The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of IGF-1

Hormone therapy to postmenopausal females increases the risk and severity of ischemic stroke. Our previous work using an animal model of menopause (reproductive senescence) shows that middle cerebral artery occlusion (MCAo) causes a larger cortical-striatal infarct in this older acyclic group as compared to younger females. Moreover, while estrogen treatment is neuroprotective in younger females, estrogen paradoxically increases infarct volume in acyclic females. We hypothesized that the neurotoxic effects of estrogen in older females occurs due to decreased availability of IGF-1, a neuroprotectant which decreases with advancing age and is down-regulated by estrogen treatment. Our data shows that plasma IGF-1 levels are significantly reduced in reproductive senescent females and further reduced by estrogen at all ages. Estrogen's neuroprotective effect on MCAo-induced cortical infarct volume in mature adult female is reversed by icv injections of IGF-1 receptor antagonist JB-1. Similarly, estrogens neurotoxic effects on cortical infarct volume in senescent females is attenuated by concurrent IGF-1 treatment, and reversed when IGF-1 is infused 4h after the onset of ischemia (delayed IGF-1 treatment). Delayed IGF-1/estrogen treatment also suppressed ischemia-induced ERK1 phosphorylation, reduced protein oxidation and stimulated an early increase in prostaglandin (PG) E2 at the infarct site. IGF-1 treatment was only protective in senescent females that received estrogen, indicating that the neuroprotective actions of this peptide require interaction with the steroid hormone receptor. These data support the hypothesis that stroke severity in older females is associated with decreased IGF-1 and further indicate that short term post-ischemic IGF-1 therapy may be beneficial for stroke.