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Updated: Sep 29, 2025
Assessment of Vascular Tone Responsiveness using Isolated Mesenteric Arteries with a Focus on Modulation by Perivascular Adipose Tissues
Published on: June 3, 2019
Neflamapimod induces vasodilation in resistance mesenteric arteries by inhibiting p38 MAPKα and downstream Hsp27
Ajay K Pandey1, Farzana Zerin1, Sreelakshmi N Menon1
1Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA, 30341, USA.
Abstract:
Neflamapimod, a selective inhibitor of p38 mitogen activated protein kinase alpha (MAPKα), is under clinical investigation for its efficacy in Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB). Here, we investigated if neflamapimod-mediated acute inhibition of p38 MAPKα could induce vasodilation in resistance-size rat mesenteric arteries. Our pressure myography data demonstrated that neflamapimod produced a dose-dependent vasodilation in mesenteric arteries. Our Western blotting data revealed that acute neflamapimod treatment significantly reduced the phosphorylation of p38 MAPKα and its downstream target heat-shock protein 27 (Hsp27) involved in cytoskeletal reorganization and smooth muscle contraction. Likewise, non-selective inhibition of p38 MAPK by SB203580 attenuated p38 MAPKα and Hsp27 phosphorylation, and induced vasodilation. Endothelium denudation or pharmacological inhibition of endothelium-derived vasodilators such as nitric oxide (NO) and prostacyclin (PGI2) had no effect on such vasodilation. Neflamapimod-evoked vasorelaxation remained unaltered by the inhibition of smooth muscle cell K+ channels. Altogether, our data for the first time demonstrates that in resistance mesenteric arteries, neflamapimod inhibits p38 MAPKα and phosphorylation of its downstream actin-associated protein Hsp27, leading to vasodilation. This novel finding may be clinically significant and is likely to improve systemic blood pressure and cognitive deficits in AD and DLB patients for which neflamapimod is being investigated.
Insights
Neflamapimod, a p38 MAPKα inhibitor, causes vasodilation in rat mesenteric arteries by reducing p38 MAPKα and Hsp27 phosphorylation. This may improve blood pressure and cognitive function in Alzheimer's and DLB patients.
Area of Science:
- Pharmacology
- Vascular Biology
- Neuroscience
Background:
- Neflamapimod targets p38 MAPKα, a kinase implicated in various cellular processes.
- Clinical trials are investigating neflamapimod for Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB).
- The vascular effects of neflamapimod, particularly in relation to p38 MAPKα inhibition, are not fully understood.
Purpose of the Study:
- To investigate whether neflamapimod-induced inhibition of p38 MAPKα causes vasodilation in resistance-size rat mesenteric arteries.
- To elucidate the molecular mechanisms underlying neflamapimod-mediated vasodilation.
- To assess the potential clinical significance of these vascular effects for AD and DLB patients.
Main Methods:
- Pressure myography was used to measure vasodilation in isolated rat mesenteric arteries.
- Western blotting was employed to assess the phosphorylation status of p38 MAPKα and its downstream target Hsp27.
- Pharmacological interventions included non-selective p38 MAPK inhibition, endothelium denudation, and blockade of nitric oxide and prostacyclin pathways, as well as smooth muscle cell K+ channels.
Main Results:
- Neflamapimod induced a dose-dependent vasodilation in rat mesenteric arteries.
- Neflamapimod significantly reduced the phosphorylation of p38 MAPKα and Hsp27.
- SB203580, a non-selective p38 MAPK inhibitor, also induced vasodilation and reduced p38 MAPKα and Hsp27 phosphorylation.
- The vasodilation was independent of the endothelium and endothelium-derived vasodilators (NO, PGI2) and unaffected by smooth muscle cell K+ channel inhibition.
Conclusions:
- Neflamapimod inhibits p38 MAPKα and downstream Hsp27 phosphorylation in resistance mesenteric arteries, leading to vasodilation.
- This vasodilation mechanism is independent of endothelial factors and smooth muscle K+ channels.
- The findings suggest neflamapimod may improve systemic blood pressure and cognitive deficits in AD and DLB patients.
