TMI-1, TNF-α-Converting Enzyme Inhibitor, Protects Against Paclitaxel-Induced Neurotoxicity in the DRG Neuronal Cells In Vitro

Kim, Yesul; Jung, Young Hoon; Park, Seung-Bin; Kim, Heekee; Kwon, Jae‐Young; Kim, Hae-Kyu; Lee, Hyeon-Jeong; Jeon, Soeun; Kim, Eun-Soo

doi:10.3389/fphar.2022.842779

Cited by 4 publications

(3 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, M2-like macrophages promote tissue repair and pain resolution via secreting anti-inflammatory cytokines. Several evidences have demonstrated that chemotherapy induces an increase in peripheral pro-inflammatory cytokines ( 43 ), such as TNF-α, IL-1β and IL-6 ( 44 – 46 ). Neuroinflammation has been considered as a potential common driver of CIPN, including PINP.…”

Section: Discussionmentioning

confidence: 99%

Resolvin D1/N-formyl peptide receptor 2 ameliorates paclitaxel-induced neuropathic pain through the activation of IL-10/Nrf2/HO-1 pathway in mice

Zhang

Zhao

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

IntroductionPaclitaxel is a chemotherapy drug that is commonly used to treat cancer, but it can cause paclitaxel-induced neuropathic pain (PINP) as a side effect. Resolvin D1 (RvD1) has been shown to be effective in promoting the resolution of inflammation and chronic pain. In this study, we evaluated the effects of RvD1 on PINP and its underlying mechanisms in mice.MethodsBehavioral analysis was used to assess the establishment of the PINP mouse model and to test the effects of RvD1 or other formulations on mouse pain behavior. Quantitative real-time polymerase chain reaction analysis was employed to detect the impact of RvD1 on 12/15 Lox, FPR2, and neuroinflammation in PTX-induced DRG neurons. Western blot analysis was used to examine the effects of RvD1 on FPR2, Nrf2, and HO-1 expression in DRG induced by PTX. TUNEL staining was used to detect the apoptosis of DRG neurons induced by BMDM conditioned medium. H2DCF-DA staining was used to detect the reactive oxygen species level of DRG neurons in the presence of PTX or RvD1+PTX treated BMDMs CM.ResultsExpression of 12/15-Lox was decreased in the sciatic nerve and DRG of mice with PINP, suggesting a potential involvement of RvD1 in the resolution of PINP. Intraperitoneal injection of RvD1 promoted pain resolution of PINP in mice. Intrathecal injection of PTX-treated BMDMs induced mechanical pain hypersensitivity in naïve mice, while pretreatment of RvD1 in BMDMs prevented it. Macrophage infiltration increased in the DRGs of PINP mice, but it was not affected by RvD1 treatment. RvD1 increased IL-10 expression in the DRGs and macrophages, while IL-10 neutralizing antibody abolished the analgesic effect of RvD1 on PINP. The effects of RvD1 in promoting IL-10 production were also inhibited by N-formyl peptide receptor 2 (FPR2) antagonist. The primary cultured DRG neurons apoptosis increased after stimulation with condition medium of PTX-treated BMDMs, but decreased after pretreatment with RvD1 in BMDMs. Finally, Nrf2-HO1 signaling was additionally activated in DRG neurons after stimulation with condition medium of RvD1+PTX-treated BMDMs, but these effects were abolished by FPR2 blocker or IL-10 neutralizing antibody.DiscussionIn conclusion, this study provides evidence that RvD1 may be a potential therapeutic strategy for the clinical treatment of PINP. RvD1/FPR2 upregulates IL-10 in macrophages under PINP condition, and then IL-10 activates the Nrf2- HO1 pathway in DRG neurons, relieve neuronal damage and PINP.

show abstract

Section: Discussionmentioning

confidence: 99%

Resolvin D1/N-formyl peptide receptor 2 ameliorates paclitaxel-induced neuropathic pain through the activation of IL-10/Nrf2/HO-1 pathway in mice

Zhang

Zhao

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Importantly, blocking signalling by TNF‐α, IL‐1β or IL‐6 reduced paclitaxel‐induced neuropathy (Al‐Mazidi et al, 2018), thus reinforcing the notion that pro‐inflammatory cytokines are prime targets for pain management. Recently, an inhibitor of TNF‐α converting enzyme,TMI‐1, was neuroprotective in DRGs by reducing TNF‐α levels and consequently reducing IL‐1β and IL‐6 in the cell culture supernatant and also attenuating the axonal degeneration induced by paclitaxel (Kim et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

A partial agonist of PPARγ prevents paclitaxel‐induced peripheral neuropathy in mice, by inhibiting neuroinflammation

