Effect of chronic administration of estradiol, progesterone, and tibolone on the expression and phosphorylation of glycogen synthase kinase‐3β and the microtubule‐associated protein tau in the hippocampus and cerebellum of female rat

Abstract

Gonadal hormones regulate expression and activation of protein tau. Tibolone is a drug used as first- choice comprehensive treatment for the relief of menopausal symptoms, because it and its various metabolites have estrogenic properties and progestogenic/androgenic effects; however, the effect on the activation of tau protein and its signaling cascade in the brain is unknown. We studied the effect of chronic administration of estradiol (E2), progesterone (P4), and tibolone (TIB) on the expression and phosphorylation of microtubule-associated protein tau and glycogen synthase kinase-3β (GSK3β) in the hippocampus and cerebellum of ovariectomized rats. Ovariectomized adult female rats were implanted with pellets of vehicle, E2, or P4 or were treated with TIB by oral administration for 60 days. The animals were sacrificed, and tissue proteins were analyzed by Western blot. We observed that, in the hippocampus, administration of E2, P4, or TIB significantly decreased the protein content of hyperphosphorylated tau and increased the tau dephosphorylated form, whereas only treatment with TIB increased the content of the phosphorylated form of GSK3β. In the cerebellum, E2 and TIB treatments resulted in a significant decrease in the expression of hyperphosphorylated tau, whereas E2 and TIB increased phosphorylated GSK3β; P4 had no effect. These results indicate that chronic administration of gonadal hormones and tibolone modulates tau and GSK3β phosphorylation in hippocampus and cerebellum of the rat and may exert a neuroprotective effect in these tissues.

Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions

“…Tibolone exerts neuroprotective and antioxidative actions in neurons (Belenichev et al, 2012;de Aguiar et al, 2008;Farfán-García et al, 2014;Pinto-Almazan et al, 2012). Besides, tibolone has shown to exert protective actions against glucose deprivation in a human astrocyte cell model, the T98G cells (Avila Rodriguez et al, 2014).…”

Tau Phosphorylation in Female Neurodegeneration: Role of Estrogens, Progesterone, and Prolactin

“…Finally, when ovariectomized female rats were chronically treated with estrogen, progesterone, and tibolone (TIB) (a widely prescribed synthetic steroid with estrogenic, progestogenic, and androgenic actions), less p-Tau in the epitope PHF-1 and more dephosphorylation in the antibody Tau-1 was detected, in both the hippocampus and the cerebellum ( 58 ). In this particular study, no changes were detected in GSK3β Ser 9 in the hippocampus, in contrast to the findings in the cerebellum, suggesting the involvement of different pathways or a region-specific action for this enzyme.…”

The Synthetic Steroid Tibolone Decreases Reactive Gliosis and Neuronal Death in the Cerebral Cortex of Female Mice After a Stab Wound Injury

“…Furthermore, tibolone decreases the activity of acetylcholinesterase and choline acetyltransferase in the medial septum/diagonal band of Broca of ovariectomized monkeys [34], suggesting a modulation of cholinergic neurons. It has also been shown that tibolone decreases the hyperphosphorylation of the neuronal protein Tau in the hippocampus and cerebellum [35]. In addition, tibolone reduces anxiety, at least in young female rats [36].…”