Structure-Neuroprotective Activity Relationships Among Estrogens and Related Molecules.
J.W. Simpkins, S.H. Yang, R. Liu, Y. Wen, D.G. Watson, E.J. Perez, T. Fan, and A.L. Day.
Department of Pharmacology and Neuroscience, University of North Texas
Health Science Center at Fort Worth, Fort Worth, TX 76107
Various lines of evidence indicate that estrogens can protect neurons
independently of transcriptional activation through estrogen receptors
(ERs). ER binding and transactivation requires stereospecific
interaction with ERa, ERb or a yet undescribed ER. We analyzed over 40
novel estrogens that vary in ER binding affinity and in
agonist/antagonist potency, and found no relationship between binding
to ERa or ERb and neuroprotective effects. Four compounds with low ER
binding were compared to 17bE2 in a middle cerebral artery (MCA)
occlusion model for cerebral ischemic injury. Equivalent
neuroprotection with 17bE2 was observed with each of these compounds:
17 a-E2, a weak estrogen, ent-E2 (the complete enantiomer of 17bE2),
and two novel estrogens, ZYC-3 and ZYC-13. To begin to describe the
ER-independent estrogen signaling mechanisms for neuroprotection, we
utilized both MCA occlusion and HT-22 cells. To date, we have
demonstrated the following: (1) 17bE2 prevents activation of NFkB that
is normally seen following ischemia. This inactivation of NFkB by
estrogens appears to be related to its ability to prevent the
phosphorylation of IkB, a reactive oxygen-stimulated event needed for
NFkB activation and (2) in HT-22 cells, 17bE2 activate then inactivate
PKCe and ERK 1/2. This activation/inactivation of PKC and ERK
signaling by 17bE2 is involved in its neuroprotective activity, as
evidenced by the potent neuroprotective effects in HT-22 cells of PKC
or MEK inhibitors. Collectively, these data suggest that
neuroprotection can be achieved through mechanisms that are independent
of ER binding and subsequent transcriptional activation by estrogens.
This provides a novel strategy for drug discovery for brain protection.
(Supported by AG10485, US Army grant DAMD 17-19-1-9473 and a grant from
Apollo BioPharmaceutics, Inc.)
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