Date of Award
Open Access Dissertation
Rosemarie M. Booze
Despite the advent of highly active antiretroviral therapy (HAART), neurological disorders develop in most people infected with human immunodeficiency virus type 1 (HIV-1). The poor CNS delivery of anti-retrovirals allows continued virus production and renders neurons susceptible to the toxic effects of released viral proteins. The neurotoxic potential of HIV-1 viral protein Tat has been shown to include excitotoxicity, oxidative stress, and mitochondrial dysfunction leading to subsequent cell death. Thus, Tat is thought to have a key role in the pathogenesis of HIV-associated neurodegeneration. Estrogens are universally considered to be neuroprotective, as such; estrogens have positive implications in the treatment of neurodegenerative disease, as well as acute neuronal death. Estrogen neuroprotective mechanisms may include a direct neuronal anti-apoptotic effect as estrogen modulates actions of key regulators of the mitochondrial/intrinsic apoptotic cascade. However, estrogen therapy is associated with increased risk of breast and uterine cancers. Estrogen receptors (ERs) are present in the brain and are thought to mediate estrogen protective actions. Compounds that selectively target estrogens protective effects without eliciting its negative side effects may serve as viable therapeutic options.
In the present study, we tested the ability of estrogen and phytoestrogens (genistein and daidzein) to protect against apoptotic signaling in cortical cell cultures exposed to Tat 1-86 (50 nM), and additionally, whether the beneficial actions of estrogen and phytoestrogens involved an estrogen receptor sensitive mechanism. We demonstrated that estrogen pretreatment significantly delayed Tat-induced cell death in primary cortical cultures. Pretreatment with 17β-estradiol or phytoestrogens attenuated the increased expression of anti-apoptotic protein Bcl-2, pro-apoptotic protein Bax and activation of caspases linked to mitochondrial apoptotic pathway following Tat exposure. In addition, select components of apoptotic pathway signaling appear more sensitive to estrogen receptor (ER) activation, as the addition of ER antagonist ICI182,780 reversed downregulation of Bax and caspase 3, while effects on Tat-induced Bcl-2 and caspase 9 expression were maintained. Moreover, the addition of preferential ERα and ERβ antagonists (MPP dihydrochloride and PHTPP) indicated that 17β-estradiol and phytoestrogen effects on caspase 3 may be mediated by both receptor subtypes, while ERβ was more involved in effects on Bax. Our data suggest that 17β-estradiol and phytoestrogen are able to intervene against HIV Tat-induced cortical neuronal dysfunction via intersecting mitochondrial apoptotic pathway signaling in an ER-sensitive manner.
Adams, S. M.(2020). 17 β-Estradiol and Phytoestrogens Attenuate Apoptotic Cell Death in HIV-1 Tat Exposed Primary Cortical Cultures. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/5986