Human immunodeficiency virus‐1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic function

Maragos, William F.; Young, Kristie Lee; Turchan, Jadwiga; Guseva, M V.; Pauly, James R.; Nath, Avi; Cass, Wayne A.

doi:10.1046/j.1471-4159.2002.01212.x

Cited by 115 publications

(94 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Evidence linking Tat to HIV-1 associated dementia includes findings that Tat increases monocyte/macrophage infiltration into brain, damage to brain-resident cells, and brain levels of TNF-α (Philippon et al, 1994;Jones et al, 1998;Nath and Geiger, 1998;Rappaport et al, 1999;Pu et al, 2003;Saha and Pahan, 2003). Further linking Tat to the pathogenesis of HIV-1 associated dementia, as we and others have shown, are findings that Tat decreases neuronal cell function and viability by directly activating neurons, by dysregulation of intracellular levels of calcium, by increasing excitotoxicity, and by synergizing with harmful effects of pro-inflammatory cytokines, other HIV-1 proteins, and drugs of abuse (Sabatier et al, 1991;Magnuson et al, 1995;Nath et al, 1996;New et al, 1997;Cheng et al, 1998;Jones et al, 1998;Kruman et al, 1998;New et al, 1998;Shi et al, 1998;Haughey et al, 1999;Bonavia et al, 2001;Gurwell et al, 2001;Maragos et al, 2002;Prendergast et al, 2002;Self et al, 2004b;Perry et al, 2005). In addition to the direct toxic effects of Tat on neurons, Tat can damage neurons indirectly through the release of toxins from macrophages and glial cells.…”

Section: Introductionmentioning

confidence: 81%

Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

Buscemi

Ramonet

Geiger

2007

Neurobiology of Disease

View full text Add to dashboard Cite

HIV-1 infection causes, with increasing prevalence, neurological disorders characterized in part by neuronal cell death. The HIV-1 protein Tat has been shown to be directly and indirectly neurotoxic. Here, we tested the hypothesis that a non-neurotoxic epitope of Tat can, through actions on immune cells, increase neuronal cell death. Tat 1-72 and a mutant Tat 1-72 lacking the neurotoxic epitope (Tat Δ31-61 ) concentration-dependently and markedly increased TNF-α production in macrophagelike differentiated human U937 and THP-1 cells, in mouse peritoneal macrophages and in mouse brain microglia. Tat 1-72 was but Tat Δ31-61 was not neurotoxic when applied directly to neurons. Supernatants from U937 cells treated with either Tat 1-72 or Tat Δ31-61 were neurotoxic and their immunoneutralization with an anti-TNF-α antibody decreased Tat 1-72 -and Tat Δ31-61 -induced neurotoxicity. Together, these results demonstrate that the neurotoxic epitope of Tat 1-72 is different from the epitope that is indirectly neurotoxic following production of TNF-α from immune cells, and suggest that therapeutic interventions against TNF-α might be beneficial against HIV-1 associated neurological disorders.

show abstract

Section: Introductionmentioning

confidence: 81%

Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

Buscemi

Ramonet

Geiger

2007

Neurobiology of Disease

View full text Add to dashboard Cite

show abstract

“…Although the exact mechanisms of brain injury underlying the interaction between HIV and methamphetamine are unclear, HIV-1 Tat protein and methamphetamine synergistically interacted to reduce striatal dopaminergic function (up to a fivefold reduction) in an in vivo rodent model (26). One possible pathway to the combined neurotoxicity might be a methamphetamine-induced increase in extracellular dopamine, which in turn would activate HIV replication.…”

Section: Discussionmentioning

confidence: 99%

Additive Effects of HIV and Chronic Methamphetamine Use on Brain Metabolite Abnormalities

