Neuroprotective actions of the synthetic estrogen 17alpha-ethynylestradiol in the hippocampus

Abstract

17alpha-ethynylestradiol (EE2), a major constituent of many oral contraceptives, is similar in structure to 17beta-estradiol, which has neuroprotective properties in several animal models. This study explored the potential neuroprotective actions of EE2 against kainic and quinolinic acid toxicity in the hippocampus of adult ovariectomized Wistar rats. A decrease in the number of Nissl-stained neurons and the induction of vimentin immunoreactivity in astrocytes was observed in the hilus of the dentate gyrus of the hippocampus after the administration of either kainic acid or quinolinic acid. EE2 prevented the neuronal loss and the induction of vimentin immunoreactivity induced by kainic acid at low (1 microg/rat) and high (10-100 microg/rat) doses and exerted a protection against quinolinic acid toxicity at a low dose (1 microg/rat) only. These observations demonstrate that EE2 exerts neuroprotective actions against excitotoxic insults. This finding is relevant for the design of new neuroprotective estrogenic compounds.

Fig. 1

Representative examples of vimentin immunoreactivity in the dentate gyrus of ovariectomized-rats injected with a cyclodextrin, b kainic acid, and c kainic acid and 100 μg 17α-ethinyl estradiol. In a and c, staining is observed in blood vessels. Vimentin immunoreactive astrocytes are detected in (b) (arrows). G Granule cell layer, H hilus. Scale bar: 100 μm

Fig. 2

Representative Nissl-stained sections from the hilus of the dentate gyrus of ovariectomized-rats injected with a, b cyclodextrin; c, d kainic acid and e, f kainic acid and 100 μg 17α-ethinyl estradiol. Scale bar: a, c, e—100 μm; b, d, f—20 μm

Fig. 3

Number of neurons in the hilus of the dentate gyrus of ovariectomized-rats injected with cyclodextrin and PBS (C), 17α-ethinyl estradiol (EE2, 100 μg/rat), kainic acid (KA) or with kainic acid and several doses (1–100 μg/rat) of 17α-ethinyl estradiol. Data are means ± SEM. Asterisk indicates significant differences (Dunn’s Method; P < 0.05) versus control value (C)

Fig. 4

Number of neurons in the hilus of the dentate gyrus of ovariectomized-rats treated with vehicle (C) or different doses (50–150 nM) of quinolinic acid. Data are means ± SEM. Asterisk indicates significant differences (Dunn’s Method; P < 0.05) versus control value (C)

Fig. 5

Representative examples of vimentin immunoreactivity in the dentate gyrus of ovariectomized-rats injected with a cyclodextrin, b quinolinic acid and c quinolinic acid and 1 μg 17α-ethinyl estradiol. In a and c, staining is observed in blood vessels. Numerous vimentin immunoreactive astrocytes are detected in (b). G Granule cell layer, H hilus. Scale bar: 100 μm

Fig. 6

Representative Nissl-stained sections from the hilus of the dentate gyrus of ovariectomized-rats injected with a, b cyclodextrin; c, d quinolinic acid and e, f quinolinic acid and 1 μg 17α-ethinyl estradiol. Scale bar: a, c, e—100 μm; b, d, f—20 μm

Fig. 7

Number of neurons in the hilus of the dentate gyrus of ovariectomized-rats treated with vehicles (C), 17α-ethinyl estradiol (EE2), quinolinic acid (QA) or with quinolinic acid and several doses (1–100 μg/rat) of 17α-ethinyl estradiol. Data are means ± SEM. Asterisk indicate significant differences (Dunn’s Method; P < 0.05) versus control value (C)