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Daidzein attenuated paclitaxel-induced neuropathic pain via the down-regulation of TRPV1/P2Y and up-regulation of Nrf2/HO-1 signaling

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Abstract

Paclitaxel (PTX) is an anti-microtubule agent, used for the treatment of various types of cancers; however, it produces painful neuropathy which limits its use. Many neuroprotective agents have been introduced to mitigate PTX-induced neuropathic pain (PINP), but they pose many adverse effects. The purpose of this study was to evaluate the pharmacological characteristics of soy isoflavone, and daidzein (DZ) in attenuating PINP. At the beginning of the investigation, the effect of DZ was confirmed through behavioral analysis, as it reduced pain hypersensitivity. Moreover, changes in the histological parameters were reversed by DZ administration along with vascular permeability. PTX administration upregulated transient receptor potential vanilloid 1 (TRPV1) channels and purinergic receptors (P2Y), contributing to hyperalgesia; but administration of DZ downregulated the TRPV1 and P2Y, thus reducing hyperalgesia. DZ increased nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), playing a pivotal role in the activation of the antioxidant pathway. DZ also decreased neuronal apoptosis by decreasing caspase-3 and Bcl2-associated X-protein (Bax), while simultaneously, increasing Bcl-2. PTX administration produced severe DNA damage, which was mitigated by DZ. Similarly, DZ administration resulted in inhibition of neuroinflammation by increasing antioxidant enzymes and reducing oxidative stress markers. PTX caused increased in production of pro-inflammatory mediators such as the cytokines production, while DZ inhibited the pro-inflammatory mediators. Additionally, in silico pharmacokinetic and toxicodynamic study of DZ was also conducted. In summary, DZ demonstrated significant neuroprotective activity against PTX induced neuropathic pain.

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Data availability

The datasets generated and analyzed in the present study are available from the corresponding author upon reasonable request.

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Author notes

  1. Sana Zafar and Yong Luo contributed equally to this work.

Authors and Affiliations

  1. Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Sana Zafar, Adnan Khan, Muhammad Ibrar Khan & Salman Khan

  2. Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Sana Zafar, Adnan Khan, Muhammad Ibrar Khan, Kifayatullah Shah & Salman Khan

  3. DHQ Teaching Hospital Timergara, Lower Dir, Timergara, KPK, Pakistan

    Adnan Khan

  4. Department of Head and Neck Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Yong Luo

  5. Department of Medical Oncology, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan, People’s Republic of China

    Li Zhang & Feng Wang

  6. Division of Radiation Physics, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China

    Chang Hu Li

  7. College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, South Korea

    Eun Kyoung Seo

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  1. Sana Zafar
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  2. Yong Luo
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  3. Li Zhang
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  4. Chang Hu Li
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  9. Feng Wang
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  10. Salman Khan
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Correspondence to Feng Wang or Salman Khan.

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Zafar, S., Luo, Y., Zhang, L. et al. Daidzein attenuated paclitaxel-induced neuropathic pain via the down-regulation of TRPV1/P2Y and up-regulation of Nrf2/HO-1 signaling. Inflammopharmacol 31, 1977–1992 (2023). https://doi.org/10.1007/s10787-023-01225-w

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