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Dually targeting human soluble epoxide hydrolase and P38 kinase to prevent neuroinflammation for the treatment of Alzheimer’s disease
Author(s) -
Liang Zhibin,
Zhang Bei,
Xu Meng,
Morisseau Christophe,
Hwang Sung Hee,
Hammock Bruce D.,
Li Qing X.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.047097
Subject(s) - neuroinflammation , kinase , inflammation , p38 mitogen activated protein kinases , neuroprotection , pharmacology , cancer research , biology , medicine , neuroscience , protein kinase a , microbiology and biotechnology , immunology
Background Alzheimer’s disease (AD) is a complex neurodegenerative disorder with no cures. While many pathological characteristics occur in the AD brain, neuroinflammation is a prevalent pathogenic stress that leads to neuronal death in AD. Targeting the brain inflammation to keep neurons alive is an attractive therapeutic strategy for AD. TPPU is a potent inhibitor of soluble epoxide hydrolase (sEH) and can enter into the brain. It has a good efficacy on many chronic inflammatory diseases in preclinical animal models ranging from mice to nonhuman primates. For central nervous system disorders, TPPU shows therapeutic effects in rodent models of neuropsychiatric syndromes associated with inflammation such as stroke, seizure, depression, and Parkinson’s disease. However, the anti‐neuroinflammatory effects and underlying mechanisms of TPPU for potential AD interventions remain elusive. Methods With an aim to develop multi‐targeted therapeutics for AD, TPPU was screened in enzymatic assays against sEHs from different mammalian species and a broad panel of human kinases for potential new targets relevant to neuroinflammation. To elucidate the molecular mechanisms, we established an AD cell model using human differentiated SH‐SY5Y nerve cells exposed to toxic amyloid oligomers and investigated the neuroprotective effects of TPPU. Cell viability was assessed by the MTS assay. The cellular levels of sEH and p38β kinase were evaluated by immunoblotting. Tau hyperphosphorylation and nuclear NF‐κB activation were assessed by ELISA. Mitochondrial function was assessed by the mitochondrial membrane potential assay. Results TPPU inhibits both human sEH and p38β kinase, two master regulators of inflammation, with nanomolar potencies and distinct selectivity. TPPU effectively prevents neuronal death by mitigating amyloid toxicity, tau hyperphosphorylation and mitochondrial dysfunction, promoting neurite outgrowth, and suppressing activation and nuclear translocation of NF‐κB for inflammatory responses in human nerve cell culture. Pairwise treatment of different selective inhibitors of sEH and p38 kinase synergizes neuroprotection, the effect of which is comparable to the TPPU treatment alone. Conclusions The study supports the argument that sEH is a novel target of AD worth pursuing. It uncovers the potential of TPPU and other sEH/p38β dual inhibitors as disease‐modifying agents targeting neuroinflammation for the treatment of Alzheimer’s disease and related CNS disorders.