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

Abstract

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 minute OGD exposure. These changes were largely suppressed by 10 μM 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 17β-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 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 at10 μM. 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 17β-estradiol and TAM attenuate neuronal excitability impairment early on in simulated ischemia model via ER activation mediated potentiation of BK K+ channels and reduction in enhanced neuronal AMPA/NMDA receptor-mediated excitotoxicity.

Estradiol Shapes Auditory Processing in the Adult Brain by Regulating Inhibitory Transmission and Plasticity-Associated Gene Expression

“…The presence or lack of TMX effect in brain slices appears to depend on the experimental system and preparations being studied. In NCM, TMX triggered robust effects in NCM neurons, suggesting that this compound is processed in our slice preparation, a finding that is consistent with results obtained in other preparations (Lin et al, 2007;Zhang et al, 2009).…”

Potential Effects of Hormone Therapy in Type 2 Idiopathic Macular Telangiectasia

“…Controversy exists as to the precise role of estrogens that can both afford neuroprotection and precipitate ischemic cerebral incidents [22,23].…”

Selective estrogen receptor modulators as brain therapeutic agents

“…Tamoxifen reduces tissue infarction and behavioral deficits in animal experimental models of stroke (Kimelberg et al 2003, Mehta et al 2003, Feng et al 2004, Kimelberg 2008 and attenuates neuronal excitability impairment caused by ischemic conditions in rat hippocampal slices incubated in oxygen-depleted and glucose-deprived medium (Zhang et al 2009). The raloxifene analog LY353381.HCl is also neuroprotective in experimental stroke (Rossberg et al 2000).…”

“…For instance, the efficacy of tamoxifen in the treatment of acute mania has been ascribed to its action as a protein kinase C inhibitor (Einat et al 2007, Zarate et al 2007). Other neuroprotective mechanisms of SERMs are mediated by classical ERs, since they are inhibited by ER antagonists, such as ICI 182 780 (Zhang et al 2009). The neuroprotective signaling of SERMs may involve the activation of kinases, such as mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and Akt (Du et al 2004, Lee et al 2009a, and the phosphorylation of CREB (Sharma et al 2007) or the inhibition of nuclear factor (NF)-kB-induced transcription (Cerciat et al 2010).…”