title: Soluble Epoxide Hydrolase Deficiency or Inhibition Attenuates MPTP-Induced Parkinsonism.
abstract: Soluble epoxide hydrolase (sEH) inhibition has been demonstrated to have beneficial effects on various diseases, such as hypertension, diabetes, and brain ischemia. However, whether sEH inhibition has therapeutic potential in Parkinson's disease is still unknown. In this paper, we found that sEH expression is increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-treated mice, and sEH deficiency and inhibition significantly attenuated tyrosine hydroxylase (TH)-positive cell loss and improved rotarod performance. The substrate of sEH, 14,15-epoxyeicosatrienoic acid (14,15-EET), protected TH-positive cells and alleviated the rotarod performance deficits of wild-type mice but not sEH-knockout mice. Moreover, the 14,15-EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) abolished the neuronal protective effects of sEH deficiency. In primary cultured cortical neurons, MPP(+) induced significant Akt inactivation in neurons from sEH wild-type mice, and this effect was not observed in neurons from knockout mice. Our data indicate that sEH deficiency and inhibition increased 14,15-EET in MPTP-treated mice, which activated the Akt-mediated protection of TH-positive neurons and behavioral functioning. We also found that sEH deficiency attenuated TH-positive cell loss in a paraquat-induced mouse model of Parkinson's. Our data suggest that sEH inhibition might be a powerful tool to protect dopaminergic neurons in Parkinson's disease.
authors.affiliation: Department of Neurobiology, Southern Medical University, Guangzhou, Guangdong Province, China.
authors.forename: Xiaocui
authors.initials: X
authors.lastname: Qin
authors.forename: Qiaoqi
authors.initials: Q
authors.lastname: Wu
authors.forename: Lifang
authors.initials: L
authors.lastname: Lin
authors.forename: Aimin
authors.initials: A
authors.lastname: Sun
authors.forename: Shuhu
authors.initials: S
authors.lastname: Liu
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Li
authors.forename: Xiong
authors.initials: X
authors.lastname: Cao
authors.forename: Tianming
authors.initials: T
authors.lastname: Gao
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Luo
authors.forename: Xinhong
authors.initials: X
authors.lastname: Zhu
authors.forename: Xuemin
authors.initials: X
authors.lastname: Wang
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000378:metabolism; D007850:Lauric Acids / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010269:Paraquat; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D045442:Rotarod Performance Test; D012995:Solubility; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D007850:Lauric Acids; D018696:Neuroprotective Agents; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid; D000218:Adamantane; D010269:Paraquat