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Research ArticleToxicology

Dendritic Spine Injury Induced by the 8-Hydroxy Metabolite of Efavirenz

Luis B. Tovar-y-Romo, Namandjé N. Bumpus, Daniel Pomerantz, Lindsay B. Avery, Ned Sacktor, Justin C. McArthur and Norman J. Haughey
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 696-703; DOI: https://doi.org/10.1124/jpet.112.195701
Luis B. Tovar-y-Romo
Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections (L.B.T-y-R., D.P., N.S., J.C.M., N.J.H.), and Departments of Pharmacology and Molecular Sciences (N.N.B., L.B.A.) and Psychiatry (N.J.H.), The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Namandjé N. Bumpus
Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections (L.B.T-y-R., D.P., N.S., J.C.M., N.J.H.), and Departments of Pharmacology and Molecular Sciences (N.N.B., L.B.A.) and Psychiatry (N.J.H.), The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Daniel Pomerantz
Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections (L.B.T-y-R., D.P., N.S., J.C.M., N.J.H.), and Departments of Pharmacology and Molecular Sciences (N.N.B., L.B.A.) and Psychiatry (N.J.H.), The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Lindsay B. Avery
Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections (L.B.T-y-R., D.P., N.S., J.C.M., N.J.H.), and Departments of Pharmacology and Molecular Sciences (N.N.B., L.B.A.) and Psychiatry (N.J.H.), The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Ned Sacktor
Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections (L.B.T-y-R., D.P., N.S., J.C.M., N.J.H.), and Departments of Pharmacology and Molecular Sciences (N.N.B., L.B.A.) and Psychiatry (N.J.H.), The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Justin C. McArthur
Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections (L.B.T-y-R., D.P., N.S., J.C.M., N.J.H.), and Departments of Pharmacology and Molecular Sciences (N.N.B., L.B.A.) and Psychiatry (N.J.H.), The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Norman J. Haughey
Department of Neurology, Richard T. Johnson Division of Neuroimmunology and Neurological Infections (L.B.T-y-R., D.P., N.S., J.C.M., N.J.H.), and Departments of Pharmacology and Molecular Sciences (N.N.B., L.B.A.) and Psychiatry (N.J.H.), The Johns Hopkins University School of Medicine, Baltimore, Maryland
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Abstract

Despite combination antiretroviral therapies (cARTs), a significant proportion of HIV-infected patients develop HIV-associated neurocognitive disorders (HAND). Ongoing viral replication in the central nervous system (CNS) caused by poor brain penetration of cART may contribute to HAND. However, it has also been proposed that the toxic effects of long-term cART may contribute to HAND. A better understanding of the neurotoxic potential of cART is critically needed in light of the use of CNS-penetrating cARTs to contend with the virus reservoir in the brain. The efavirenz (EFV) metabolites 7-hydroxyefavirenz (7-OH-EFV) and 8-hydroxyefavirenz (8-OH-EFV) were synthesized and purified, and their chemical structures were confirmed by mass spectrometry and NMR. The effects of EFV, 7-OH-EFV, and 8-OH-EFV on calcium, dendritic spine morphology, and survival were determined in primary neurons. EFV, 7-OH-EFV, and 8-OH-EFV each induced neuronal damage in a dose-dependent manner. However, 8-OH-EFV was at least an order of magnitude more toxic than EFV or 7-OH-EFV, inducing considerable damage to dendritic spines at a 10 nM concentration. The 8-OH-EFV metabolite evoked calcium flux in neurons, which was mediated primarily by L-type voltage-operated calcium channels (VOCCs). Blockade of L-type VOCCs protected dendritic spines from 8-OH-EFV-induced damage. Concentrations of EFV and 8-OH-EFV in the cerebral spinal fluid of HIV-infected subjects taking EFV were within the range that damaged neurons in culture. These findings demonstrate that the 8-OH metabolite of EFV is a potent neurotoxin and highlight the importance of directly determining the effects of antiretroviral drugs and drug metabolites on neurons and other brain cells.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant AA0017408], the National Institutes of Health National Institute of Mental Health [Grants MH077542, MH075673, MH075673, MH71150]; the National Institutes of Health National Institute on Aging [Grant AG034849]; and the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS049465].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.195701.

  • ABBREVIATIONS:

    cART
    combination antiretroviral therapy
    AM
    acetoxymethyl ester
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    ANOVA
    analysis of variance
    ARV
    antiretroviral drug
    [Ca2+]c
    cytosolic calcium
    CNS
    central nervous system
    CSF
    cerebrospinal fluid
    EFV
    efavirenz
    7-OH-EFV
    7-hydroxyefavirenz
    8-OH-EFV
    8-hydroxyefavirenz
    F-EFV
    fluorinated analog of EFV
    HAND
    HIV-associated neurocognitive disorders
    HPLC
    high-performance liquid chromatography
    MK-801
    (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine
    NBQX
    2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline
    NMDA
    N-methyl-d-aspartate
    P450
    cytochrome P450
    PBS
    phosphate-buffered saline
    PPADS
    4-[(E)-{4-formyl-5-hydroxy-6-methyl-3-[(phosphonooxy)methyl]pyridin-2-yl}diazenyl]benzene-1,3-disulfonic acid
    VOCC
    voltage-operated calcium channel.

  • Received April 16, 2012.
  • Accepted September 10, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
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Research ArticleToxicology

Efavirenz Metabolites Damage Neuronal Spines

Luis B. Tovar-y-Romo, Namandjé N. Bumpus, Daniel Pomerantz, Lindsay B. Avery, Ned Sacktor, Justin C. McArthur and Norman J. Haughey
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 696-703; DOI: https://doi.org/10.1124/jpet.112.195701

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Research ArticleToxicology

Efavirenz Metabolites Damage Neuronal Spines

Luis B. Tovar-y-Romo, Namandjé N. Bumpus, Daniel Pomerantz, Lindsay B. Avery, Ned Sacktor, Justin C. McArthur and Norman J. Haughey
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 696-703; DOI: https://doi.org/10.1124/jpet.112.195701
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