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IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats.

Zheng W, Huang W, Liu S, Levitt RC, Candiotti KA, Lubarsky DA, Hao S - Mol Pain (2014)

Bottom Line: IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold.The area under the effect-time curves (AUC) in mechanical threshold in rats inoculated with the HSV vectors expressing IL-10, was increased compared with the control vectors, indicating antinociceptive effect of the IL-10 vectors.The blocking of the signaling of these proinflammatory molecules is able to reduce HIV-related neuropathic pain, which provide a novel mechanism-based approach to treating HIV-associated neuropathic pain using gene therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, 1550 NW 10th Ave, Fox BLDG, Rm 304C, Miami, FL 33136, USA. shao@med.miami.edu.

ABSTRACT

Background: HIV-associated sensory neuropathy affects over 50% of HIV patients and is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy (HAART). Evidence shows that painful HIV sensory neuropathy is influenced by neuroinflammatory events that include the proinflammatory molecules, MAP Kinase, tumor necrosis factor-α (TNFα), stromal cell-derived factor 1-α (SDF1α), and C-X-C chemokine receptor type 4 (CXCR4). However, the exact mechanisms of painful HIV sensory neuropathy are not known, which hinders our ability to develop effective treatments. In this study, we investigated whether inhibition of proinflammatory factors reduces the HIV-associated neuropathic pain state.

Results: Neuropathic pain was induced by peripheral HIV coat protein gp120 combined with 2',3'-dideoxycytidine (ddC, one of the nucleoside reverse transcriptase inhibitors (NRTIs)). Mechanical threshold was tested using von Frey filament fibers. Non-replicating herpes simplex virus (HSV) vectors expressing interleukin 10 (IL10) were inoculated into the hindpaws of rats. The expression of TNFα, SDF1α, and CXCR4 in the lumbar spinal cord and L4/5 dorsal root ganglia (DRG) was examined using western blots. IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold. The anti-allodynic effect of IL-10 expression mediated by the HSV vectors lasted more than 3 weeks. The area under the effect-time curves (AUC) in mechanical threshold in rats inoculated with the HSV vectors expressing IL-10, was increased compared with the control vectors, indicating antinociceptive effect of the IL-10 vectors. The HSV vectors expressing IL-10 also concomitantly reversed the upregulation of p-p38, TNFα, SDF1α, and CXCR4 induced by gp120 in the lumbar spinal dorsal horn and/or the DRG at 2 and/or 4 weeks.

Conclusion: The blocking of the signaling of these proinflammatory molecules is able to reduce HIV-related neuropathic pain, which provide a novel mechanism-based approach to treating HIV-associated neuropathic pain using gene therapy.

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The effect of IL-10 mediated by HSV vectors on the expression of SDF1α in the DRG and the spinal cord at 2 or 4 weeks. Rats with neuropathic pain were inoculated with QHIL10 or Q0ZHG 1 week post gp120 with ddC. In the control group, rats received the sham surgery with saline IP injection and Q0ZHG (sham + sal + Q0ZHG). The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM. (A and B) Two weeks post vector injection, the L4/5 DRG (A) and the SDH (B) were harvested, and the expression of SDF1α was tested using western blots. ** P < 0.01 vs. control, # P < 0.05, ## P < 0.01 vs gp120 + ddC + Q0ZHG, n = 4 rats. (C and D) Four weeks post vector injection, the L4/5 DRG (C) and the SDH (D) were harvested, and the expression of SDF1α was tested using western blots. # P < 0.05 vs. gp120 + ddC + Q0ZHG, n = 4 rats.
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Figure 4: The effect of IL-10 mediated by HSV vectors on the expression of SDF1α in the DRG and the spinal cord at 2 or 4 weeks. Rats with neuropathic pain were inoculated with QHIL10 or Q0ZHG 1 week post gp120 with ddC. In the control group, rats received the sham surgery with saline IP injection and Q0ZHG (sham + sal + Q0ZHG). The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM. (A and B) Two weeks post vector injection, the L4/5 DRG (A) and the SDH (B) were harvested, and the expression of SDF1α was tested using western blots. ** P < 0.01 vs. control, # P < 0.05, ## P < 0.01 vs gp120 + ddC + Q0ZHG, n = 4 rats. (C and D) Four weeks post vector injection, the L4/5 DRG (C) and the SDH (D) were harvested, and the expression of SDF1α was tested using western blots. # P < 0.05 vs. gp120 + ddC + Q0ZHG, n = 4 rats.

Mentions: TNFα enhances the expression of CXCR4, which facilitates the chemotactic invasiveness of the cultured human mesenchymal stem cells toward SDF1α [33]. We have reported that IL-10 is able to suppress overexpression of mRNA and protein of TNFα induced by formalin into the hindpaws [8]. However, it is not known if IL10 reduced production of SDF1α in vivo in the gp120 + ddC-induced neuropathic pain state. In this study, we investigated whether the overexpression of IL10 mediated by the HSV vectors reduced SDF1α in the neuropathic pain state. In the DRG samples 2 weeks post vector injection, there was a significant increase in SDF1α in neuropathic rats with Q0ZHG compared with that in sham rats (P < 0.01, Figure 4A); the expression of SDF1α in the DRG in neuropathic rats with QHIL10, was markedly lower than that in neuropathic rats with Q0ZHG (P < 0.05, Figure 4A). In the SDH samples 2 weeks post vector injection, there was a significant increase in SDF1α in neuropathic rats with Q0ZHG compared with that in the sham rats (P < 0.01, Figure 4B); expression of SDF1α in neuropathic rats treated with QHIL10 was markedly lower than that in neuropathic rats with Q0ZHG (P < 0.01, Figure 4B).


IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats.

