Puerarin Relieves Paclitaxel-Induced Neuropathic Pain: The Role of Nav1.8 β1 Subunit of Sensory Neurons.

Xiao-Long Zhang,Wei-An Zeng,Ren-Chun Lai,Xian-Ying Cao,Man-Xiu Xie

doi:10.3389/fphar.2018.01510

Xiao-Long Zhang, Wei-An Zeng + Show 3 more

Open Access

https://doi.org/10.3389/fphar.2018.01510

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Abstract

Currently there is no effective treatment available for clinical patients suffering from neuropathic pain induced by chemotherapy paclitaxel. Puerarin is a major isoflavonoid extracted from the Chinese medical herb kudzu root, which has been used for treatment of cardiovascular disorders and brain injury. Here, we found that puerarin dose-dependently alleviated paclitaxel-induced neuropathic pain. At the same time, puerarin preferentially reduced the excitability and blocked the voltage-gated sodium (Nav) channels of dorsal root ganglion (DRG) neurons from paclitaxel-induced neuropathic pain rats. Furthermore, puerarin was a more potent blocker of tetrodotoxin-resistant (TTX-R) Nav channels than of tetrodotoxin-sensitive (TTX-S) Nav channels in chronic pain rats’ DRG neurons. In addition, puerarin had a stronger blocking effect on Nav1.8 channels in DRG neurons of neuropathic pain rats and β1 subunit siRNA can abolish this selective blocking effect on Nav1.8. Together, these results suggested that puerarin may preferentially block β1 subunit of Nav1.8 in sensory neurons contributed to its anti-paclitaxel induced neuropathic pain effect.

Highlights

Paclitaxel, a microtubule-targeted agent extracted from Taxus brevifolia (Wani et al, 1971), is commonly used to treat various types of cancers, such as non-small cell lung, ovarian, and breast cancers (Armstrong et al, 2006; Sandler et al, 2006; Miller et al, 2007)
Our results showed that local application of puerarin dosedependently attenuated paclitaxel-induced mechanical allodynia and thermal hyperalgesia
The current study showed that the IC50 of puerarin for resting and inactivated Nav channels in dorsal root ganglion (DRG) neurons was 105 and 489 times lower in paclitaxel-induced neuropathic pain rats than in control rats

Summary

Introduction

Paclitaxel, a microtubule-targeted agent extracted from Taxus brevifolia (Wani et al, 1971), is commonly used to treat various types of cancers, such as non-small cell lung, ovarian, and breast cancers (Armstrong et al, 2006; Sandler et al, 2006; Miller et al, 2007). The mechanisms are not well understood, the use of paclitaxel is often related with peripheral neuropathy that mainly manifests as tingling, numbness, cold, and burning/shooting pain (Dougherty et al, 2004; Loprinzi et al, 2011; Reeves et al, 2012). A previous study showed that application of paclitaxel could enhance excitability of primary sensory neurons in dorsal root ganglion (DRG) (Zhang and Dougherty, 2014). There is currently no effective therapeutic drug to avoid or minimize the neuropathic pain induced by paclitaxel.

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