The gonadal steroid 17β-estradiol (E2) has shown powerful cytoprotective effect on cells. In addition to
classical genomic mechanisms of action, E2 also exerts non-classical effects on intracellular signal transduction.
Extensive studies during the past two decades have provided evidence that the E2-induced non-classical signaling on
second messenger molecules plays a critical role in the neuroprotective effect of E2. These observations provide a unique
basis for developing non-classical estrogen-like signaling activators that may have potential for clinical use in
neuroprotection. In spite of the extensive research over the past decade reviewed here, we are just starting to appreciate
the importance and potential of these compounds. Hence, we first describe the molecular characteristics and effects of
these activators. Second, we survey recent data as to possible mechanisms underlying the ameliorative actions of selective
non-classical estrogen-like signaling activation. In addition, the pitfalls and future aspects of “non-classical”-line
activators and its clinical relevance will also be discussed.
Keywords: Estradiol, non-classical estrogen-like signaling activators, ANGELS, estren, compound A, compound B,
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