Dataset Information

Alpha-lipoic acid downregulates TRPV1 receptor via NF-κB and attenuates neuropathic pain in rats with diabetes.

ABSTRACT:

Aims

Painful diabetic neuropathy (PDN) is a refractory complication of diabetes. The study aimed to investigate the role of α-lipoic acid (ALA) on the regulation of transient receptor potential vanilloid-1 (TRPV1) in dorsal root ganglion (DRG) neurons of rats with diabetes.

Methods

Whole-cell patch-clamp recordings were employed to measure neuronal excitability in DiI-labeled DRG neurons of control and streptozotocin (STZ)-induced diabetic rats. Western blotting and immunofluorescence assays were used to determine the expression and location of NF-κBp65 and TRPV1.

Results

STZ-induced hindpaw pain hypersensitivity and neuronal excitability in L4-6 DRG neurons were attenuated by intraperitoneal injection with ALA once a day lasted for one week. TRPV1 expression was enhanced in L4-6 DRGs of diabetic rats compared with age-matched control rats, which was also suppressed by ALA treatment. In addition, TRPV1 and p65 colocated in the same DRG neurons. The expression of p65 was upregulated in L4-6 DRGs of diabetic rats. Inhibition of p65 signaling using recombinant lentiviral vectors designated as LV-NF-κBp65 siRNA remarkably suppressed TRPV1 expression. Finally, p65 expression was downregulated by ALA treatment.

Conclusion

Our findings demonstrated that ALA may alleviate neuropathic pain in diabetes by regulating TRPV1 expression via affecting NF-κB.

SUBMITTER: Zhang BY

PROVIDER: S-EPMC7298987 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Alpha-lipoic acid downregulates TRPV1 receptor via NF-κB and attenuates neuropathic pain in rats with diabetes.

Zhang Bing-Yu BY Zhang Yi-Lian YL Sun Qian Q Zhang Ping-An PA Wang Xi-Xi XX Xu Guang-Yin GY Hu Ji J Zhang Hong-Hong HH

CNS neuroscience & therapeutics 20200316 7

<h4>Aims</h4>Painful diabetic neuropathy (PDN) is a refractory complication of diabetes. The study aimed to investigate the role of α-lipoic acid (ALA) on the regulation of transient receptor potential vanilloid-1 (TRPV1) in dorsal root ganglion (DRG) neurons of rats with diabetes.<h4>Methods</h4>Whole-cell patch-clamp recordings were employed to measure neuronal excitability in DiI-labeled DRG neurons of control and streptozotocin (STZ)-induced diabetic rats. Western blotting and immunofluoresc ...[more]

PMID: 32175676

Similar Datasets

Project description:Cancer pain is one of the most common and serious symptoms of cancer patients. At present, the agents used for the prevention or treatment of cancer pain do not act with optimal safety and efficacy. The nuclear factor kappa B (NF-κB) signaling pathway and its downstream inflammatory factors interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) play an important regulatory role in the developmental process of cancer pain. IKKβ is a key molecule of the IκB (IKK) kinase that propagates cellular responses to inflammation. Previous studies have shown that phosphorylation and degradation of the IκBα protein promotes the activation of NF-κB and the expression of TNF-α, IL-1β, and IL-6, participating in the formation and development of cancer pain. Chanling Gao (CLG) is a compound preparation of traditional Chinese medicine. It contains specific functions, namely nourishing Yin, activating blood circulation and relieving pain and dysfunction syndrome. It is used in the treatment of a variety of pain disorders including cancer-induced bone pain (CIBP), which has a certain relief effect. However, its mechanism of action still remains unclear. In the present study, a rat model of tibia CIBP was successfully established using the Walker 256 breast cancer cell line. The IKKβ/NF-κB signaling pathway and its related factors TNF-α, IL-1β, and IL-6 were used as the entry points to explore the effect of CLG on CIBP and their possible mechanisms of action. The results indicated that CLG improved the body mass of the CIBP rat model and increased the pain threshold in rats. CLG significantly inhibited the degradation of IκBα and the levels of p-IκBα, p-IKKβ, and p-p65 NF-κB proteins in the spinal cord of CIBP rats, inhibiting the contents of TNF-α, IL-1β, and IL-6. Therefore, we conclude that the analgesic effect of CLG in this rat model of CIBP may be related to the inhibition of the IKKβ/NF-κB signaling pathway and the reduction of synthesis and release of TNF-α, IL-1β, and IL-6.

