Oestrogen signalling and neuroprotection in cerebral ischaemia.

17β-Oestradiol (E(2)) is an important hormone signal that regulates multiple tissues and functions in the body. This review focuses on the neuroprotective actions of E(2) in the brain against cerebral ischaemia and the potential underlying mechanisms. A particular focus of the review will be on the role of E(2) to attenuate NADPH oxidase activation, superoxide and reactive oxygen species generation and reduce oxidative stress in the ischaemic brain as a potentially key neuroprotective mechanism. Evidence of a potential novel role of extranuclear oestrogen receptors in mediating E(2) signalling and neuroprotective actions is also discussed. An additional subject is the growing evidence indicating that periods of long-term oestrogen deprivation, such as those occurring after menopause or surgical menopause, may lead to loss or attenuation of E(2) signalling and neuroprotective actions in the brain, as well as enhanced sensitivity of the hippocampus to ischaemic stress damage. These findings have important implications with respect to the 'critical period hypothesis', which proposes that oestrogen replacement must be initiated at peri-menopause in humans to exert its beneficial cardiovascular and neural effects. The insights gained from these various studies will prove valuable for guiding future directions in the field.