Estrone, but not 17β-estradiol, attenuates kainate-induced seizures and toxicity in male mice

Abstract

Estrogens change the susceptibility to seizures in humans and experimental animals. In this study, the effect of estrone and 17 beta-estradiol on kainate-induced seizures and neurotoxicity was investigated in male mice. Pre-treatment with estrone (250-1000 micrograms/kg) at 24 and 2 hours before kainate (40 mg/kg) administration significantly decreased both the percentage of animals with clonic seizures and their mortality (the latter at a dose of 1000 micrograms/kg only). On the other hand, 17 beta-estradiol (10-500 micrograms/kg) had no effect on seizures, and its dose of 10 micrograms/kg increased mortality. When given alone at a dose of 1 mg/kg, tamoxifen, an antagonist at estrogene receptors, did not affect the kainate-induced seizures, but prevented the anticonvulsant effect of estrone. A histological analysis showed that 73% of mice injected with vehiculum and kainate incurred hippocampal damage. Estrone (2000 micrograms/kg) decreased the percentage of animals with hippocampal neuronal loss down to 43%, and that effect was not antagonized by tamoxifen. Pretreatment of mice with 17 beta-estradiol had no effect on the kainate-induced neuronal loss. Additionally, we found that kainate injected i.p. had a profound effect on the immune system of mice, as reflected by a decrease in the thymus weight and an increased metabolic activity of splenocytes. The anticonvulsive dose of estrone (1000 micrograms/kg) did not change the immunoreactivity of either control or kainate-treated mice. In conclusion, the obtained data indicate that estrone, but not 17 beta-estradiol, attenuates the kainate-induced seizures, mortality and excitotoxicity in male mice. Moreover, it is suggested that the suppressive effect of estrone on clonic seizures involves intracellular receptors, whereas its antineurotoxic activity seems to depend on a non-genomic mechanism.

Contribution of estrogen receptor subtypes, ERα, ERβ, and GPER1 in rapid estradiol-mediated enhancement of hippocampal synaptic transmission in mice

“…Estrone has a lower affinity for ERa, ERb, and GPER1 (Bhavnani, 2003;Kuiper et al, 1997;Thomas et al, 2005). Moreover, in many cases, estrone influences cell physiology (Barha and Galea, 2010;Budziszewska et al, 2001;Kelly et al, 1980;Mermelstein et al, 1996;Thomas et al, 2005) and cognitive function (McClure et al, 2013) in a manner different from estradiol. Together, the results indicate that the enhanced responsiveness of EB over selective agonists is not due to EB metabolites.…”

Different Forms of Oestrogen Rapidly Upregulate Cell Proliferation in the Dentate Gyrus of Adult Female Rats

“…E 1 , the predominate form of oestrogen found in post‐menopausal women (4), originates primarily from the ovaries, adrenal cortex and adipose tissue, with 25% of circulating E 1 being converted from 17β‐E 2 via enzymes in the family 17‐hydroxysteriod dehydrogenases in the ovaries. Despite the fact that these oestrogens can be interconverted, E 1 and 17β‐E 2 have been shown to have some differential effects on neuroprotection (5, 6). E 1 is used in many hormone replacement therapies (HRTs), and is the primary oestrogen in Premarin, the most popular HRT and the HRT used in the controversial NIH‐controlled Women’s Health Initiative study (7).…”

“…Despite the fact that it is routinely used in HRTs, very little research has focused on E 1 . However, these few studies indicate that E 1 is neuroprotective against several different insults (5, 6) and can alter oestrogen receptor (ER) subtypes independently of the effects of 17β‐E 2 . Recently, Jin et al.…”

Seizure facilitating activity of the oral contraceptive ethinyl estradiol

“…Vehicle was given to control groups. The EE dosage was selected based on previous reports and also to be comparable to clinically relevant levels during OC therapy (Budziszewska et al, 2001; Reddy, 2004; Reddy, 2010; Herzog, 2015). …”