Soy isoflavones genistein and daidzein exert anti-apoptotic actions via a selective ER-mediated mechanism in neurons following HIV-1 Tat(1-86) exposure.

Background: HIV-1 viral protein Tat partially mediates the neural dysfunction and neuronal cell death associated with HIV-1 induced neurodegeneration and neurocognitive disorders. Soy isoflavones provide protection against various neurotoxic insults to maintain neuronal function and thus help preserve neurocognitive capacity.

Methodology/principal Findings: We demonstrate in primary cortical cell cultures that 17β-estradiol or isoflavones (genistein or daidzein) attenuate Tat(1-86)-induced expression of apoptotic proteins and subsequent cell death.

Adolescent HIV-1 transgenic rats: evidence for dopaminergic alterations in behavior and neurochemistry revealed by methamphetamine challenge.

Since the introduction of combination antiretroviral therapy (cART) in the mid-90s, the most severe forms of HIV-1-associated neurocognitive disorders (HAND) have diminished. However, milder forms of HAND remain prevalent. Basic and clinical studies implicate alterations in the dopaminergic (DAergic) system in HIV-1 infection.

D1/NMDA receptors and concurrent methamphetamine+ HIV-1 Tat neurotoxicity.

The interactive effects of HIV-1 infection and methamphetamine (METH) abuse in producing cognitive dysfunction represent a serious medical problem; however, the neural mechanisms underlying this interactive neurotoxicity remain elusive. In this study, we report that a combination of low, sub-toxic doses of METH + HIV-1 Tat 1-86 B, but not METH + HIV-1 gp120, directly induces death of rodent midbrain neurons in vitro. The effects of D1- and NMDA-receptor specific antagonists (SCH23390 and MK-801, respectively) on the neurotoxicity of different doses of METH or HIV-1 Tat alone and on the METH + HIV-1Tat interaction in midbrain neuronal cultures suggest that the induction of the cell death cascade by METH and Tat requires both dopaminergic (D1) and N-methyl D-aspartate (NMDA) receptor-mediated signaling.

ER-β mediates 17β-estradiol attenuation of HIV-1 Tat-induced apoptotic signaling.

The protective actions of estrogen have been well evaluated in various models of neurodegeneration. These neuroprotective mechanisms may include a direct neuronal antiapoptotic effect as estrogen modulates actions of key regulators of the mitochondrial/intrinsic apoptotic cascade. We tested the ability of estrogen to protect against apoptotic signaling in cortical cell cultures exposed to Tat 1-86 (50 nM), and additionally, whether the beneficial actions of estrogen involved an estrogen receptor sensitive mechanism.

Evidence for developmental dopaminergic alterations in the human immunodeficiency virus-1 transgenic rat.

Neurologic impairments associated with human immunodeficiency virus (HIV) infection in pediatric patients may affect quality of life, and can develop despite antiretroviral therapy (ART). Behavioral changes observed in clinical studies of HIV-infected children suggest alterations in dopaminergic neurotransmission. Findings from our model of choice, the HIV-1 transgenic rat, reveal a significant increase in phosphorylated tyrosine hydroxylase protein expression and a decrease in dopamine transporter mRNA, without changes in tyrosine hydroxylase (TH) or dopamine transporter (DAT) protein or in more general markers of protein and gene expression levels in the HIV-1 transgenic rat midbrain.

Attenuated neurotoxicity of the transactivation-defective HIV-1 Tat protein in hippocampal cell cultures.

This study reports that the cysteine 22-->glycine 22 substitution in the HIV-1 Tat 1-86 B significantly attenuates its neurotoxicity. Consistent with previous studies, direct interactions of rat hippocampal cells with Tat 1-86 B were shown to cause dose-dependent and time-dependent neurotoxicity associated with activation of caspases from the mitochondrial apoptotic pathway. Despite the similar binding/uptake properties, Cys22 Tat 1-86 B failed to induce significant neurotoxicity and activation of caspases 9 and 3/7 in hippocampal primary cultures.

Neuronal survival and resistance to HIV-1 Tat toxicity in the primary culture of rat fetal neurons.

In this study we report that primary cultures of rat fetal neurons contain subpopulations of cells that may be sensitive or resistant to HIV-1 Tat neurotoxicity. We demonstrate that rapid binding/uptake of Tat 1-86 for 2 h was sufficient to trigger caspase activation and neurodegeneration in rat fetal midbrain cell cultures. The uptake of Tat was followed by an increase in MCP1 (CCL2) immunoreactivity.

Different effects of selective dopamine uptake inhibitors, GBR 12909 and WIN 35428, on HIV-1 Tat toxicity in rat fetal midbrain neurons.

Drug abuse is a risk factor for neurological complications in HIV infection. Cocaine has been shown to exacerbate HIV-associated brain pathology and enhance neurotoxicity of HIV-1 Tat and gp120 proteins. In this study, we found that the selective inhibitor of dopamine transporter (DAT) function, 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-4-(3-phenylpropyl) piperazine (GBR 12909, vanoxerine), but not the selective inhibitors of serotonin and norepinephrine (SERT and NET) transporters, sertraline and nizoxetine, emulated cocaine-mediated enhancement of Tat neurotoxicity in rat fetal midbrain primary cell cultures.

Neurotoxicity of HIV-1 Tat protein: involvement of D1 dopamine receptor.

Neurotoxic viral proteins released from HIV-infected cells are believed to play a major role in the pathogenesis of the dementia displayed in a significant number of AIDS patients. HIV-1 associated neuropathology severely affects dopaminergic regions of the brain. Growing evidence indicates that HIV-1 neurotoxic proteins, such as Tat may affect the function of the dopamine transmission system.

Dopaminergic marker proteins in the substantia nigra of human immunodeficiency virus type 1-infected brains.

With the advent of highly active antiretroviral therapy, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is becoming a more chronic, manageable disease; nevertheless, the prevalence of neurological complications of AIDS is increasing. In this study, protein levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the substantia nigra of HIV-infected brains and -seronegative controls were determined by immunoblotting. The immunoreactivity of neuronal specific enolase (NSE) was used to assess cell loss.

Cocaine-mediated enhancement of Tat toxicity in rat hippocampal cell cultures: the role of oxidative stress and D1 dopamine receptor.

It is becoming widely accepted that psychoactive drugs can significantly alter the progression of neuropathological changes in the HIV-infected brain. The use of cocaine can aggravate the neurotoxic effects of HIV-1 proteins such as HIV-1 transactivating protein Tat and virus' envelope protein gp120. HIV-1 Tat is believed to play an important role in pathogenesis of HIV dementia (HAD).

HIV-1 Tat neurotoxicity in primary cultures of rat midbrain fetal neurons: changes in dopamine transporter binding and immunoreactivity.

HIV-1 neurotoxic proteins (Tat, gp120) are believed to play a major role in pathogenesis of dementia in a significant portion of the AIDS patient population. Dopaminergic systems appear to be particularly important in HIV-associated dementia. In the current studies, we determined that primary cell cultures prepared from the midbrain of 18-day-old rat fetuses are sensitive to Tat neurotoxicity and investigated the possible effects of Tat on DAT-specific ligand binding and DAT immunoreactivity in rat fetal midbrain cultures.

Cell culture models of oxidative stress and injury in the central nervous system.

Constantly growing body of evidence suggests that hallmarks of oxidative stress are present in various central nervous system (CNS) disorders. Technological advantages in cell culturing made it possible to use neural cell/tissue cultures as experimental models for investigation of molecular mechanisms which underlie the development of oxidative stress condition, damage and adaptive responses to oxidative insults. This review is focused on the application of cell culture methodology for studies of oxidative stress condition in the brain.

Vitamin E protects against alcohol-induced cell loss and oxidative stress in the neonatal rat hippocampus.

Oxidative stress has been proposed as a possible mechanism underlying nervous system deficits associated with Fetal Alcohol Syndrome (FAS). Current research suggests that antioxidant therapy may afford some level of protection against the teratogenic effects of alcohol. This study examined the effectiveness of antioxidant treatment in alleviating biochemical, neuroanatomical, and behavioral effects of neonatal alcohol exposure.

Temporal relationships between HIV-1 Tat-induced neuronal degeneration, OX-42 immunoreactivity, reactive astrocytosis, and protein oxidation in the rat striatum.

HIV-1 transactivating protein Tat is neurotoxic and is believed to play a role in the development of AIDS-associated dementia complex. Neurotoxicity of Tat may be associated with oxidative stress. In this study we examined temporal progression of histopathological changes induced by a single microinjection of Tat 1-72 into the rat striatum.