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

Abstract

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.

Keywords: Dorsal root ganglia; HIV; Monocyte; Peripheral neuropathy; Polyamine biosynthesis inhibitor; Rhesus.

Figure 1. Overall DRG pathology is reduced in MGBG-treated animals compared to controls

Overall DRG pathology was scored on a scale of zero (no significant findings) to three (severe pathology) at increments of 0.5 in lumbar, sacral, and thoracic regions and were averaged in each animal. Pathology was scored based on the degree and presence of satellitosis, neuronophagia, and Nageotte nodules. Bars represent the average overall DRG pathology mean ± SEM. Groups were compared with a Mann-Whitney T-test. *P<0.05.

Figure 2. MGBG treatment reduces the number of macrophages in and cell traffic to the DRG

The numbers of CD68+ (A-C), CD163+ (D-F), MAC387+ (G-I), BrdU+ (J-L), and CD3+ (M-O) cells per mm² of tissue were counted in DRG from control animals and MGBG-treated animals. Representative images of DRG from control animals (A, D, G, J, M) and MGBG-treated animals (B, E, H, K, N) are shown. Data are shown as mean ± SEM (C, F, I, L, O). Groups were compared with a Mann-Whitney T-test. *P<0.05; **P<0.01; ****P<0.0001.

Figure 3. MGBG treatment does not allow for regeneration of peripheral nerves

IENFD was measured at 20 dpi and at necropsy in control (A) and in MGBG-treated (B) groups. Changes in IENFD between time points assessed with a Wilcoxon matched-pairs signed rank test. A p value less than 0.05 was considered significant.