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HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a

Gene Therapy volume 23, pages 340–348 (2016)Cite this article

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Abstract

Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite the extensive research, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. Loss of GABAergic tone may have an important role in the neuropathic pain state. Glutamic acid decarboxylase 67 (GAD67) is one of the isoforms that catalyze GABA synthesis. Here, we used recombinant herpes simplex virus (HSV-1) vectors that encode gad1 gene to evaluate the therapeutic potential of GAD67 in peripheral HIV gp120-induced neuropathic pain in rats. We found that (1) subcutaneous inoculation of the HSV vectors expressing GAD67 attenuated mechanical allodynia in the model of HIV gp120-induced neuropathic pain, (2) the anti-allodynic effect of GAD67 was reduced by GABA-A and-B receptors antagonists, (3) HSV vectors expressing GAD67 reversed the lowered GABA-IR expression and (4) the HSV vectors expressing GAD67 suppressed the upregulated mitochondrial superoxide and Wnt5a in the spinal dorsal horn. Taken together, our studies support the concept that recovering GABAergic tone by the HSV vectors may reverse HIV-associated neuropathic pain through suppressing mitochondrial superoxide and Wnt5a. Our studies provide validation of HSV-mediated GAD67 gene therapy in the treatment of HIV-related neuropathic pain.

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Acknowledgements

The study was supported by the NIH DA026734 (SH), DA025527 (SH), NS066792 (SH) and DA34749 (SH). HK and MK were supported by Professor Hiroshi Iwasaki (Anesthesiology, Asahikawa Medical University, Japan). RCL was supported by NIH DE022903. We greatly acknowledge Dr David Fink and Dr Marina Mata for providing the high-quality HSV vectors and the excellent technical assistance of Vikram Thakur (University of Michigan, Ann Arbor, MI, USA). We thank Professor Yuan Zhu (Department of Medicine, University of Michigan, MI, USA) for his anti-GABA antibody. We thank the helpful comments of Drs Goins William and Joseph C Glorioso (Microbiology and Molecular Genetics, University of Pittsburgh, PA, USA).

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Authors and Affiliations

  1. Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA

    H Kanda, M Kanao, S Liu, H Yi, T Iida, R C Levitt, K A Candiotti, D A Lubarsky & S Hao

  2. Department of Anesthesiology, Asahikawa Medical University, Asahikawa, Japan

    H Kanda, M Kanao & T Iida

  3. Hussman Institute of Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA

    R C Levitt

  4. Veterans Affairs Medical Center, Miami, FL, USA

    R C Levitt

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  1. H Kanda
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Kanda, H., Kanao, M., Liu, S. et al. HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a. Gene Ther 23, 340–348 (2016). https://doi.org/10.1038/gt.2016.3

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