Estradiol and 3β-diol protect female cortical astrocytes by regulating connexin 43 Gap Junctions

While estrogens have been described to protect or preserve neuronal function in the face of insults such as oxidative stress, the prevailing mechanistic model would suggest that these steroids exert direct effects on the neurons. However, there is growing evidence that glial cells, such as astrocytes, are key cellular mediators of protection. Noting that connexin 43 (Cx43), a protein highly expressed in astrocytes, plays a key role in mediating inter-cellular communication, we hypothesized that Cx43 is a target of estradiol (E2), and the estrogenic metabolite of DHT, 3 beta-diol. Additionally, we sought to determine if either or both of these hormones attenuate oxidative stress-induced cytotoxicity by eliciting a reduction in Cx43 expression or inhibition of Cx43 channel permeability. Using primary cortical astrocytes, we found that E2 and 3 beta-diol were each protective against the mixed metabolic/oxidative insult, iodoacetic acid (IAA). Moreover, these effects were blocked by estrogen receptor antagonists. However, E2 and 3 beta-diol did not alter Cx43 mRNA levels in astrocytes but did inhibit IAA-induced Cx43 gap junction opening/permeability. Taken together, these data implicate astrocyte Cx43 gap junction as an understudied mediator of the cytoprotective effects of estrogens in the brain. Given the wide breadth of disease states associated with Cx43 function/dysfunction, further understanding the relationship between gonadal steroids and Cx43 channels may contribute to a better understanding of the biological basis for sex differences in various diseases.

Automated summary

Estrogens have been shown to protect neuronal function in the presence of oxidative stress, and this protection may be mediated by the glial cells, specifically astrocytes, through the protein connexin 43 (Cx43). This study found that estradiol (E2) and the estrogenic metabolite 3 beta-diol were protective against oxidative stress in astrocytes, and this protection was dependent on estrogen receptors. However, the hormones did not affect Cx43 mRNA levels but inhibited Cx43 channel permeability. Understanding the relationship between gonadal steroids and Cx43 channels may contribute to a better understanding of sex differences in various diseases.