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RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats.

ABSTRACT: Chemotherapeutic drugs are widely utilized in the treatment of human cancers. Painful chemotherapy-induced neuropathy is a common, debilitating, and dose-limiting side effect for which there is currently no effective treatment. Previous studies have demonstrated the potential utility of peptides from the marine snail from the genus Conus for the treatment of neuropathic pain. ?-Conotoxin RgIA and a potent analog, RgIA4, have previously been shown to prevent the development of neuropathy resulting from the administration of oxaliplatin, a platinum-based antineoplastic drug. Here, we have examined its efficacy against paclitaxel, a chemotherapeutic drug that works by a mechanism of action distinct from that of oxaliplatin. Paclitaxel was administered at 2 mg/kg (intraperitoneally (IP)) every other day for a total of 8 mg/kg. Sprague Dawley rats that were co-administered RgIA4 at 80 µg/kg (subcutaneously (SC)) once daily, five times per week, for three weeks showed significant recovery from mechanical allodynia by day 31. Notably, the therapeutic effects reached significance 12 days after the last administration of RgIA4, which is suggestive of a rescue mechanism. These findings support the effects of RgIA4 in multiple chemotherapeutic models and the investigation of ?9?10 nicotinic acetylcholine receptors (nAChRs) as a non-opioid target in the treatment of chronic pain.

SUBMITTER: Huynh PN

PROVIDER: S-EPMC7024385 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats.

Huynh Peter N PN Giuvelis Denise D Christensen Sean S Tucker Kerry L KL McIntosh J Michael JM

Marine drugs 20191221 1

Chemotherapeutic drugs are widely utilized in the treatment of human cancers. Painful chemotherapy-induced neuropathy is a common, debilitating, and dose-limiting side effect for which there is currently no effective treatment. Previous studies have demonstrated the potential utility of peptides from the marine snail from the genus <i>Conus</i> for the treatment of neuropathic pain. α-Conotoxin RgIA and a potent analog, RgIA4, have previously been shown to prevent the development of neuropathy r ...[more]

PMID: 31877728

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Project description:Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that preferentially acts within mitochondria, to reduce mitochondrial damage and neuropathic pain resulting from the chemotherapeutic drug paclitaxel. In vitro, paclitaxel caused a 50% reduction in mitochondrial membrane potential and metabolic rate, independent of concentration (20-100 μmol/L). Mitochondrial volume was increased dose-dependently by paclitaxel (200% increase at 100 μmol/L). These effects were prevented by co-treatment with 1 μmol/L melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co-exposure to 1 μmol/L melatonin of either the breast cancer cell line MCF-7 or the ovarian carcinoma cell line A2780. In a rat model of paclitaxel-induced painful peripheral neuropathy, pretreatment with oral melatonin (5/10/50 mg/kg), given as a daily bolus dose, was protective, dose-dependently limiting development of mechanical hypersensitivity (19/43/47% difference from paclitaxel control, respectively). Melatonin (10 mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel-induced elevated 8-isoprostane F2 α levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel-induced reduction in C-fibre activity-dependent slowing (by 64%). Notably, melatonin limited the development of mechanical hypersensitivity in both male and female animals (by 50/41%, respectively), and an additive effect was found when melatonin was given with the current treatment, duloxetine (75/62% difference, respectively). Melatonin is therefore a potential treatment to limit the development of painful neuropathy resulting from chemotherapy treatment.

Project description:Background Paclitaxel is commonly used as a cancer chemotherapy drug that frequently causes peripheral neuropathic pain. Inflammasome is a multiprotein complex consisting of Nod-like receptor proteins (NLRPs), apoptosis-associated speck-like protein, and caspase-1, which functions to switch on the inflammatory process and the release of interleukin-1?. Growing evidences have supported that peripheral interleukin-1? is critical in enhancing paclitaxel-induced neuropathic pain. However, whether activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain is still unclear. Results Paclitaxel induced mechanical allodynia of rats from day 3 and worsened gradually till 3 weeks after injection. Paclitaxel resulted in expression of NLRP3 and activated fragments of caspase-1 and interleukin-1? in L4-6 dorsal root ganglia and sciatic nerve three weeks after injection, indicating activation of NLRP3 inflammasome. The expression of NLRP3 was located in CD68-labeled macrophages infiltrating in L4-6 dorsal root ganglia and sciatic nerve, and paclitaxel increased the expression of NLRP3 in macrophage. Moreover, the paclitaxel elicited mitochondria damage, which became swollen and enlarged in macrophages and axons of sciatic nerve three weeks after injection. In vitro, paclitaxel increased the number of damaged mitochondria and mitochondrial reactive oxygen species production in the rat alveolar macrophage cell line NR8383. The administration of a non-specific reactive oxygen species scavenger, phenyl-N-tert-butylnitrone, markedly alleviated mechanical allodynia and inhibited the activation of NLRP3 inflammasome in L4-6 dorsal root ganglia and sciatic nerve of the paclitaxel-induced neuropathic pain model. Conclusions Paclitaxel induced mechanical allodynia and activation of NLRP3 inflammasome in infiltrated macrophages of L4-6 dorsal root ganglia and sciatic nerve. Paclitaxel elicited mitochondria damage and reactive oxygen species production may result in activation of NLRP3 inflammasome in peripheral nerve, which contributes to paclitaxel-induced neuropathic pain.

Dataset Information

RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats.

Publications

RgIA4 Accelerates Recovery from Paclitaxel-Induced Neuropathic Pain in Rats.

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