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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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Related in: MedlinePlus

The effect of IL-10 mediated by the HSV vectors on the expression of p-p38 in the DRG and the SDH at 2 or 4 weeks. Rats with neuropathic pain were inoculated with QHIL10 or Q0ZHG 1 week post gp120 application with ddC. In the control group, rats received the sham surgery with saline IP injection and Q0ZHG (sham + sal + Q0ZHG). (A and B) Two weeks post vector injection, the L4/5 DRG (A) and the SDH (B) were harvested, and the expression of p-p38 was tested using western blots. The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM, **P < 0.01 vs. control group, # 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 p-p38 was tested using western blots. The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM, *P < 0.05, **P < 0.01 vs. control, # P < 0.05, ## P < 0.01 vs gp120 + ddC + Q0ZHG, n = 4 rats.
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Figure 2: The effect of IL-10 mediated by the HSV vectors on the expression of p-p38 in the DRG and the SDH at 2 or 4 weeks. Rats with neuropathic pain were inoculated with QHIL10 or Q0ZHG 1 week post gp120 application with ddC. In the control group, rats received the sham surgery with saline IP injection and Q0ZHG (sham + sal + Q0ZHG). (A and B) Two weeks post vector injection, the L4/5 DRG (A) and the SDH (B) were harvested, and the expression of p-p38 was tested using western blots. The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM, **P < 0.01 vs. control group, # 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 p-p38 was tested using western blots. The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM, *P < 0.05, **P < 0.01 vs. control, # P < 0.05, ## P < 0.01 vs gp120 + ddC + Q0ZHG, n = 4 rats.

Mentions: Activated MAP kinase p-p38 plays important role in the maintenance of inflammatory/neuropathic pain [3,8,32]. In this study, we investigated whether the over-expression of IL10 mediated by the HSV vectors reduced p-p38 in the gp120 + ddC model. The L4/5 DRG and the SDH were harvested on 2 weeks post vector injection. The pooled L4/5 DRG and the SDH were used for western blots. The data were presented as mean ± SEM and were compared using one way ANOVA with a post hoc PLSD test (StatView), n = 4 rats. In the DRG samples 2 weeks post vector injection, neuropathic rats inoculated with Q0ZHG showed a statistically significant increase in the expression of p-p38 compared with that in the sham with Q0ZHG (P < 0.01 vs sham + sal + Q0ZHG, Figure 2A); the expression of p-p38 in neuropathic rats with QHIL10 was markedly lower than that with Q0ZHG (P < 0.05 vs gp120 + ddC + QOZHG, Figure 2A). In the SDH samples 2 weeks post vector injection, the expression of p-p38 in neuropathic rats with Q0ZHG was markedly increased compared with that in sham rats (P <0.01 vs sham + sal + Q0ZHG, Figure 2B); p-p38 in neuropathic rats with QHIL10 was lower than that with Q0ZHG (P <0.01 vs gp120 + ddC + QOZHG, Figure 2B).


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 the HSV vectors on the expression of p-p38 in the DRG and the SDH at 2 or 4 weeks. Rats with neuropathic pain were inoculated with QHIL10 or Q0ZHG 1 week post gp120 application with ddC. In the control group, rats received the sham surgery with saline IP injection and Q0ZHG (sham + sal + Q0ZHG). (A and B) Two weeks post vector injection, the L4/5 DRG (A) and the SDH (B) were harvested, and the expression of p-p38 was tested using western blots. The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM, **P < 0.01 vs. control group, # 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 p-p38 was tested using western blots. The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM, *P < 0.05, **P < 0.01 vs. control, # P < 0.05, ## P < 0.01 vs gp120 + ddC + Q0ZHG, n = 4 rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: The effect of IL-10 mediated by the HSV vectors on the expression of p-p38 in the DRG and the SDH at 2 or 4 weeks. Rats with neuropathic pain were inoculated with QHIL10 or Q0ZHG 1 week post gp120 application with ddC. In the control group, rats received the sham surgery with saline IP injection and Q0ZHG (sham + sal + Q0ZHG). (A and B) Two weeks post vector injection, the L4/5 DRG (A) and the SDH (B) were harvested, and the expression of p-p38 was tested using western blots. The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM, **P < 0.01 vs. control group, # 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 p-p38 was tested using western blots. The data were analyzed using one way ANOVA with post hoc PLSD test, mean ± SEM, *P < 0.05, **P < 0.01 vs. control, # P < 0.05, ## P < 0.01 vs gp120 + ddC + Q0ZHG, n = 4 rats.
Mentions: Activated MAP kinase p-p38 plays important role in the maintenance of inflammatory/neuropathic pain [3,8,32]. In this study, we investigated whether the over-expression of IL10 mediated by the HSV vectors reduced p-p38 in the gp120 + ddC model. The L4/5 DRG and the SDH were harvested on 2 weeks post vector injection. The pooled L4/5 DRG and the SDH were used for western blots. The data were presented as mean ± SEM and were compared using one way ANOVA with a post hoc PLSD test (StatView), n = 4 rats. In the DRG samples 2 weeks post vector injection, neuropathic rats inoculated with Q0ZHG showed a statistically significant increase in the expression of p-p38 compared with that in the sham with Q0ZHG (P < 0.01 vs sham + sal + Q0ZHG, Figure 2A); the expression of p-p38 in neuropathic rats with QHIL10 was markedly lower than that with Q0ZHG (P < 0.05 vs gp120 + ddC + QOZHG, Figure 2A). In the SDH samples 2 weeks post vector injection, the expression of p-p38 in neuropathic rats with Q0ZHG was markedly increased compared with that in sham rats (P <0.01 vs sham + sal + Q0ZHG, Figure 2B); p-p38 in neuropathic rats with QHIL10 was lower than that with Q0ZHG (P <0.01 vs gp120 + ddC + QOZHG, Figure 2B).

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