Epoxide Hydrolase enzyme as a therapeutic target against Alzheimer's Disease
Alzheimer’s Disease (AD) represents a serious problem for the population health due to the increase in the life expectancy. Inflammation in AD is widely present and it is considered as a contributor to the cognitive loss and neurodegeneration. Epoxyeicosatrienoic acids (EETs) have anti-inflammatory...
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| Tipo de recurso: | tesis de maestría |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/177882 |
| Acceso en línea: | http://hdl.handle.net/10261/177882 |
| Access Level: | acceso abierto |
| Palabra clave: | Soluble epoxide hydrolase Inhibitors Epoxyeicosatrienoic acids (EET’s) Neuroinflammation |
| Sumario: | Alzheimer’s Disease (AD) represents a serious problem for the population health due to the increase in the life expectancy. Inflammation in AD is widely present and it is considered as a contributor to the cognitive loss and neurodegeneration. Epoxyeicosatrienoic acids (EETs) have anti-inflammatory properties which disappear when the enzyme soluble Epoxide Hydrolase (sEH) metabolizes them to the corresponding dihydroxyeicosatrienoic acids (DHETs). SEH is emerging as a promising pharmacological target because allows the increase of EETs and keep them active. The aim of the present study was to calculate the half maximal inhibitory concentration (IC50) of a newly synthetized sEH inhibitors (UB21, UB23, UB24, UB28, EPB50 and EV52), study their toxicity and the anti-inflammatory effects. SH-SY5Y cell cultures were used to the IC50 calculation and the toxicity of each sEHi. To study the inflammatory effects, lipopolysaccharide (LPS) stimulated microglial, BV2 cells were used to obtain conditioned media with the proinflammatory mediators. Modulation of the inflammatory pathways iNOS and NFĸB, and the release of proinflammatory cytokines were analyzed by techniques of Western Blot, immunocytochemistry and ELISA. All agents showed a higher inhibitory potency than the reference compound 1-Trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), being the IC50 of UB23 and UB28 at nanomolar range. EV52 could not been tested due to their random activity values. All sEHi were not cytotoxic at the anticipated concentrations, except EV52. The preliminary testing of anti-inflammatory effects unveils UB23 as the best candidate |
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