Neuroprotective effects of phenolic A ring oestrogens.
We have formulated the 'phenolic A ring hypothesis' for the neuroprotective effects of oestrogens based upon several observations: (i) structure-activity relationships show that a phenolic A ring and at least two additional rings are required for neuroprotection while oestrogenicity requirements are more stringent; (ii) neuroprotection with phenolic A ring compounds occurs in cells that lack oestrogen receptors and are not antagonized by anti-oestrogens; (iii) phenolic A ring compounds rapidly activate a variety of signal transduction pathways that are known to be involved in cell homeostasis; and (iv) in vivo, treatment with oestrogens results in a neuronal type-independent neuronal protection from ischaemic insult. Potential mechanisms of actions that may be involved in the neuroprotective effects of phenolic A ring compounds are: (i) oestrogen redox cycling that potently inhibits oxidative stress; (ii) interactions with signal transduction pathways including the transcription factor cAMP response element binding protein; and (iii) induction of anti-apoptotic proteins. These signalling pathways may individually or collectively contribute to the plethora of neuronal cell types that are protected from a variety of insults by oestrogen-like compounds.
Green
P S
PS
Center for the Neurobiology of Aging, University of Florida, Gainesville 32610, USA.
Yang
S H
SH
Simpkins
J W
JW
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism; D004195:Disease Models, Animal; D004967:Estrogens / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D062385:Hydroxybenzoates; D018696:Neuroprotective Agents / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship
D004967:Estrogens; D062385:Hydroxybenzoates; D018696:Neuroprotective Agents; D011960:Receptors, Estrogen; C017616:phenolic acid