ArticleJournal of Alzheimer's disease : JAD2015
Selective Brain-Targeted Antagonism of p38 MAPKα Reduces Hippocampal IL-1β Levels and Improves Morris Water Maze Performance in Aged Rats.
Article in Journal of Alzheimer's disease : JAD, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 82 citations in OpenAlex.
- Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.Nature communications · 2022Trial
- A phase 2 double-blind placebo-controlled 24-week treatment clinical study of the p38 alpha kinase inhibitor neflamapimod in mild Alzheimer's disease.Alzheimer's research & therapy · 2021Trial
- Article
- Aberrant tau accumulation caused by MAPT mutations induces early pathological changes in axonal transport that are rescued by p38α inhibition.Nature neuroscience · 2026Article
- Advances in the treatment of Alzheimer's disease.Frontiers in pharmacology · 2026Review
- Neuroinflammation in Huntington's disease: Causes, consequences, and treatment strategies.Journal of Huntington's disease · 2025Review
- Neuronal p38 MAPK Signaling Contributes to Cisplatin-Induced Peripheral Neuropathy.Antioxidants (Basel, Switzerland) · 2025Article
- Shedding light on microglial dysregulation in Alzheimer's disease: exploring molecular mechanisms and therapeutic avenues.Inflammopharmacology · 2025Review
- Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy.Cell reports · 2025Article
- Network Pharmacology of miR-146a-5p as a Potential Anti-Inflammatory Agent in Preventing Alzheimer's Disease.Current Alzheimer research · 2025Article
- Endosomal traffic disorders: a driving force behind neurodegenerative diseases.Translational neurodegeneration · 2024Review
- A small molecule p38α MAPK inhibitor, MW150, attenuates behavioral deficits and neuronal dysfunction in a mouse model of mixed amyloid and vascular pathologies.Brain, behavior, & immunity - health · 2024Article
- Poly-GR repeats associated with ALS/FTD geneScience signaling · 2024Article
- Cancer drugs with high repositioning potential for Alzheimer's disease.Expert opinion on emerging drugs · 2023Review
- Inflammatory signaling pathways in the treatment of Alzheimer's disease with inhibitors, natural products and metabolites (Review).International journal of molecular medicine · 2023Review
- Review
- NF-κB Pathway and Its Inhibitors: A Promising Frontier in the Management of Alzheimer's Disease.Biomedicines · 2023Review
- Therapeutic Strategies Aimed at Improving Neuroplasticity in Alzheimer Disease.Pharmaceutics · 2023Review
- Omics-based biomarkers discovery for Alzheimer's disease.Cellular and molecular life sciences : CMLS · 2022Review
- Medicinal Herbs and Their Derived Ingredients Protect against Cognitive Decline in In Vivo Models of Alzheimer's Disease.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
1 author.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundP38 mitogen activated protein kinase (MAPK) α modulates microglia-mediated inflammatory responses and a number of neuronal physiological processes.
objectiveTo evaluate pre-clinically the pharmacological effects in the brain of p38 MAPKα inhibition with a brain-penetrant specific chemical antagonist.
methodsVX-745, a blood-brain barrier penetrant, highly selective p38 MAPKα inhibitor, and clinical stage investigational drug, was utilized. Initially, a pilot study in 26-month-old Tg2576 mice was conducted. Subsequently, a definitive dose-response study was conducted in aged (20-22 months) rats with identified cognitive deficits; n = 15 per group: vehicle, 0.5, 1.5, and 4.5 mg/kg VX-745 by oral gavage twice daily for 3 weeks. Assessments in aged rats included IL-1β, PSD-95, TNFα protein levels in hippocampus; and Morris water maze (MWM) test for cognitive performance.
resultsDrug effect could not be assessed in Tg2576 mice, as little inflammation was evident. In cognitively-impaired aged rats, VX-745 led to significantly improved performance in the MWM and significant reduction in hippocampal IL-1β protein levels, though the effects were dissociated as the MWM effect was evident at a lower dose level than that required to lower IL-1β. Drug concentration-effect relationships and predicted human doses were determined.
conclusionsSelective inhibition of p38 MAPKα with VX-745 in aged rats reduces hippocampal IL-1β levels and improves performance in the MWM. As the two effects occur at different dose levels, the behavioral effect appears to be via a mechanism that is independent of reducing cytokine production. The predicted human doses should minimize risks of systemic toxicity.
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