Viral vector mediated continuous expression of interleukin-10 in DRG alleviates pain in type 1 diabetic animals

Thakur, Vikram; Gonzalez, Mayra A.; Chattopadhyay, Munmun

doi:10.1016/j.mcn.2016.01.006

Cited by 28 publications

(13 citation statements)

References 46 publications

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“…Activation of TLR4 induces production or release TNF-α in DRG 8 . Increased expression of pro-inflammatory cytokines such as TNF-α in the peripheral nervous system suggests the possibility of change in pain perception in diabetes 9 , 10 . The possibility exists that TLR4 signaling is correlated with the modulation of inflammatory mediator TNF-α and increase the sensitivity of nociception.…”

Section: Introductionmentioning

confidence: 99%

Interactions of Notch1 and TLR4 signaling pathways in DRG neurons of in vivo and in vitro models of diabetic neuropathy

Chen

Yin

et al. 2017

Sci Rep

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Understanding the interactions between Notch1 and toll-like receptor 4 (TLR4) signaling pathways in the development of diabetic peripheral neuropathy may lead to interpretation of the mechanisms and novel approaches for preventing diabetic neuropathic pain. In the present study, the interactions between Notch1 and TLR4 signaling pathways were investigated by using dorsal root ganglion (DRG) from diabetic neuropathic pain rats and cultured DRG neurons under high glucose challenge. The results showed that high glucose induced not only Notch1 mRNA, HES1 mRNA, and TLR4 mRNA expression, but also Notch1 intracellular domain (NICD1) and TLR4 protein expression in DRG neurons. The proportion of NICD1-immunoreactive (IR) and TLR4-IR neurons in DRG cultures was also increased after high glucose challenge. The above alterations could be partially reversed by inhibition of either Notch1 or TLR4 signaling pathway. Inhibition of either Notch1 or TLR4 signaling pathway could improve mechanical allodynia and thermal hyperalgesia thresholds. Inhibition of Notch1 or TLR4 signaling also decreased tumor necrosis factor-α (TNF-α) levels in DRG from diabetic neuropathic rats. These data imply that the interaction between Notch1 and TLR4 signaling pathways is one of the important mechanisms in the development or progression of diabetic neuropathy.

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Section: Introductionmentioning

confidence: 99%

Interactions of Notch1 and TLR4 signaling pathways in DRG neurons of in vivo and in vitro models of diabetic neuropathy

Chen

Yin

et al. 2017

Sci Rep

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“…In a peripheral neuropathic pain model in type 1 diabetic animals, continuous delivery of IL-10 by vectors in the nerve fibers mediated transduction in the dorsal root ganglion, and alleviated the nociceptive and stress responses. IL-10 also inhibits the development of painful neuropathy by decreasing stress in the dorsal root ganglion [39].…”

Section: Discussionmentioning

confidence: 99%

Interleukin-10 Protects Schwann Cells against Advanced Glycation End Products-Induced Apoptosis via NF-κB Suppression

Bao²,

Men

et al. 2019

Exp Clin Endocrinol Diabetes

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Demyelination resulting from Schwann cell injury is a main pathological feature of diabetic neuropathy, and a key contributor to this process may be inflammation due to advanced glycation end products (AGEs). Therefore, protection by anti-inflammation agents is anticipated. In this study, we showed that interleukin-10 (IL-10), an anti-inflammatory cytokine, inhibits apoptosis of Schwann cells induced by AGEs in vitro. We isolated and cultured Schwann cells from rat sciatic nerves. As detected by flow cytometry, apoptosis of Schwann cells markedly increased following incubation with AGEs for 48 h. However, pretreatment with IL-10 inhibited AGE-induced apoptosis. The effect of IL-10 on NF-κB, which is a very important regulator of inflammation, was also evaluated, and results showed high levels of phospho-NF-κB and nuclear localization of NF-κB in cells incubated with AGEs but low levels of phospho-NF-κB and cytoplasmic localization in the cells incubated with IL-10, indicating the activation of NF-κB by AGEs and inhibition of NF-κB by IL-10. Moreover, incubating Schwann cells with an NF-κB inhibitor (caffeic acid phenethyl ester) for 30 min before adding AGEs mimicked IL-10, lowering the amount of reactive oxygen species and activity of caspase-3 and also decreasing apoptosis in Schwann cells. These results indicate that IL-10 may protect Schwann cells against AGE-induced apoptosis by attenuating oxidative stress via the inhibition of activation of NF-κB.

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“…Herpes simplex virus-mediated gene transfer has been suggested to be an ideal strategy for gene therapy of chronic pain in a few recent studies ( Guedon et al, 2015 ; Thakur et al, 2016 ; Meidahl et al, 2017 ). It has a natural ability to infect predominantly sensory nerves after peripheral administration and provides long-term protein expression in a restricted appropriate region of the body ( Goss et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Low GRK2 Underlies Hyperalgesic Priming by Glial Cell-Derived Neurotrophic Factor

Wang

Eijkelkamp

et al. 2018

Front. Pharmacol.

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Background: We recently identified the balance between the level of G protein coupled receptor kinase 2 (GRK2) and Epac1 in nociceptors as a key factor in the transition from acute to chronic pain that occurs in mice ‘primed’ by an inflammatory stimulus. Here, we examined the contribution of GRK2 and Epac-signaling to growth factor-induced hyperalgesic priming.Methods: Mice were primed by intraplantar injection with glial cell-derived neurotrophic factor (GDNF). Mechanical allodynia in response to PGE2 was followed over time in primed and non-primed animals. GRK2 protein levels in dorsal root ganglion (DRG) neurons were quantified by immunohistochemistry. The effect of herpes simplex virus (HSV)-GRK2 amplicons to restore GRK2 levels or of an Epac inhibitor on PGE2 allodynia in primed mice was examined.Results: Glial cell-derived neurotrophic factor-induced hyperalgesia disappeared within 12 days. The hyperalgesic response to a subsequent intraplantar injection of PGE2 was prolonged from <24 h in control mice to more than 72 h in GDNF-primed mice. In male and female primed mice, PGE2 hyperalgesia was inhibited by oral administration of the Epac inhibitor ESI-09, while the drug had no effect in control mice. Mice primed with GDNF had reduced levels of GRK2 in IB4(+) small DRG neurons, but normal GRK2 levels in IB4(-) DRG neurons. Intraplantar administration of HSV-GRK2 amplicons to increase GRK2 protein levels prevented the prolongation of PGE2-induced hyperalgesia in GDNF-primed mice.Conclusion: Low GRK2 in nociceptors is critical to develop a primed state in response to GDNF and leads to engagement of Epac signaling and transition to chronic PGE2-induced hyperalgesia. Increasing GRK2 protein or inhibiting Epac signaling may represent new avenues for preventing transition to a chronic pain state.

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Viral vector mediated continuous expression of interleukin-10 in DRG alleviates pain in type 1 diabetic animals

Cited by 28 publications

References 46 publications

Interactions of Notch1 and TLR4 signaling pathways in DRG neurons of in vivo and in vitro models of diabetic neuropathy

Interactions of Notch1 and TLR4 signaling pathways in DRG neurons of in vivo and in vitro models of diabetic neuropathy

Interleukin-10 Protects Schwann Cells against Advanced Glycation End Products-Induced Apoptosis via NF-κB Suppression

Low GRK2 Underlies Hyperalgesic Priming by Glial Cell-Derived Neurotrophic Factor

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