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Title

Mechanisms of neuroprotection of soluble epoxide hydrolase enzyme inhibition in Alzheimer's disease models

AuthorsCorpas, Rubén ; Clotet Perarnau, Núria; Aguirre, S.; García-Lara, Elisa; Slevin, Mark; Griñán-Ferré, Christian; Galdeano, Carles; Vázquez, S.; Suñol, Cristina ; Pallàs, Mercè; Sanfeliu, Coral
Issue Date10-Jul-2019
CitationFENS Regional Meeting (2019)
AbstractAim: Chronic neuroinflammation associated with aging contributes to the onset and progression of Alzheimer’s disease (AD). Epoxyeicosatrienoic acids (EETs) are endogenous mediators that have several protective functions including antiinflammatory effects. EETs beneficial effects diminish when the enzyme soluble epoxide hydrolase (sEH) metabolizes them to the corresponding dihydroxyeicosatrienoic acids. Previous results showed that sEH inhibition mitigates cognitive impairment and AD-like brain pathology in SAMP8 and 5XFAD mouse models of senescence and AD, respectively. Here we investigate the underlying mechanisms of neuroinflammation and proteostasis changes related to cognitive loss and its neuroprotection by sEH inhibitors. Methods: We used the known sEH inhibitor TPPU and the compound newly synthesized UB-EV-52. sEH inhibitors were administered through drinking water in the 5XFAD transgenic AD mouse models. In in vitro experiments, they were added to the media of microglia cell lines BV2 and HCM3, and neuroblastoma SH-SY5Y, previously treated with lipopolysaccharide or monomeric C- reactive protein as proinflammatory stimulus. As endpoints we analyzed inflammatory and survival pathways, and changes in proteostasis. Results: Our findings confirmed the beneficial effects of sEH inhibition, reducing the cognitive impairment, increase of proteolytic mechanism against aberrant proteins with decline of Aβ and tau pathology, and decrease of inflammatory markers that suggests a protection against inflammaging. Moreover, UB-EV-52 agent showed higher inhibitory potency than TPPU and no cytotoxicity. Conclusion: These results reinforce sEH as promising pharmacological target to fight against AD and other brain diseases that might be triggered by inflammaging processes
DescriptionTrabajo presentado en el FENS Regional Meeting, celebrado en Belgrado (Sebia), del 10 al 13 de julio de 2019
URIhttp://hdl.handle.net/10261/201871
Appears in Collections:(IIBB) Comunicaciones congresos
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