Graphical abstract sEH inhibitors APAU mediated neuroprotection against ROT induced toxicity A Mitochondria: Power house of the cell containing complex I-IV in the respiratory chain responsible for generation of ATP. B Rotenone: Potent mitochondria complex-I inhibitor, results in leakage of electron from the mitochondrial respiratory resulting in the formation of free radical (ROS). C ROS: ROT induced ROS are naturally neutralized by antioxidant enzymes. Whereas ROT is also reported to decreased the activity of antioxidant enzymes thereby decreasing its gene expression. This in turn results in the altered redox dynamics. D Increase in levels of ROS results in oxidative damage to lipids, protein and DNA resulting in loss of its function. ROT also induces release of inflammatory mediators such as IL-6, COX-1 and COX-2. Oxidative stress and inflammatory damage results in the activation various apoptotic pathways including Jnk, c-jun, caspase 3 resulting in cell death. E EET's are synthesized from arachidonic cascade at various sites such as astrocytes, dopaminergic neurons, blood vessels ect. F Arachidonic acids (AA) mainly undergo 3 pathways COX, LOX, Cytochrome P450. In presence of Cytochrome 2C and 2 J, AA is broken down into EET's which gets rapidly metabolized by sEH. Inhibition of sEH promotes the cytoprotective actions of EET's. G EET's mainly act by increasing the gene expression of antioxidant enzymes which in turn neutralizes the ROT induced ROS. Thereby decreasing the further progression of oxidative damage. H EET's attenuate inflammation by decreasing the ROT induced gene expression of inflammatory mediators. They also attenuate apoptosis by inhibiting the phosphorylation of JNK, c-jun and activation of caspase 3 mediated apoptosis. Highlights • APAU has potentials to ameliorate disease progression in Parkinson's disease. • APAU modulates oxidative stress, inflammation and apoptosis in Parkinson's disease. • APAU showed significant cytoprotection against rotenone toxicity in N27 cell line. • APAU significantly attenuated rotenone induced neurodegeneration in Drosophila. Abstract Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, play a crucial role in cytoprotection by attenuating oxidative stress, inflammation 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. [ABSTRACT FROM AUTHOR]