PMID- 30472438
OWN - NLM
STAT- MEDLINE
DCOM- 20190318
LR  - 20210112
IS  - 1872-9711 (Electronic)
IS  - 0161-813X (Print)
IS  - 0161-813X (Linking)
VI  - 70
DP  - 2019 Jan
TI  - Soluble epoxide hydrolase inhibitor, APAU, protects dopaminergic neurons against 
      rotenone induced neurotoxicity: Implications for Parkinson's disease.
PG  - 135-145
LID - S0161-813X(18)30318-8 [pii]
LID - 10.1016/j.neuro.2018.11.010 [doi]
AB  - Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, play a crucial 
      role in cytoprotection by attenuating oxidative stress, in fl ammation and 
      apoptosis. EETs are rapidly metabolised in vivo by the soluble epoxide hydrolase 
      (sEH). Increasing the half life of EETs by inhibiting the sEH enzyme is a novel 
      strategy for neuroprotection. In the present study, sEH inhibitors APAU was 
      screened in silico and further evaluated for their antiparkinson activity against 
      rotenone (ROT) induced neurodegeneration in N27 dopaminergic cell line and 
      Drosophila melanogaster model of Parkinson disease (PD). In the in vitro study 
      cell viability (MTT and LDH release assay), oxidative stress parameters (total 
      intracellular ROS, hydroperoxides, protein oxidation, lipid peroxidation, 
      superoxide dismutase, catalase, glutathione peroxidise, glutathione reductase, 
      glutathione, total antioxidant status, mitochondrial complex-1activity and 
      mitochondrial membrane potential), inflammatory markers (IL-6, COX-1 and COX-2), 
      and apoptotic markers (JNK, phospho-JNK, c-jun, phospho-c-jun, pro and active 
      caspase-3) were assessed to study the neuroprotective effects. In vivo activity 
      of APAU was assessed in Drosophila melanogaster by measuring survival rate, 
      negative geotaxis, oxidative stress parameters (total intracellular ROS, 
      hydroperoxides, glutathione levels) were measured. Dopamine and its metabolites 
      were estimated by LC-MS/MS analysis. In the in silico study the molecule, APAU 
      showed good binding interaction at the active site of sEH (PDB: 1VJ5). In the in 
      vitro study, APAU significantly attenuated ROT induced changes in oxidative, 
      pro-inflammatory and apoptotic parameters. In the in vivo study, APAU 
      significantly attenuates ROT induced changes in survival rate, negative geotaxis, 
      oxidative stress, dopamine and its metabolites levels (p < 0.05). Our study, 
      therefore, concludes that the molecule APAU, has significant neuroprotection 
      benefits against rotenone induced Parkinsonism.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Lakkappa, Navya
AU  - Lakkappa N
AD  - Department of Pharmacology, JSS College of Pharmacy, Ooty, India.
FAU - Krishnamurthy, Praveen T
AU  - Krishnamurthy PT
AD  - Department of Pharmacology, JSS College of Pharmacy, Ooty, India. Electronic 
      address: praveentk7812@gmail.com.
FAU - M D, Pandareesh
AU  - M D P
AD  - Department of Neurochemistry, National Institute of Mental Health & Neuro 
      Sciences, Bangalore, India.
FAU - Hammock, Bruce D
AU  - Hammock BD
AD  - Department of Entomology and Nematology, and Comprehensive Cancer Research 
      Center, University of California, Davis, United States.
FAU - Hwang, Sung Hee
AU  - Hwang SH
AD  - Department of Entomology and Nematology, and Comprehensive Cancer Research 
      Center, University of California, Davis, United States.
LA  - eng
GR  - R01 ES002710/ES/NIEHS NIH HHS/United States
GR  - R37 ES002710/ES/NIEHS NIH HHS/United States
GR  - T32 ES007059/ES/NIEHS NIH HHS/United States
GR  - U54 NS079202/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20181122
PL  - Netherlands
TA  - Neurotoxicology
JT  - Neurotoxicology
JID - 7905589
RN  - 0 (Antiparkinson Agents)
RN  - 0 (Insecticides)
RN  - 0 (Neuroprotective Agents)
RN  - 03L9OT429T (Rotenone)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Animals
MH  - Antiparkinson Agents/chemistry/pharmacology/*therapeutic use
MH  - Cell Line
MH  - Cell Survival/drug effects/physiology
MH  - Crystallography, X-Ray
MH  - Dopaminergic Neurons/*drug effects/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drosophila melanogaster
MH  - Epoxide Hydrolases/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Insecticides/toxicity
MH  - Male
MH  - Neuroprotective Agents/chemistry/pharmacology/therapeutic use
MH  - Parkinsonian Disorders/*chemically induced/metabolism/*prevention & control
MH  - Rats
MH  - Rotenone/*toxicity
PMC - PMC6873230
MID - NIHMS1033853
OTO - NOTNLM
OT  - APAU
OT  - Apoptosis
OT  - Epoxyeicosatrienoic acids
OT  - Inflammation
OT  - Neuroprotection
OT  - Oxidative stress
OT  - Parkinson
OT  - Soluble epoxide hydrolase
COIS- Conflict of interest The author declares that there is no conflict of interest.
EDAT- 2018/11/26 06:00
MHDA- 2019/03/19 06:00
PMCR- 2020/01/01
CRDT- 2018/11/26 06:00
PHST- 2018/08/07 00:00 [received]
PHST- 2018/11/12 00:00 [revised]
PHST- 2018/11/13 00:00 [accepted]
PHST- 2018/11/26 06:00 [pubmed]
PHST- 2019/03/19 06:00 [medline]
PHST- 2018/11/26 06:00 [entrez]
PHST- 2020/01/01 00:00 [pmc-release]
AID - S0161-813X(18)30318-8 [pii]
AID - 10.1016/j.neuro.2018.11.010 [doi]
PST - ppublish
SO  - Neurotoxicology. 2019 Jan;70:135-145. doi: 10.1016/j.neuro.2018.11.010. Epub 2018 
      Nov 22.