Extranuclear Estrogen Receptors Mediate the Neuroprotective Effects of Estrogen in the Rat Hippocampus 英文参考文献.docVIP

ExtranuclearEstrogenReceptorsMediatethe NeuroprotectiveEffectsofEstrogenintheRat Hippocampus Li-caiYang1.,Quan-GuangZhang2.,Cai-fengZhou1.,FangYang1,Yi-dongZhang1,Rui-minWang1*, DarrellW.Brann2* 1ExperimentalandResearchCenter,NorthChinaCoalMedicalUniversity,Tangshan,Hebei,People’sRepublicofChina,2InstituteofMolecularMedicineandGenetics, MedicalCollegeofGeorgia,Augusta,Georgia,UnitedStatesofAmerica Abstract Background: 17b-estradiol (E2) has been implicated to exert neuroprotective effects in the brain following cerebral ischemia.Classically,E2isthoughttoexertitseffectsviagenomicsignalingmediatedbyinteractionwithnuclearestrogen receptors.However,theroleandcontributionofextranuclearestrogenreceptors(ER)isunclearandwasthesubjectofthe currentstudy. Methodology/PrincipalFindings:Toaccomplishthisgoal,weemployedtwoE2conjugates(E2dendrimer,EDC,andE2- BSA) that can interact with extranuclear ER and exert rapid nongenomic signaling, but lack the ability to interact with nuclearERduetotheirinabilitytoenterthenucleus.EDCorE2-BSA(10mM)wasinjectedicv60minpriortoglobalcerebral ischemia(GCI).FITC-taggedEDCorE2-BSArevealedhighuptakeinthehippocampalCA1regionaftericvinjection,witha membrane (extranuclear) localization pattern in cells. Both EDC and E2-BSA exerted robust neuroprotection in the CA1 againstGCI,andtheeffectwasblockedbytheERantagonist,ICI182,780.EDCandE2-BSAbothrapidlyenhancedactivation oftheprosurvivalkinases,ERKandAkt,whileattenuatingactivationoftheproapoptotickinase,JNKfollowingGCI,effects thatwereblockedbyICI182,780.AdministrationofanMEKorPI3KinhibitorblockedtheneuroprotectiveeffectsofEDCand E2-BSA. Further studies showed that EDC increased p-CREB and BDNF in the CA1 region in an ERK- and Akt-dependent manner,andthatcognitiveoutcomeafterGCIwaspreservedbyEDCinanER-dependentmanner. Conclusions/Significance: In conclusion, the current study demonstrates that activation of extranuclear ER results in inductionofERK-Akt-CREB-BDNFsignalinginthehippocampalCA1region,whichsign