An oral form of methylglyoxal-bis-guanylhydrazone reduces monocyte activation and traffic to the dorsal root ganglia in a primate model of HIV-peripheral neuropathy
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Peripheral neuropathy (PN) is a major comorbidity of HIV infection that is caused in part by chronic immune activation. HIV-PN is associated with infiltration of monocytes/macrophages to the dorsal root ganglia (DRG) causing neuronal loss and formation of Nageotte nodules. Here, we used an oral form of methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine biosynthesis inhibitor, to specifically reduce activation of myeloid cells. MGBG is selectively taken up by monocyte/macrophages in vitro and inhibits HIV p24 expression and DNA viral integration in macrophages. Here, MGBG was administered to nine SIV-infected, CD8-depleted rhesus macaques at 21 days post-infection (dpi). An additional nine SIV-infected, CD8-depleted rhesus macaques were used as untreated controls. Cell traffic to tissues was measured by in vivo BrdU pulse labeling. MGBG treatment significantly diminished DRG histopathology and reduced the number of CD68+ and CD163+ macrophages in DRG tissue. The number of recently trafficked BrdU+ cells in the DRG was significantly reduced with MGBG treatment. Despite diminished DRG pathology, intraepidermal nerve fiber density (IENFD) did not recover after treatment with MGBG. These data suggest that MGBG alleviated DRG pathology and inflammation.
KeywordsHIV Rhesus Peripheral neuropathy Dorsal root ganglia Monocyte Polyamine biosynthesis inhibitor
This work was funded by NIH/NINDS RO1 NS040237 (awarded to KC Williams), R01. The conflict of interest statement is correct. NS082116 (awarded to TH Burdo), and U19MH08183 (awarded to MS McGrath). We would like to thank Pathologica for providing MGBG and Wedgwood Pharmacy for formulating MGBG and the placebo. We would also like to thank the veterinary staff at the NEPRC and TNRPC for the animal care and for assisting with necropsies and tissue collection.
Compliance with ethical standards
All animals used in this study were handled in strict accordance with American Association for Accreditation of Laboratory Animal Care with the approval of the Institutional Animal Care and Use Committee of Harvard University (protocol number 04420) and Tulane University (protocol numbers P0066 and P0263). Animals were housed at the New England Primate Research Center (NERPC, Southborough, MA) or Tulane National Primate Research Center (TNPRC, Covington, LA).
Conflicts of interest
Michael McGrath is a shareholder and consultant in Pathologica, LLC. For the remaining authors, there are no conflicts of interests.
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