G protein-coupled oestrogen receptor stimulation ameliorates iron- and ovariectomy-induced memory impairments through the cAMP/PKA/CREB signalling pathway.

Iron accumulation in the brain has been associated with neurodegenerative disorders, and imaging studies in humans indicate that iron content in brain regions correlates with poor performance in cognitive tasks. In rats, iron overload impairs memory retention in a variety of memory tasks. Although the effects of iron on cognition in rodents are extensively reported, no previous study has been conducted in female rats. The incidence of certain dementias, such as Alzheimer's disease, is higher in women after menopause compared to aged-matched men. The role of oestrogen depletion in memory deficits in menopausal women is still a matter of debate. The present study aimed to characterise the effects of iron overload on memory in female rats by investigating the effects of ovariectomy (OVX, an experimental model of oestrogen depletion) in rats submitted to iron overload, as well as examining the effects of G protein-coupled oestrogen receptor (GPER) agonism on memory impairments induced by iron and OVX. Female rats received iron (30 mg kg , orally) or vehicle at postnatal days 12-14 and were submitted to OVX in adulthood. Results showed that either iron or OVX impaired memory for object placement and inhibitory avoidance. The selective GPER agonist G1, administered immediately after training, reversed both iron- and OVX-induced memory impairments. G1 effects were abolished by protein kinase A (PKA) inhibition, suggesting the involvement of the cAMP/PKA/CREB signalling pathway. The search for novel oestrogen agonists with positive effects on cognition may be promising for the development of treatments for memory disorders.