Dataset Information

Alphalipoic Acid Prevents Oxidative Stress and Peripheral Neuropathy in Nab-Paclitaxel-Treated Rats through the Nrf2 Signalling Pathway.

ABSTRACT: Peripheral neuropathy is the major dose-limiting side effect of paclitaxel (PTX), affecting both the quality of life and the survival of cancer patients. Nab-paclitaxel (nab-PTX) was developed to provide additional clinical benefits and overcome the safety drawbacks of solvent-based PTX. However, the prevalence of peripheral neuropathy induced by nab-PTX was reported higher than that induced by solvent-based PTX. Upon investigation, oxidative stress plays a major role in the toxicity of nab-PTX. In order to assess if the antioxidant alphalipoic acid (?-LA) could prevent the nab-PTX-induced peripheral neuropathy, Sprague-Dawley (SD) rats were treated with three doses of ?-LA (15, 30, and 60?mg/kg in normal saline, i.p., q.d. (days 1-30)) and/or nab-PTX (7.4?mg/kg in normal saline, i.v., q.w. (days 8, 15, and 22)). Body weight and peripheral neuropathy were measured and assessed regularly during the study. The assessment of peripheral neuropathy was performed by the von Frey and acetone tests. A tumor xenograft model of pancreatic cancer was used to assess the impact of ?-LA on the antitumor effect of nab-PTX. Results showed that ?-LA significantly ameliorated the peripheral neuropathy induced by nab-PTX (p < 0.05) without promoting tumor growth or reducing the chemotherapeutic effect of nab-PTX in a tumor xenograft model. Moreover, ?-LA might significantly reverse the superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) levels altered by nab-PTX in the serum and the spinal cord of rats. Furthermore, ?-LA could reverse the mRNA and protein expressions of Nrf2 (nuclear factor erythroid 2-related factor 2) and three Nrf2-responsive genes (HO-1, ?-GCLC, and NQO1) altered by nab-PTX in the dorsal root ganglion (DRG) of rats. In conclusion, our study suggests that ?-LA could prevent oxidative stress and peripheral neuropathy in nab-PTX-treated rats through the Nrf2 signalling pathway without diminishing chemotherapeutic effect.

SUBMITTER: Sun H

PROVIDER: S-EPMC6387730 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Alphalipoic Acid Prevents Oxidative Stress and Peripheral Neuropathy in Nab-Paclitaxel-Treated Rats through the Nrf2 Signalling Pathway.

Sun Hong H Sun Hong H Guo Xi X Wang Ziteng Z Wang Peipei P Zhang Zhe Z Dong Jihong J Zhuang Rongyuan R Zhou Yuhong Y Ma Guo G Cai Weimin W

Oxidative medicine and cellular longevity 20190210

Peripheral neuropathy is the major dose-limiting side effect of paclitaxel (PTX), affecting both the quality of life and the survival of cancer patients. Nab-paclitaxel (nab-PTX) was developed to provide additional clinical benefits and overcome the safety drawbacks of solvent-based PTX. However, the prevalence of peripheral neuropathy induced by nab-PTX was reported higher than that induced by solvent-based PTX. Upon investigation, oxidative stress plays a major role in the toxicity of nab-PTX. ...[more]

PMID: 30881589

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Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling condition accompanying several cancer drugs, including the front-line chemotherapeutic agent paclitaxel. Although CIPN can force dose reduction or even discontinuation of chemotherapy, affecting survival in cancer patients, there is no US Food and Drug Administration-approved treatment for CIPN. CIPN in mice is characterized by neuropathic pain (eg, mechanical allodynia) in association with oxidative stress and neuroinflammation in dorsal root ganglia (DRGs), as well as retraction of intraepidermal nerve fibers. Here, we report that paclitaxel-induced mechanical allodynia is associated with transcriptional increase in matrix metalloproteinase (MMP) 2 and 9 and decrease in metallopeptidase inhibitor 1 (TIMP1), a strong endogenous MMP9 inhibitor. Consistently, MMP9 protein levels are increased in DRG neurons in vivo and in vitro after paclitaxel treatment, and it is demonstrated, for the first time, that intrathecal injections of exogenous TIMP1 or a monoclonal antibody targeting MMP9 (MMP9 mAb) significantly prevented and reversed paclitaxel-induced mechanical allodynia in male and female mice. Analyses of DRG tissues showed that MMP9 mAb significantly decreased oxidative stress and neuroinflammatory mediators interleukin-6 and tumor necrosis factor α, as well as prevented paclitaxel-induced loss of intraepidermal nerve fibers. These findings suggest that MMP signaling plays a key role in paclitaxel-induced peripheral neuropathy, and MMP9 mAb may offer new therapeutic approaches for the treatment of CIPN. PERSPECTIVE: Chemotherapy-induced peripheral neuropathy (CIPN) remains ineffectively managed in cancer patients, potentially leading to the discontinuation of an otherwise life-saving treatment. Here, we demonstrate that a monoclonal antibody targeting MMP9 alleviates neuropathic pain and several mechanisms linked to CIPN. This study is particularly relevant, because a humanized MMP9 antibody is already in advanced clinical trials for the treatment of colitis and cancer, and it may be straightforwardly repurposed for the relief of CIPN.

Project description:PurposePaclitaxel-induced peripheral neuropathy (PIPN) is increasingly becoming one of the most widespread adverse effects in the treatment of cancer patients, and further precipitate neuroinflammation in the nervous system. Interestingly, Shaoyao Gancao Decoction (SGD), a traditional Chinese analgesic prescription, has emerged as a primary adjuvant to chemotherapy in relieving side effects, especially in the case of PIPN. However, the underlying mechanism of SGD functioning in PIPN remains elusive. Accordingly, the current study set out to explore the potential axis implicated in the functioning of SGD in PIPN.MethodsFirst, network pharmacology was adopted to predict the role of the transient receptor potential vanilloid type 1 (TRPV1) protein in treating PIPN with SGD. Subsequently, the effects of SGD treatment on mechanical allodynia and thermal hyperalgesia were evaluated in rat PIPN models. Based on the bioinformatics information and current literature, paclitaxel activates toll-like receptor 4 (TLR4) induces the sensitization of TRPV1 mechanistically. Thereafter, TLR4-myeloid-differentiation response gene 88 (MyD88) signaling and TRPV1 expression patterns in dorsal root ganglias (DRGs) were measured by means of Western blotting, qPCR and immunofluorescence.ResultsInitial bioinformatics reared a total of 105 bioactive compounds and 1075 target genes from SGD. In addition, 40 target genes intersected with PIPN were considered as potential therapeutic genes. Based on the network analysis, SGD was found to exert its analgesic effect by reducing the expression of TRPV1. Further experimentation validated that SGD exerted an analgesic effect on thermal hyperalgesia in PIPN models, such that this protective effect was associated with the suppression of TRPV1 and TLR4-MyD88 Signaling over-expression.ConclusionCollectively, our findings indicated that SGD ameliorates PIPN by inhibiting the over-expression of TLR4-MyD88 Signaling and TRPV1, and further highlights the use of SGD as a potential alternative treatment for PIPN.

Dataset Information

Alphalipoic Acid Prevents Oxidative Stress and Peripheral Neuropathy in Nab-Paclitaxel-Treated Rats through the Nrf2 Signalling Pathway.

Publications

Alphalipoic Acid Prevents Oxidative Stress and Peripheral Neuropathy in Nab-Paclitaxel-Treated Rats through the Nrf2 Signalling Pathway.

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