Gabapentin and Duloxetine Prevent Oxaliplatin- and Paclitaxel-Induced Peripheral Neuropathy by Inhibiting Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Phosphorylation in Spinal Cords of Mice.

Katsumasa Tsurushima,Masanobu Tsubaki,Tomoya Takeda,Mikihiro Matsumoto,Natsuki Kato,Keisuke Tateishi,Shozo Nishida,Toshihiko Ishizaka

doi:10.3390/ph14010030

Abstract

Chemotherapy-induced peripheral neuropathy is a common factor in limiting therapy which can result in therapy cessation or dose reduction. Gabapentin, a calcium channel inhibitor, and duloxetine, a serotonin noradrenaline reuptake inhibitor, are used to treat a variety of pain conditions such as chronic low back pain, postherpetic neuralgia, and diabetic neuropathy. It has been reported that administration of gabapentin suppressed oxaliplatin- and paclitaxel-induced mechanical hyperalgesia in rats. Moreover, duloxetine has been shown to suppress oxaliplatin-induced cold allodynia in rats. However, the mechanisms by which these drugs prevent oxaliplatin- and paclitaxel-induced neuropathy remain unknown. Behavioral assays were performed using cold plate and the von Frey test. The expression levels of proteins were examined using western blot analysis. In this study, we investigated the mechanisms by which gabapentin and duloxetine prevent oxaliplatin- and paclitaxel-induced neuropathy in mice. We found that gabapentin and duloxetine prevented the development of oxaliplatin- and paclitaxel-induced cold and mechanical allodynia. In addition, our results revealed that gabapentin and duloxetine suppressed extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in the spinal cord of mice. Moreover, PD0325901 prevented the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 activation in the spinal cord of mice. In summary, our findings suggest that gabapentin, duloxetine, and PD0325901 prevent the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 phosphorylation in mice. Therefore, inhibiting ERK1/2 phosphorylation could be an effective preventive strategy against oxaliplatin- and paclitaxel-induced neuropathy.

Highlights

No significant differences were observed in withdrawal latency at any time point by the combination treatment with 10 mg/kg duloxetine, 6 mg/kg oxaliplatin, or 6 mg/kg paclitaxel compared with the combination treatment with 30 mg/kg duloxetine and 6 mg/kg oxaliplatin or 6 mg/kg paclitaxel (Figures 3A and 4A)
These results indicate that gabapentin and duloxetine suppress oxaliThese observations indicate that inhibition of extracellular signal-regulated protein kinase 1/2 (ERK1/2) activation by a MEK inhibitor corplatinand paclitaxel-induced neuropathy inhibiting the expression of phosphorylated relate with the prevention oxaliplatinandbypaclitaxel-induced neuropathic-like pain by pre-treatment with gabapentin, and duloxetine
Our study suggests that the analgesic effects of gabapentin, duloxetine, and PD0325901 against the development of oxaliplatin- and paclitaxel-induced neuropathiclike pain behavior in mice are mediated via the inhibition of ERK1/2 activation

Summary

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting adverse effect of multiple chemotherapeutic agents, including oxaliplatin and paclitaxel, which can result in therapy cessation or dose reduction [1,2,3]. Platinum drugs (oxaliplatin and cisplatin), vinca alkaloids (vincristine and vinblastine), taxanes (paclitaxel and docetaxel), and bortezomib induce the most severe effects on the peripheral nervous system [4,5,6,7]. Pharmaceuticals 2021, 14, 30 about the mechanisms involved in the development of CIPN, no drugs are currently available to prevent or treat CIPN. The identification of drugs that effectively prevent or treat CIPN is important

Methods

Results

Discussion

Conclusion