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Inhibition of catechol-O-methyl transferase (COMT) by tolcapone restores reductions in microtubule-associated protein 2 (MAP2) and synaptophysin (SYP) following exposure of neuronal cells to neurotropic HIV

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Abstract

This investigation aimed to assess whether inhibition of cathecol-O-methyl transferase (COMT) by tolcapone could provide neuroprotection against HIV-associated neurodegenerative effects. This study was conducted based on a previous work, which showed that a single nucleotide polymorphism (SNP) at position 158 (val158met) in COMT, resulted in 40 % lower COMT activity. Importantly, this reduction confers a protective effect against HIV-associated neurocognitive disorders (HAND), which have been linked to HIV-associated brain changes. SH-SY5Y-differentiated neurons were exposed to macrophage-propagated HIV (neurotropic MACS2-Br strain) in the presence or absence of tolcapone for 6 days. RNA was extracted, and qPCR was performed using Qiagen RT2 custom array consisting of genes for neuronal and synaptic integrity, COMT and pro-inflammatory markers. Immunofluorescence was conducted to validate the gene expression changes at the protein level. Our findings demonstrated that HIV significantly increased the messenger RNA (mRNA) expression of COMT while reducing the expression of microtubule-associated protein 2 (MAP2) (p = 0.0015) and synaptophysin (SYP) (p = 0.012) compared to control. A concomitant exposure of tolcapone ameliorated the perturbed expression of MAP2 (p = 0.009) and COMT (p = 0.024) associated with HIV. Immunofluorescence revealed a trend reduction of SYP and MAP2 with exposure to HIV and that concomitant exposure of tolcapone increased SYP (p = 0.016) compared to HIV alone. Our findings demonstrated in vitro that inhibition of COMT can ameliorate HIV-associated neurodegenerative changes that resulted in the decreased expression of the structural and synaptic components MAP2 and SYP. As HIV-associated dendritic and synaptic damage are contributors to HAND, inhibition of COMT may represent a potential strategy for attenuating or preventing some of the symptoms of HAND.

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Acknowledgments

This study is funded by the grant “COMT Genotype and Executive Function in HIV Infection and Methamphetamine Use” (Exploratory/Developmental Research Grant Program (Parent R21)) awarded by the National Institute of Health (NIH) 2010–2013. (R21DA027273). TL conducted the tissue culture experiment and data analysis; GC, PG, MC and IE contributed in the methodological design of the experiment; AE was responsible for the macrophages culture and generating viral supernatant; CB contributed in the statistical analyses; LG contributed in experimental troubleshooting; and all authors were involved in editing of the manuscript drafts and approved the final manuscript.

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Psychiatry, The University of Melbourne, Level 1 North, Main Block, Royal Hospital, 3050, Melbourne, VIC, Australia

    Ting Ting Lee, Gursharan Chana, Chad A. Bousman & Ian P. Everall

  2. Centre for Neural Engineering, Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia

    Ting Ting Lee & Gursharan Chana

  3. Centre for Biomedical Research, Burnet Institute, Melbourne, Australia

    Paul R. Gorry, Anne Ellett, Melissa J. Churchill & Lachlan R. Gray

  4. NorthWestern Mental Health, Melbourne Health, Melbourne, Australia

    Ian P. Everall

  5. The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia

    Ian P. Everall

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  1. Ting Ting Lee
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Correspondence to Ian P. Everall.

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Lee, T.T., Chana, G., Gorry, P.R. et al. Inhibition of catechol-O-methyl transferase (COMT) by tolcapone restores reductions in microtubule-associated protein 2 (MAP2) and synaptophysin (SYP) following exposure of neuronal cells to neurotropic HIV. J. Neurovirol. 21, 535–543 (2015). https://doi.org/10.1007/s13365-015-0354-y

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