Project description:BackgroundAnti-nerve growth factor (NGF) monoclonal antibodies (anti-NGF mAbs) have been reported to significantly attenuate pain, but the mechanism involved has not been fully elucidated, and the serious adverse events associated with mAbs seriously limit their clinical use. This study further investigated the mechanism by which peripheral NGF is involved in neuropathic pain and found safe, natural compounds that target NGF to attenuate neuropathic pain.MethodsNociception was assessed by the Von Frey hair and Hargreaves' methods. Western-blotting, qPCR and immunofluorescence were used to detect the cell signaling pathway. RAW264.7 macrophages and RSC96 Schwann cells were cultured for in vitro evaluation.ResultsIntraplantar administration of anti-NGF mAbs suppressed the expression of phosphorylated transforming growth factor-β-activated kinase 1 (TAK1) in the dorsal root ganglion (DRG) and sciatic nerve. Intraplantar administration of a TAK1 inhibitor attenuated CCI-induced neuropathic pain and suppressed the expression of phosphorylated mitogen-activated protein kinases (MAPKs) in the DRG and sciatic nerve. Perisciatic nerve administration of levo-corydalmine (l-CDL) on the operated side obviously attenuated CCI-induced neuropathic pain and suppressed the expression of mNGF and proNGF. In addition, l-CDL-induced antinociception was reversed by intraplantar administration of NGF. Further results indicated that l-CDL-induced suppression of phosphorylated TAK1, MAPKs, and p65 and expression of the proinflammatory cytokines TNF-α and IL-1β in the DRG and sciatic nerve were all abolished by NGF. In addition, in vitro experiments indicated that l-CDL suppressed the secretion of NGF and proNGF in RAW264.7 macrophages and RSC96 Schwann cells, which was abolished by AP-1 and CREB agonists, respectively.ConclusionsThis study showed NGF inhibition suppressed TAK1 in the periphery to attenuate CCI-induced neuropathic pain through inhibition of downstream MAPK and p65 signaling. The natural compound l-CDL inhibited NGF secretion by macrophages and Schwann cells and downstream TAK1-MAPK/NF-κB signaling in the periphery to attenuate CCI-induced neuropathic pain. Video abstract Proposed mechanisms underlying the effect of l-CDL in periphery of CCI rats. In CCI rats, macropahages and Schwann cells could secret NGF to act on the receptors in the periphery to activate TAK1-MAPK/NF-κB axis and promote the release of proinflammatory cytokines, including TNF-α and IL-1β to promote neuropathic pain. l-CDL decreased the secretion of NGF through inhibiting AP-1 and CREB respectively in RAW264.7 and RSC96 Schwann cells to attenuate CCI-induced neuropathic pain by inhibiting the TAK1-p38 MAPK/NF-κB signaling pathway.

Project description:BackgroundNeuropathic pain (NP) is a prevalent disease, which badly impairs the life quality of patients. The underlying mechanism of NP is still not fully understood. It has been reported that spinal Annexin A10 (ANXA10) contributes to NP. This study aims at exploring the underlying mechanisms of spinal ANXA10 in regulating NP in rats.MethodsSpinal nerve ligation (SNL) was adopted to establish a NP model in rats. After SNL, paw withdrawal threshold and paw withdrawal latency were recorded to measure pain behaviors, RT-PCR was used to check the change of the expression of spinal ANXA10 mRNA, western blot analysis was used to detect the change of the protein level of ANXA10, nuclear factor kappa B (NF-κB), and maisrix metalloproteinase-9 (MMP-9) in the spinal cord. The levels of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukine-1β (IL-1β), and interleukine-6 (IL-6), were explored by ELISA kits. The effects of both knockdown of spinal ANXA10 and inhibition of NF-κB on pain behaviors and the expression of MMP-9 and proinflammatory cytokines were investigated.ResultsOur present findings highlighted that SNL caused pain hypersensitivity and increased the expression of spinal ANXA10/pNF-κB, TNF-α, IL-1β, and IL-6 both in the early and late phase of NP in rats, while spinal MMP-9 was only slightly increased in the early phase of NP. Knockdown of ANXA10 at the spinal cord level suppressed the SNL-induced hyperalgesia and blocked the activation of NF-κB, TNF-α and IL-1β both in the early and late phase of NP. Spinal ANXA10 knockdown could prevent the upregulation of spinal MMP-9 in the early phase and inhibit IL-6 expression in the late phase of SNL-induced NP.ConclusionsIn conclusion, spinal ANXA10/NF-κB/MMP-9 pathway, along with the activation of proinflammatory cytokines, was involved in the SNL-induced NP. MMP-9 may act as the downstream target of ANXA10/NF-κB pathway in the development rather than the maintenance of NP.

Dataset Information

Alpha-lipoic acid downregulates TRPV1 receptor via NF-κB and attenuates neuropathic pain in rats with diabetes.

Aims

Methods

Results

Conclusion

Publications

Alpha-lipoic acid downregulates TRPV1 receptor via NF-κB and attenuates neuropathic pain in rats with diabetes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets