RT Journal Article
T1 Seladin-1/DHCR24 Is Neuroprotective by Associating EAAT2 Glutamate Transporter to Lipid Rafts in Experimental Stroke
A1 Hernández Jiménez, Macarena
A1 Martínez López, Diego
A1 Gabandé Rodríguez, Enrique
A1 Martín Segura, Adrián
A1 Lizasoaín Hernández, Ignacio
A1 Ledesma, María D.
A1 Dotti, Carlos G.
A1 Moro Sánchez, María Ángeles
AB Background and purpose: 3β-Hydroxysteroid-Δ24 reductase (DHCR24) or selective alzheimer disease indicator 1 (seladin-1), an enzyme of cholesterol biosynthetic pathway, has been implicated in neuroprotection, oxidative stress, and inflammation. However, its role in ischemic stroke remains unexplored. The aim of this study was to characterize the effect of seladin-1/DHCR24 using an experimental stroke model in mice.Methods: Dhcr24(+/-) and wild-type (WT) mice were subjected to permanent middle cerebral artery occlusion. In another set of experiments, WT mice were treated intraperitoneally either with vehicle or U18666A (seladin-1/DHCR24 inhibitor, 10 mg/kg) 30 minutes after middle cerebral artery occlusion. Brains were removed 48 h after middle cerebral artery occlusion for infarct volume determination. For protein expression determination, peri-infarct region was obtained 24 h after ischemia, and Western blot or cytometric bead array was performed.Results: Dhcr24(+/-) mice displayed larger infarct volumes after middle cerebral artery occlusion than their WT littermates. Treatment of WT mice with the seladin-1/DHCR24 inhibitor U18666A also increased ischemic lesion. Inflammation-related mediators were increased after ischemia in Dhcr24(+/-) mice compared with WT counterparts. Consistent with a role of cholesterol in proper function of glutamate transporter EAAT2 in membrane lipid rafts, we found a decreased association of EAAT2 with lipid rafts after ischemia when DHCR24 is genetically deleted or pharmacologically inhibited. Accordingly, treatment with U18666A decreases [(3)H]-glutamate uptake in cultured astrocytes.Conclusions: These results support the idea that lipid raft integrity, ensured by seladin-1/DHCR24, plays a crucial protective role in the ischemic brain by guaranteeing EAAT2-mediated uptake of glutamate excess.
PB American Heart Association
YR 2015
FD 2015-12-01
LK https://hdl.handle.net/20.500.14352/113609
UL https://hdl.handle.net/20.500.14352/113609
LA eng
NO Hernández-Jiménez, M., Martínez-López, D., Gabandé-Rodríguez, E., Martín-Segura, A., Lizasoain, I., Ledesma, M. D., Dotti, C. G., & Moro, M. A. (2016). Seladin-1/DHCR24 Is Neuroprotective by Associating EAAT2 Glutamate Transporter to Lipid Rafts in Experimental Stroke. Stroke, 47(1), 206–213. https://doi.org/10.1161/STROKEAHA.115.010810
DS Docta Complutense
RD 26 dic 2025