiura, H Tanaka
1Department of Neuropharmacology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo, Japan. yasuda-sn@igakuken.or.jp
Abstract:
Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by various cellular stresses, as well as in response to inflammatory cytokines. In the central nervous systems (CNS), activation of the p38 MAPK pathway constitutes a key step in the development of several diseases, and the molecular mechanisms mediated by p38 MAPK signaling have been defined. Activation of this cascade releases pro-inflammatory cytokines that are known to be involved in cerebral ischemia, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), neuropathic pain and depression. In AD, stimulated p38 MAPK may trigger the hyperphosphorylation of a neural microtubule-associated protein, tau. In addition, we have recently revealed that activation of p38 MAPK signaling decreases dendritic spine number, which may be associated with memory impairment after epileptic seizures. Thus, p38 MAPK can serve as a target for novel drug development for neural diseases. p38 MAPK inhibitors have been studied extensively in both preclinical experiments and clinical trials for inflammatory diseases. New p38 MAPK inhibitors are now being tested in phase II clinical trials for neuropathic pain and depression. Here, we review current and possible future applications of p38 MAPK inhibitors as therapeutic agents in neural diseases.
Insights
p38 mitogen-activated protein kinases (MAPKs) are involved in numerous neural diseases. Inhibitors targeting this pathway show promise for treating conditions like Alzheimer's, Parkinson's, and neuropathic pain.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- p38 mitogen-activated protein kinases (MAPKs) are activated by cellular stress and inflammatory cytokines.
- The p38 MAPK pathway plays a critical role in the central nervous system (CNS) and is implicated in various neurological disorders.
Purpose of the Study:
- To review the current and potential therapeutic applications of p38 MAPK inhibitors in treating neural diseases.
- To highlight the molecular mechanisms of p38 MAPK signaling in CNS disorders.
Main Methods:
- Literature review of preclinical and clinical studies on p38 MAPK inhibitors.
- Analysis of the role of p38 MAPK in neuroinflammation and neurodegeneration.
Main Results:
- p38 MAPK activation is linked to pro-inflammatory cytokine release, contributing to diseases such as cerebral ischemia, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), neuropathic pain, and depression.
- In AD, p38 MAPK may induce tau hyperphosphorylation, and in epilepsy, it can decrease dendritic spine number, potentially causing memory impairment.
- p38 MAPK inhibitors are under investigation and in clinical trials for inflammatory and neurological conditions.
Conclusions:
- p38 MAPK represents a significant therapeutic target for a range of neural diseases.
- Further research and clinical trials are warranted to explore the full potential of p38 MAPK inhibitors in CNS therapeutics.
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