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.