Effective Relief of Neuropathic Pain by Adeno-Associated Virus-Mediated Expression of a Small Hairpin Rna against GTP Cyclohydrolase 1

Author:

Kim Sung Jin1,Lee Won Il1,Lee Yoon Sun2,Kim Dong Hou34,Chang Jin Woo5,Kim Seong Who24,Lee Heuiran4

Affiliation:

1. Departments of Microbiology, University of Ulsan College of Medicine, Seoul, Korea

2. Biochemistry & Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea

3. Anatomy & Cell Biology, University of Ulsan College of Medicine, Seoul, Korea

4. Research Institute for Biomacromolecules, University of Ulsan, Seoul, Korea

5. Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea

Abstract

Background Recent studies show that transcriptional activation of GTP cyclohydrolase I (GCH1) in dorsal root ganglia (DRG) is significantly involved in the development and persistency of pain symptoms. We thus hypothesize that neuropathic pain may be attenuated by down-regulation of GCH1 expression, and propose a gene silencing system for this purpose. Results To interrupt GCH1 synthesis, we designed a bidirectional recombinant adeno-associated virus encoding both a small hairpin RNA against GCH1 and a GFP reporter gene (rAAV-shGCH1). After rAAV-shGCH1 was introduced into the sciatic nerve prior to or following pain-inducing surgery, therapeutic efficacy and the underlying mechanisms were subsequently validated in animal models. The GFP expression data indicates that rAAV effectively delivered transgenes to DRG. Subsequently reduced GCH1 expression was evident from immunohistochemistry and western-blotting analysis. Along with the down-regulation of GCH1, the von Frey test correspondingly indicated a sharp decline in pain symptoms upon both pre- and post-treatment with rAAV-shGCH1. Interestingly, GCH1 down-regulation additionally led to decreased microglial activation in the dorsal horn, implying an association between pain attenuation and reduced inflammation. Conclusion Therefore, the data suggests that GCH1 levels can be reduced by introducing rAAV-shGCH1, leading to pain relief. Based on the results, we propose that GCH1 modulation may be developed as a clinically applicable gene therapy strategy to treat neuropathic pain.

Publisher

SAGE Publications

Subject

Anesthesiology and Pain Medicine,Cellular and Molecular Neuroscience,Molecular Medicine

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