Zheng W, Huang W, Liu S, Levitt RC, Candiotti KA, Lubarsky DA, Hao S - Mol Pain (2014)

The effect of IL-10 mediated by HSV vectors on the expression of SDF1α in the DRG and the spinal cord at 2 or 4 weeks. Rats with neuropathic pain were inoculated with QHIL10 or Q0ZHG 1 week post gp120 with ddC. In the control group, rats received the sham surgery with saline IP injection and Q0ZHG (sham + sal + Q0ZHG). The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM. (A and B) Two weeks post vector injection, the L4/5 DRG (A) and the SDH (B) were harvested, and the expression of SDF1α was tested using western blots. ** P < 0.01 vs. control, # P < 0.05, ## P < 0.01 vs gp120 + ddC + Q0ZHG, n = 4 rats. (C and D) Four weeks post vector injection, the L4/5 DRG (C) and the SDH (D) were harvested, and the expression of SDF1α was tested using western blots. # P < 0.05 vs. gp120 + ddC + Q0ZHG, n = 4 rats.
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Figure 4: The effect of IL-10 mediated by HSV vectors on the expression of SDF1α in the DRG and the spinal cord at 2 or 4 weeks. Rats with neuropathic pain were inoculated with QHIL10 or Q0ZHG 1 week post gp120 with ddC. In the control group, rats received the sham surgery with saline IP injection and Q0ZHG (sham + sal + Q0ZHG). The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM. (A and B) Two weeks post vector injection, the L4/5 DRG (A) and the SDH (B) were harvested, and the expression of SDF1α was tested using western blots. ** P < 0.01 vs. control, # P < 0.05, ## P < 0.01 vs gp120 + ddC + Q0ZHG, n = 4 rats. (C and D) Four weeks post vector injection, the L4/5 DRG (C) and the SDH (D) were harvested, and the expression of SDF1α was tested using western blots. # P < 0.05 vs. gp120 + ddC + Q0ZHG, n = 4 rats.
Mentions: TNFα enhances the expression of CXCR4, which facilitates the chemotactic invasiveness of the cultured human mesenchymal stem cells toward SDF1α [33]. We have reported that IL-10 is able to suppress overexpression of mRNA and protein of TNFα induced by formalin into the hindpaws [8]. However, it is not known if IL10 reduced production of SDF1α in vivo in the gp120 + ddC-induced neuropathic pain state. In this study, we investigated whether the overexpression of IL10 mediated by the HSV vectors reduced SDF1α in the neuropathic pain state. In the DRG samples 2 weeks post vector injection, there was a significant increase in SDF1α in neuropathic rats with Q0ZHG compared with that in sham rats (P < 0.01, Figure 4A); the expression of SDF1α in the DRG in neuropathic rats with QHIL10, was markedly lower than that in neuropathic rats with Q0ZHG (P < 0.05, Figure 4A). In the SDH samples 2 weeks post vector injection, there was a significant increase in SDF1α in neuropathic rats with Q0ZHG compared with that in the sham rats (P < 0.01, Figure 4B); expression of SDF1α in neuropathic rats treated with QHIL10 was markedly lower than that in neuropathic rats with Q0ZHG (P < 0.01, Figure 4B).

Bottom Line: IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold.The area under the effect-time curves (AUC) in mechanical threshold in rats inoculated with the HSV vectors expressing IL-10, was increased compared with the control vectors, indicating antinociceptive effect of the IL-10 vectors.The blocking of the signaling of these proinflammatory molecules is able to reduce HIV-related neuropathic pain, which provide a novel mechanism-based approach to treating HIV-associated neuropathic pain using gene therapy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, 1550 NW 10th Ave, Fox BLDG, Rm 304C, Miami, FL 33136, USA. shao@med.miami.edu.

ABSTRACT

Background: HIV-associated sensory neuropathy affects over 50% of HIV patients and is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy (HAART). Evidence shows that painful HIV sensory neuropathy is influenced by neuroinflammatory events that include the proinflammatory molecules, MAP Kinase, tumor necrosis factor-α (TNFα), stromal cell-derived factor 1-α (SDF1α), and C-X-C chemokine receptor type 4 (CXCR4). However, the exact mechanisms of painful HIV sensory neuropathy are not known, which hinders our ability to develop effective treatments. In this study, we investigated whether inhibition of proinflammatory factors reduces the HIV-associated neuropathic pain state.

Results: Neuropathic pain was induced by peripheral HIV coat protein gp120 combined with 2',3'-dideoxycytidine (ddC, one of the nucleoside reverse transcriptase inhibitors (NRTIs)). Mechanical threshold was tested using von Frey filament fibers. Non-replicating herpes simplex virus (HSV) vectors expressing interleukin 10 (IL10) were inoculated into the hindpaws of rats. The expression of TNFα, SDF1α, and CXCR4 in the lumbar spinal cord and L4/5 dorsal root ganglia (DRG) was examined using western blots. IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold. The anti-allodynic effect of IL-10 expression mediated by the HSV vectors lasted more than 3 weeks. The area under the effect-time curves (AUC) in mechanical threshold in rats inoculated with the HSV vectors expressing IL-10, was increased compared with the control vectors, indicating antinociceptive effect of the IL-10 vectors. The HSV vectors expressing IL-10 also concomitantly reversed the upregulation of p-p38, TNFα, SDF1α, and CXCR4 induced by gp120 in the lumbar spinal dorsal horn and/or the DRG at 2 and/or 4 weeks.

Conclusion: The blocking of the signaling of these proinflammatory molecules is able to reduce HIV-related neuropathic pain, which provide a novel mechanism-based approach to treating HIV-associated neuropathic pain using gene therapy.

Show MeSH
Related in: MedlinePlus