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Early Minocycline Treatment Prevents a Decrease in Striatal Dopamine in an SIV Model of HIV-Associated Neurological Disease

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Abstract

HIV-infected individuals, even with antiretroviral therapy, often display cognitive, behavioral and motor abnormalities and have decreased dopamine (DA) levels. Minocycline prevents encephalitis and neurodegeneration in SIV models, suggesting that it might also protect against nigrostriatal dopaminergic system dysfunction. Using an SIV/macaque model of HIV-associated CNS disease, we demonstrated that striatal levels of DA were significantly lower in macaques late in infection and that levels of the metabolite DOPAC also tended to be lower. DA levels declined more than its metabolites, indicating a dysregulation of DA production or catabolism. Minocycline treatment beginning at 12 but not 21 days postinoculation prevented striatal DA loss. DA decline was not due to direct loss of dopaminergic projections to the basal ganglia as there was no difference in tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter 2 or synaptophysin between minocycline-treated and untreated macaques. SIV-infected macaques had significantly higher monoamine oxidase (MAO) activity than uninfected macaques, although MAO activity was not affected by minocycline. Oxidative/nitrosative stress was examined by nitrotyrosine staining in the deep white matter and was lower in SIV-infected, minocycline-treated macaques compared with untreated macaques. These data suggest that minocycline, which has antioxidant activity, has a protective effect on DA homeostasis when administered at an appropriate time in SIV neuropathogenesis.

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Authors and Affiliations

  1. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 North Broadway Street, BRB 819, Baltimore, MD, 21205, USA

    Kelly A. Meulendyke, Mikhail V. Pletnikov, Elizabeth L. Engle, David R. Graham & M. Christine Zink

  2. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 N Wolfe St., CMSC-9-111, Baltimore, MD, 21287, USA

    Mikhail V. Pletnikov

  3. Department of Biostatistics and Epidemiology, Foster School of Medicine, Texas Tech University Health Sciences Center, 4801 Alberta Avenue, El Paso, TX, 79905, USA

    Patrick M. Tarwater

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  1. Kelly A. Meulendyke
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  2. Mikhail V. Pletnikov
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Correspondence to M. Christine Zink.

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Authors who are guarantors: MCZ

Studies were supported by grants from the National Institute of Mental Health: R01 MH069116, R01 MH087233, and R01 MH085554.

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Meulendyke, K.A., Pletnikov, M.V., Engle, E.L. et al. Early Minocycline Treatment Prevents a Decrease in Striatal Dopamine in an SIV Model of HIV-Associated Neurological Disease. J Neuroimmune Pharmacol 7, 454–464 (2012). https://doi.org/10.1007/s11481-011-9332-1

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