Aging is associated with a reduction in metabolic function, insulin resistance, increased incidence of neurodegenerative diseases, and memory–cognitive dysfunction. In aging females, loss of gonadal function determines the beginning of the period of reduced metabolic function. Estrogens have neuroprotective effects, but the mechanisms by which they exert these effects remain unclear. The effects of estradiol treatment on the activation of the IRS-1 signaling pathway, the interactions between ER and IRS-1 and the p85 subunit of PI3-k, together with the possible effects of estradiol treatment on Glut-3 and Glut-4 levels, were investigated in female rats. The level of expression of each glucose transporter was greater in control and estradiol-treated groups than in the ovariectomized group. Interactions of ER46–IRS-1, ER46–p85, and p85–IRS-1, as well as IRS-1 phosphorylation, appeared to increase with estradiol treatment. The results indicate that estradiol treatment improves some aspects of neuronal homeostasis that are affected by aging; this may indicate that estradiol has neuroprotective effects in female rats. Additional animal studies are required to clarify the neuroprotective role of estradiol in relation to other important molecules involved in the IRS-1–PI3-k signaling pathway.