Tamoxifen mediated estrogen receptor activation protects against early impairment of hippocampal neuron excitability in an oxygen/glucose deprivation brain slice ischemia model.
Pretreatment of ovarectomized rats with estrogen shows long-term protection via activation of the estrogen receptor (ER). However, it remains unknown whether activation of the ER can provide protection against early neuronal damage when given acutely. We simulated ischemic conditions by applying oxygen and glucose deprived (OGD) solution to acute male rat hippocampal slices and examined the neuronal electrophysiological changes. Pyramidal neurons and interneurons showed a time-dependent membrane potential depolarization and reduction in evoked action potential frequency and amplitude over a 10 to 15 min OGD exposure. These changes were largely suppressed by 10 microM TAM. The TAM effect was neuron-specific as the OGD-induced astrocytic membrane potential depolarization was not altered. The TAM effect was mediated through ER activation because it could be simulated by 17beta-estradiol and was completely inhibited by the ER inhibitor ICI 182, 780, and is therefore an example of TAM's selective estrogen receptor modulator (SERM) action. We further show that TAM's effects on OGD-induced impairment of neuronal excitability was largely due to activation of neuroprotective BK channels, as the TAM effect was markedly attenuated by the BK channel inhibitor paxilline at 10 microM. TAM also significantly reduced the frequency and amplitude of AMPA receptor mediated spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons which is an early consequence of OGD. Altogether, this study demonstrates that both 17beta-estradiol and TAM attenuate neuronal excitability impairment early on in a simulated ischemia model via ER activation mediated potentiation of BK K(+) channels and reduction in enhanced neuronal AMPA/NMDA receptor-mediated excitotoxicity.
Zhang
Huaqiu
H
Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan, 430030, PR China.
Xie
Minjie
M
Schools
Gary P
GP
Feustel
Paul F
PF
Wang
Wei
W
Lei
Ting
T
Kimelberg
Harold K
HK
Zhou
Min
M
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009924:Organ Culture Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D011960:Receptors, Estrogen / Q000819:agonists* / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use
D051036:Large-Conductance Calcium-Activated Potassium Channels; D018696:Neuroprotective Agents; D026902:Potassium Channel Blockers; D018091:Receptors, AMPA; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D004958:Estradiol