This manuscript shows that estrogen conjugates, which cannot enter the nucleus based on size or charge and therefore activate extranuclear estrogen receptor (ER), are protective against cerebral ischemia (i.e. strokes) in rats. The ability of rats to recover learning and memory skills following stroke is improved in the presence of estrogen conjugates and measured using a Morris water maze test, for which I found a cool video on YouTube (gotta love the background music):
http://www.youtube.com/watch?v=LrCzSIbvSN4
The authors associate this observation with increased survival of CA1 hippocampal neurons through increased AKT, ERK, and CREB activation and BDNF production, as well as downregulation of active JNK (known to activate apoptotic pathways).
Thanks for the video Natalie, it really puts figure 1C into perspective. (And the background music is awesome).
ReplyDeleteI think this paper was a long read but their in vivo work probably was not trivial either. I think because of this, it makes for a convincing argument. I wonder, though, whether these protective effects are mediated through both ER alpha and beta or just alpha. And there is also some suggestion that it may be mediated specifically through membrane bound ER. It would be nice for someone to further investigate the mechanism behind ER mediated signaling of these ERK-Akt-CREB-and BDNF pathways.
Besides clarifying roles of ERa and ERb, I think another part worth further exploring is the interrelatioship between the extranuclear and nuclear ER in neuroprotection. The authors discussed that EDC nongenomic signaling is independent of ER nuclear signaling, however, E2 nongenomic and genomic signaling are connected. What about giving both EDC and E2 simultaneously?
ReplyDeleteI think it would be interesting to compare Justin's compounds to the E2 conjugates they used here. The purpose of creating those compounds was to isolate the membrane/cytoplasmatic pathway from the nuclear and allow the study of the specific effect. and I agree with Chaowei that it will also be interesting to compare the full effect of E2.
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