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Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV-seropositive individuals with cognitive impairment

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Abstract

Elevated cerebrospinal fluid (CSF) levels of markers of oxidative stress, neuronal injury, and inflammation and decreased neurotransmitter levels have been reported in HIV-associated neurocognitive disorders (HAND). Minocycline may have a neuroprotective effect by inhibiting inducible nitric oxide synthase, which produces nitric oxide, a compound that induces oxygen free radical production. In A5235, “Phase II, Randomized, Placebo-Controlled, Double-Blind Study of Minocycline in the Treatment of HIV-Associated Cognitive Impairment,” minocycline was not associated with cognitive improvement, but the effect on the above CSF measures was not examined previously. The objective of this study was to examine the effect of minocycline on markers of oxidative stress, neuronal injury, neurotransmitter levels, and inflammation from CSF in participants in A5235. One hundred seven HIV+ individuals received either minocycline 100 mg or placebo orally every 12 h for 24 weeks. Twenty-one HIV+ individuals received the optional lumbar punctures. Lipid and protein markers of oxidative stress (e.g., ceramides and protein carbonyls), glutamate, neurotransmitter precursors, kynurenine metabolites, neurofilament heavy chain, and inflammatory cytokines were measured in the CSF before and after treatment. The 24-week change in ceramides was larger in a beneficial direction in the minocycline group compared to the placebo group. The two groups did not differ in the 24-week changes for other markers.

These results suggest that minocycline may decrease lipid markers of oxidative stress (ceramides) in individuals with HAND; however, an effect of minocycline on other CSF markers was not observed. A larger sample size is needed to further validate these results.

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Acknowledgments

The authors would like to thank Marie Sonderman for administrative support. The statistical analysis was carried out by S. Miyahara. This study was supported in part by the AIDS Clinical Trials Group (ACTG) funded by the following: NIAID, AI38858, AI38855, AI27670, AI27668, AI27658, AI34853, AI127660, AI27664, AI27659, AI25903, AI25915, AI046376, AI46370, AI46381, AI50410, AI25868, AI46386, CFAR AI 127757, the Neurologic AIDS Research Consortium, NS32228, NS081196, NS055628, MH075673, MH64409, AI 068634 and GCRC Units funded by the National Center for Research Resources (NCRR), RR00052, RR00044, RR00046. The NCT number for this study is NCT 00361257. This study is registered in Clinical Trials.gov. Participating site ACTG Clinical Trials Unit (CTU) grant numbers include the following:

University of California, San Diego Antiviral Research CTU Grant AI069432; Johns Hopkins University CTU Grant AI069465; CTSA Grant UL1 RR025005; UCLA School of Medicine CTU Grant AI069424; Washington University (St. Louis) CTU Grant AI069495; The Research & Education Group-Portland CRS CTU Grant AI069503; Henry Ford Hospital CRS CTU Grant AI069503; Massachusetts General Hospital CTU Grant AI069472; NYU/NYC HHC at Bellevue CTU Grant AI069532; Univ. of Colorado Hospital CTU Grant AI069450; Northwestern University CTU Grant AI069471; Virginia Commonwealth University Medical Center CRS CTU Grant AI069503; University of Washington (Seattle) CTU Grant AI069434; University of North Carolina CTU Grant AI069423; University of Rochester Medical Center CTU Grant AI069511; Emory University, The Ponce de Leon Center CTU Grant AI069452; and University of Pennsylvania, Philadelphia CTU Grant AI069467-04.

The project described was supported by Award Number AI068636 from the National Institute of Allergy and Infectious Diseases, National Institute of Mental Health (NIMH), and National Institute of Dental and Craniofacial Research (NIDCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ned Sacktor, Norman Haughey, Julia L. Drewes, David Graham, M.Christine Zink & Carlos A. Pardo

  2. Harvard School of Public Health, Boston, MA, USA

    Sachiko Miyahara & Scott Evans

  3. University of Rochester, Rochester, NY, USA

    Giovanni Schifitto

  4. Northwestern University, Chicago, IL, USA

    Bruce Cohen

  5. National Institute of Health, Bethesda, MD, USA

    Caroline Anderson & Avindra Nath

  6. AIDS Clinical Trials Group (ACTG) Operation Center, Silver Spring, MD, USA

    Sean McCarthy & Lara Hosey

  7. Washington University, St. Louis, MO, USA

    David Clifford

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  1. Ned Sacktor
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  2. Sachiko Miyahara
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  3. Scott Evans
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  4. Giovanni Schifitto
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  6. Norman Haughey
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  15. David Clifford
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Correspondence to Ned Sacktor.

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Sacktor, N., Miyahara, S., Evans, S. et al. Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV-seropositive individuals with cognitive impairment. J. Neurovirol. 20, 620–626 (2014). https://doi.org/10.1007/s13365-014-0292-0

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  • DOI: https://doi.org/10.1007/s13365-014-0292-0

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