Benvenutti,

Wolff,

Corrêa

et al. 2023

British J Pharmacology

View full text Add to dashboard Cite

Background and PurposeChemotherapy‐induced peripheral neuropathy (CIPN) is a common side effect of paclitaxel (PTX), affecting 30 to 50% of patients. The increase in survival rate and the concern with patients' quality of life have encouraged the search for new tools to prevent PTX‐induced neuropathy. This study presents the glitazone 4‐[(Z)‐(2,4‐dioxo‐1,3‐thiazolidin‐5‐ylidene)methyl]‐N‐phenylbenzene‐sulfonamide (TZD‐A1) as PPARγ partial‐agonist, its toxicological profile, and effect on PTX‐induced CIPN in mice.Experimental ApproachThe interaction of TZD‐A1 with PPARγ was tested using in silico docking analysis and in vitro reporter gene assay. The pharmacokinetics and toxicity were evaluated using in silico, in vitro and in vivo analysis. The effects of TZD‐A1 on CIPN were investigated in PTX‐injected mice. Axonal and DRG damage, mitochondrial complex activity, and cytokine levels, BDNF, Nrf2 and PPARγ were also evaluated.Key ResultsDocking analysis predicted TZD‐A1 interaction with PPARγ compatible for partial agonists, data corroborated by the in vitro reporter gene assay. TZD‐A1 presented oral bioavailability and safety profile evidenced by in silico, in vitro and in vivo experiments. PTX‐injected mice, concomitantly treated with TZD‐A1 by systemic or oral route, presented reduction of mechanical and thermal hypersensitivity. The mechanisms involved in TZD‐A1 effect seem to be the inhibition of neuroinflammation and mitochondrial damage by increasing Nrf2 and PPARγ levels together with BDNF upregulation.Conclusion and ImplicationsTZD‐A1, partially activating PPARγ, caused neuroprotection and reduced the hypersensitivity induced by PTX. Allied to its safety profile and good bioavailability, TZD‐A1 is a promising drug candidate to prevent and treat CIPN in cancer patients.

show abstract

“…Knockdown of the 1L-1R gene in highly TRPV1expressing mice alleviated mechanical pain [32], while pretreatment with TRPV1 inhibitor in subcutaneously injected 1L-1β rats significantly alleviated heat pain allergy [33]. Both agonists [34] and inhibitors [35] of TRPV1 affect TNF-α-induced pain behavior, and TNF-α inhibitors can modulate neuropathic pain by reversing the up-regulation of TRPV1 [36]. Moreover, relief of peripheral neuropathic pain occurs by inhibiting TRPV1 upregulation in DRG and glial cell activation and TNF-α expression [37].…”

Section: Discussionmentioning

confidence: 99%

Silencing P2X7R Alleviates Diabetic Neuropathic Pain Involving TRPV1 via PKCε/P38MAPK/NF-κB Signaling Pathway in Rats

Chen

Wang

Xing

et al. 2022

IJMS

View full text Add to dashboard Cite

Transient receptor potential vanillic acid 1 (TRPV1) is an ion channel activated by heat and inflammatory factors involved in the development of various types of pain. The P2X7 receptor is in the P2X family and is associated with pain mediated by satellite glial cells. There might be some connection between the P2X7 receptor and TRPV1 in neuropathic pain in diabetic rats. A type 2 diabetic neuropathic pain rat model was induced using high glucose and high-fat diet for 4 weeks and low-dose streptozocin (35 mg/kg) intraperitoneal injection to destroy islet B cells. Male Sprague Dawley rats were administrated by intrathecal injection of P2X7 shRNA and p38 inhibitor, and we recorded abnormal mechanical and thermal pain and nociceptive hyperalgesia. One week later, the dorsal root ganglia from the L4-L6 segment of the spinal cord were harvested for subsequent experiments. We measured pro-inflammatory cytokines, examined the relationship between TRPV1 on neurons and P2X7 receptor on satellite glial cells by measuring protein and transcription levels of P2X7 receptor and TRPV1, and measured protein expression in the PKCε/P38 MAPK/NF-κB signaling pathway after intrathecal injection. P2X7 shRNA and p38 inhibitor relieved hyperalgesia in diabetic neuropathic pain rats and modulated inflammatory factors in vivo. P2X7 shRNA and P38 inhibitors significantly reduced TRPV1 expression by downregulating the PKCε/P38 MAPK/NF-κB signaling pathway and inflammatory factors in dorsal root ganglia. Intrathecal injection of P2X7 shRNA alleviates nociceptive reactions in rats with diabetic neuropathic pain involving TRPV1 via PKCε/P38 MAPK/NF-κB signaling pathway.

show abstract

TMI-1, TNF-α-Converting Enzyme Inhibitor, Protects Against Paclitaxel-Induced Neurotoxicity in the DRG Neuronal Cells In Vitro

Cited by 4 publications

References 37 publications

Resolvin D1/N-formyl peptide receptor 2 ameliorates paclitaxel-induced neuropathic pain through the activation of IL-10/Nrf2/HO-1 pathway in mice

Resolvin D1/N-formyl peptide receptor 2 ameliorates paclitaxel-induced neuropathic pain through the activation of IL-10/Nrf2/HO-1 pathway in mice

A partial agonist of PPARγ prevents paclitaxel‐induced peripheral neuropathy in mice, by inhibiting neuroinflammation

Silencing P2X7R Alleviates Diabetic Neuropathic Pain Involving TRPV1 via PKCε/P38MAPK/NF-κB Signaling Pathway in Rats

Contact Info

Product

Resources

About