Chang

Ernst²,

Speck³

et al. 2005

AJP

162

120

View full text Add to dashboard Cite

Objective-Proton magnetic resonance spectroscopy ( 1 H-MRS) showed decreased neuronal marker N-acetylaspartate and increased glial marker myo-inositol in subjects with chronic methamphetamine use and in subjects infected with HIV. The authors sought to determine whether HIV and a history of chronic methamphetamine use might have additive or interactive effects on brain metabolite abnormalities.Method-1 H-MRS was performed in 68 HIV-positive subjects (24 with a history of chronic methamphetamine use with a lifetime exposure of a mean of 2,167 g [SD=2,788] and last use a mean of 4.9 months earlier [SD=6.0]; 44 with no history of drug abuse) and 75 HIV-negative subjects (36 with a history of chronic methamphetamine use with a lifetime exposure of a mean of 8,241 g [SD=16,850] and last use a mean of 6.3 months earlier [SD=7.8]; 39 with no history of drug abuse). Concentrations of N-acetylaspartate, creatine, choline, and myo-inositol were measured in the frontal cortex, frontal white matter, and basal ganglia.Results-HIV-negative subjects with a history of chronic methamphetamine use showed lower concentrations of the neuronal marker N-acetylaspartate in the frontal white matter and basal ganglia and higher concentrations of choline compounds and the glial marker myo-inositol in the frontal cortex, relative to subjects with no history of drug abuse. HIV-positive status was associated with lower concentrations of N-acetylaspartate and creatine in the frontal cortex and higher concentrations of myo-inositol in the white matter, compared with HIV-negative status.Compared to the mean concentrations of metabolites in HIV-negative subjects with no history of drug abuse, the mean concentrations in subjects with HIV and chronic methamphetamine use showed additive effects on N-acetylaspartate in all three regions (−9% in the basal ganglia, −7% in the frontal white matter, and −6% in the frontal gray matter), on creatine in the basal ganglia (−7%), and on myo-inositol in the frontal white matter (+11%).Conclusions-The combined effects of HIV and chronic methamphetamine use were consistent with an additive model, suggesting additional neuronal injury and glial activation due to the comorbid conditions.Address correspondence and reprint requests to Dr. Chang, Department of Medicine, John A. Burns School of Medicine, University of Hawaii, 1356 Lusitana St., 7th Floor, Honolulu, HI 96813; LChang@hawaii.edu. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptMethamphetamine, a psychostimulant with reinforcing effects similar to those of cocaine (1), has re-emerged as a major drug of abuse worldwide and is commonly used among HIVinfected individuals. In Thailand, both inhalation and injection of methamphetamine are associated with higher risk for HIV infection (2). Similarly, studies and large surveys in the United States (California and New York) consistently found that even noninjection methamphetamine use contributes to higher rates of unprotected sexual activity in both men and wo...

show abstract

“…However, several associated lines of investigation offer strong support for this possibility. First, the neurotoxic HIV Tat protein interacts synergistically with methamphetamine and causes greater toxicity in mice than either agent alone (Maragos et al, 2002;Cass et al, 2003). HIV-positive individuals who abuse methamphetamine suffer greater neuronal damage than nonabusers (Langford et al, 2003).…”

Section: Downloaded Frommentioning

confidence: 99%

Methamphetamine Neurotoxicity in Dopamine Nerve Endings of the Striatum Is Associated with Microglial Activation

Thomas

Walker²,

Benjamins³

et al. 2004

J Pharmacol Exp Ther

280

282

View full text Add to dashboard Cite

Methamphetamine intoxication causes long-lasting damage to dopamine nerve endings in the striatum. The mechanisms underlying this neurotoxicity are not known but oxidative stress has been implicated. Microglia are the major antigen-presenting cells in brain and when activated, they secrete an array of factors that cause neuronal damage. Surprisingly, very little work has been directed at the study of microglial activation as part of the methamphetamine neurotoxic cascade. We report here that methamphetamine activates microglia in a dose-related manner and along a time course that is coincident with dopamine nerve ending damage. Prevention of methamphetamine toxicity by maintaining treated mice at low ambient temperature prevents drug-induced microglial activation. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which damages dopamine nerve endings and cell bodies, causes extensive microglial activation in striatum as well as in the substantia nigra. In contrast, methamphetamine causes neither microglial activation in the substantia nigra nor dopamine cell body damage. Dopamine transporter antagonists (cocaine, WIN 35,428 [(Ϫ)-2-␤-carbomethoxy-3-␤-(4-fluorophenyl)tropane 1,5-naphthalenedisulfonate], and nomifensine), selective D1 (SKF 82958 [(Ϯ)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide]), D2 (quinpirole), or mixed D1/D2 receptor agonists (apomorphine) do not mimic the effect of methamphetamine on microglia. Hyperthermia, a prominent and dangerous clinical response to methamphetamine intoxication, was also ruled out as the cause of microglial activation. Together, these data suggest that microglial activation represents an early step in methamphetamine-induced neurotoxicity. Other neurochemical effects resulting from methamphetamine-induced overflow of DA into the synapse, but which are not neurotoxic, do not play a role in this response.

show abstract

Human immunodeficiency virus‐1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic function

Cited by 115 publications

References 63 publications

Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-α-mediated neurotoxicity

Additive Effects of HIV and Chronic Methamphetamine Use on Brain Metabolite Abnormalities

Methamphetamine Neurotoxicity in Dopamine Nerve Endings of the Striatum Is Associated with Microglial Activation

Contact Info

Product

Resources

About