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A Dual‐Inhibitor of Soluble Epoxide Hydrolase and p38 Kinase Alleviating Tau Hyperphosphorylation and Amyloid Neurotoxicity for Potential Treatment of Neuroinflammation in Alzheimer's Disease
Author(s) -
Liang Zhibin,
Morisseau Christophe,
Hwang Sung Hee,
Hammock Bruce D.,
Li Qing X.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.559.2
Subject(s) - neuroinflammation , neurotoxicity , p38 mitogen activated protein kinases , kinase , pharmacology , hyperphosphorylation , epoxide hydrolase 2 , chemistry , cancer research , medicine , biochemistry , protein kinase a , disease , enzyme , toxicity , organic chemistry
Alzheimer's disease (AD) is the most common dementia that cannot be prevented, cured or even slowed. Neuroinflammation associated with tau hyperphosphorylation and amyloid toxicity is a major hallmark in AD. Soluble epoxide hydrolase (sEH) and p38 kinase are therapeutic targets involving in inflammatory signaling. Development of selective inhibitors to modulate both sEH and p38 kinase is an attractive strategy for AD. We herein studied a potent and blood‐brain barrier permeable sEH inhibitor, 1‐(1‐propanoylpiperidin‐4‐yl)‐3‐[4‐(trifluoromethoxy)phenyl] urea (TPPU) (half maximum inhibition concentration, IC50, 0.64 nM), on neuroprotection in a human AD neuronal model. TPPU effectively alleviates tau hyperphosphorylation and amyloid neurotoxicity in vitro with a half maximum effective concentration (EC50) value of 49 nM. In vitro kinase selectivity profiling indicated that TPPU is a specific p38β kinase inhibitor with an IC50 value of 0.27 μM. The results suggested that TPPU shows a synergistic effect of neuropharmacology through a dual inhibition of sEH and p38. Additional knowledge of TPPU on the neuroinflammatory protection against tau and amyloid pathologies warrants further investigation. Support or Funding Information This work was supported in part by the NIH National Institute on Minority Health and Health Disparities grant 8G12MD007601. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .