Estrogen attenuates gp120- and tat1-72-induced oxidative stress and prevents loss of dopamine transporter function

Abstract

Postmenopausal women who are infected with HIV are at risk for experiencing dementia and Parkinson's-like symptoms associated with low levels of estrogen. Neurotoxic damage leading to these symptoms may involve HIV-associated proteins gp120 and/or tat(1-72) (tat). Our hypothesis is that 17beta-Estradiol (E(2)) is an effective agent for protection against gp120/tat-induced damage associated with increased oxidative stress, with particular focus on peroxynitrite-induced oxidative stress. We used SK-N-SH cells and striatal synaptosomes from Sprague-Dawley rats as model systems to assess neuroprotection by E(2). Cells coincubated with SIN-1(3-morpholinosydnonimine) or tat and gp120, together or separately, significantly increased oxidative stress on the SK-N-SH cells, as indicated by the increase in the levels of dichlorofluorescein (DCFH) fluorescence. These data suggest that a component of tat and gp120 neurotoxicity may be due to increased oxidative stress. Coincubation with E(2) attenuated tat- and gp120-induced increase in fluorescence. Coincubation with progesterone had no effect on tat-induced fluorescence, whereas coincubation with the E(2) antagonist ICI 182,780 and E(2) completely prevented the effects observed with E(2) alone. Both gp120 and tat decreased [(3)H] dopamine uptake into striatal synaptosomes by decreasing the V(max) of the dopamine transporter (DAT). Pretreatment of synaptosomes with E(2) (100 nM) partially reversed this reduction. In conclusion, E(2) appears to be effective for preventing the oxidative stress and loss of DAT function associated with gp120/tat neurotoxicity.

Wingless-type Mammary Tumor Virus Integration Site Family, Member 5A (Wnt5a) Regulates Human Immunodeficiency Virus Type 1 (HIV-1) Envelope Glycoprotein 120 (gp120)-induced Expression of Pro-Inflammatory Cytokines via the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) and c-Jun N-terminal Kinase (JNK) Signaling Pathways

“…This working model illustrates a Wnt5a signaling cascade that coordinates the neuroinflammaory responses to HIV gp120. gp120 is a major viral coat protein that causes HIV-1-associated CNS neuroinflammation and neurotoxicity (59,60). However, the molecular mechanism by which gp120 elicits neuroinflammation in vivo is still incompletely understood.…”

Pyruvate protects mitochondria from oxidative stress in human neuroblastoma SK-N-SH cells

“…SK-N-SH cells respond to numerous insults including β-amyloid, mitochondrial permeability transition, and serum deprivation, indicating that this cell line could be very useful in the assessment of neurotoxicity and neuroprotection [4]. SK-N-SH cells have been used by this and other laboratories [5,20,21,46,[48][49][50][51]56] as an in vitro model for studying potential neuroprotection mechanisms. Multiple mechanisms have been suggested to contribute to the cytoprotective effect of pyruvate.…”

Memantine Upregulates BDNF and Prevents Dopamine Deficits in SIV-Infected Macaques: A Novel Pharmacological Action of Memantine

“…Clinical features of HIV dementia are attributed to a dysfunction in dopaminergic systems (Koutsilieri et al, 2002b). Moreover, dopaminergic cell loss is evident in the substantia nigra of AIDS patients (Itoh et al, 2000), and HIV proteins affect dopamine function (Theodore et al, 2006;Wallace et al, 2006). We have shown previously that dopamine deficits constitute initial evidence for brain dysfunction in a susceptible brain region, the putamen in early SIV-infection (Scheller et al, 2005).…”