Neuroprotective and neurotoxic outcomes of androgens and estrogens in an oxidative stress environment

Abstract

Background: The role of sex hormones on cellular function is unclear. Studies show androgens and estrogens are protective in the CNS, whereas other studies found no effects or damaging effects. Furthermore, sex differences have been observed in multiple oxidative stress-associated CNS disorders, such as Alzheimer's disease, depression, and Parkinson's disease. The goal of this study is to examine the relationship between sex hormones (i.e., androgens and estrogens) and oxidative stress on cell viability. Methods: N27 and PC12 neuronal and C6 glial phenotypic cell lines were used. N27 cells are female rat derived, whereas PC12 cells and C6 cells are male rat derived. These cells express estrogen receptors and the membraneassociated androgen receptor variant, AR45, but not the full-length androgen receptor. N27, PC12, and C6 cells were exposed to sex hormones either before or after an oxidative stressor to examine neuroprotective and neurotoxic properties, respectively. Estrogen receptor and androgen receptor inhibitors were used to determine the mechanisms mediating hormone-oxidative stress interactions on cell viability. Since the presence of AR45 in the human brain tissue was unknown, we examined the postmortem brain tissue from men and women for AR45 protein expression. Results: Neither androgens nor estrogens were protective against subsequent oxidative stress insults in glial cells. However, these hormones exhibited neuroprotective properties in neuronal N27 and PC12 cells via the estrogen receptor. Interestingly, a window of opportunity exists for sex hormone neuroprotection, wherein temporary hormone deprivation blocked neuroprotection by sex hormones. However, if sex hormones are applied following an oxidative stressor, they exacerbated oxidative stress-induced cell loss in neuronal and glial cells.

Unexpected Role of Physiological Estrogen in Acute Stress-Induced Memory Deficits

“…Together, these studies and others ( Shansky et al, 2004 , 2009 ) indicate that estrogen is not universally protective, and the interaction of stress and estrogen on memory is complex. Hormone levels, whether these were endogenous or exogenous, delivery regimen, period of deprivation, stressor type, memory task, time of day, and the underlying brain regions and networks are all crucial in interpreting the interactions between estrogen, stress, and memory ( Holmes et al, 2002 ; McLaughlin et al, 2008 ; Barha et al, 2010 ; Babb et al, 2014 ; Korol and Pisani, 2015 ; Graham and Scott, 2018 ; Duong et al, 2020 ).…”

Steroid Sulfation in Neurodegenerative Diseases

“…Regarding the unconjugated steroids, the reactions between DHEA and androst-5-ene-3β,17β-diol, androstenedione and testosterone and estrone and estradiol are preferentially conducted in the reductase direction (Purohit and Foster, 2012;Mostaghel, 2013). generally act as neuroprotective substances (Fargo et al, 2009;Spence and Voskuhl, 2012;Duong et al, 2020;Yang et al, 2020) and promote neurogenesis and neuro-regeneration (Pillerová et al, 2021;Azcoitia et al, 2019). These processes in the brain take place through classical nuclear steroid receptors (estrogen receptor α and β-ERα and ERβ, androgen receptor-AR, progesterone receptor-PR), non-classical membraneassociated steroid receptors (AR, ERα, ERβ) and transmembrane receptors (zinc transporter protein 9, G protein coupled estrogen receptor 1) (Pillerová et al, 2021).…”

“…Particularly E2 exert pleiotropic effects there, facilitating learning and memory ( Frick, 2015 ; Sun et al, 2019 ; Luine and Frankfurt, 2012 ; Tozzi et al, 2020 ; Dieni et al, 2020 ), as well as influencing emotional ( Altemus, 2019 ) and sexual behavior ( Diotel et al, 2018 ). They generally act as neuroprotective substances ( Fargo et al, 2009 ; Spence and Voskuhl, 2012 ; Duong et al, 2020 ; Yang et al, 2020 ) and promote neurogenesis and neuro-regeneration ( Pillerová et al, 2021 ; Azcoitia et al, 2019 ). These processes in the brain take place through classical nuclear steroid receptors (estrogen receptor α and β-ERα and ERβ, androgen receptor-AR, progesterone receptor-PR), non-classical membrane-associated steroid receptors (AR, ERα, ERβ) and transmembrane receptors (zinc transporter protein 9, G protein coupled estrogen receptor 1) ( Pillerová et al, 2021 ).…”

Androgens and Parkinson's Disease: A Review of Human Studies and Animal Models

“… 60 In a dopaminergic cell line (N27 cells), flutamide inhibited testosterone-induced apoptosis, 61 and apoptosis effect of testosterone was recently reported to be mediated by a membrane androgen receptor in N27 cells. 62 A case report showed that low-dose cyproterone acetate treatment reduced sexual acting out in a man with PD and dementia without relevant side effects. 63 As reviewed above, there are limited studies with the androgen receptor inhibitors in PD, whereas the 5α-reductase inhibitors have led to recent interesting findings.…”