Tamoxifen mediated estrogen receptor activation protects against early impairment of hippocampal neuron excitability in an oxygen/glucose deprivation brain slice ischemia model

Autor: Paul F. Feustel, Huaqiu Zhang, Harold K. Kimelberg, Gary P. Schools, Wei Wang, Ting Lei, Minjie Xie, Min Zhou
Rok vydání: 2009
Předmět:
Male
Selective Estrogen Receptor Modulators
medicine.medical_specialty
BK channel
Excitotoxicity
Action Potentials
Estrogen receptor
AMPA receptor
medicine.disease_cause
Hippocampus
Neuroprotection
Article
Rats
Sprague-Dawley
Organ Culture Techniques
Internal medicine
Potassium Channel Blockers
medicine
Animals
Large-Conductance Calcium-Activated Potassium Channels
Receptors
AMPA
skin and connective tissue diseases
Molecular Biology
Neurons
Estradiol
biology
Pyramidal Cells
General Neuroscience
Excitatory Postsynaptic Potentials
Depolarization
Rats
Tamoxifen
Neuroprotective Agents
Endocrinology
Receptors
Estrogen
nervous system
Cytoprotection
Hypoxia-Ischemia
Brain
biology.protein
Excitatory postsynaptic potential
NMDA receptor
Neurology (clinical)
hormones
hormone substitutes
and hormone antagonists
Developmental Biology
Zdroj: Brain Research. 1247:196-211
ISSN: 0006-8993
DOI: 10.1016/j.brainres.2008.10.015
Popis: 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.
Databáze: OpenAIRE
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