Inhibition of microRNA-155 Reduces Neuropathic Pain During Chemotherapeutic Bortezomib via Engagement of Neuroinflammation.

Zongsheng Duan,Jian Zhang,Jing Li,Hushan Wang,Xiaochuan Pang

doi:10.3389/fonc.2020.00416

Zongsheng Duan, Jian Zhang + Show 3 more

Open Access

https://doi.org/10.3389/fonc.2020.00416

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Abstract

As a chemotherapeutic agent, bortezomib (BTZ) is used for the treatment of multiple myeloma with adverse effect of painful peripheral neuropathy. Our current study was to determine the inhibitory effects of blocking microRNA-155 (miR-155) signal on BTZ-induced neuropathic pain and the underlying mechanisms. We employed real time RT-PCR and western blot analysis to examine the miR-155 and expression of pro−inflammatory tumor necrosis factor-α receptor (TNFR1) in the dorsal horn of the spinal cord. Its downstream signals p38-MAPK and JNK and transient receptor potential ankyrin 1 (TRPA1) were also determined. Mechanical pain and cold sensitivity were assessed by behavioral test. In result, inhibition of miR-155 significantly attenuated mechanical allodynia and thermal hyperalgesia in BTZ rats, which was accompanied with decreasing expression of TNFR1, p38-MAPK, JNK, and TRPA1. In contrast, miRNA-155 mimics amplified TNFR1-TRPA1 pathway and augmented mechanical pain and cold sensitivity. In addition, mechanical and thermal hypersensitivity induced by miRNA-155 mimics were attenuated after blocking TNFR1, p38-MAPK, JNK, and TRPA1. Overall, we show the key role of miR-155 in modifying BTZ-induced neuropathic pain through TNFR1-TRPA1 pathway, suggesting that miR-155 is a potential target in preventing neuropathic pain development during intervention of BTZ.

Highlights

Bortezomib (BTZ) is an inhibitor of the proteasome complex and is primarily used to treat multiple myeloma [1, 2]
Protein expression of TNFR1, transient receptor potential ankyrin 1 (TRPA1) and p-p38-MAPK/p-JNK were not observed to be changed after application of miR-155 inhibitor scramble (P > 0.05, BTZ vs. BTZ with scramble)
BTZ is frequently applied for treatment of multiple myeloma [1,2,3], but painful neuropathy and heightened cold sensitivity are main complications during application of BTZ [3]

Summary

Introduction

Bortezomib (BTZ) is an inhibitor of the proteasome complex and is primarily used to treat multiple myeloma [1, 2]. It is noteworthy to determine molecular mediators of BTZ-induced neuropathy in order to provide a base for application of drugs and further to make therapeutic strategies with chemotherapeutic in patients with multiple myeloma. MicroRNAs (miRNAs) are small noncoding endogenous RNA molecules, repressing their target mRNA through complementary binding in the message 3′-UTR [4]. They have important effects in processes of multiple physiological responses including cell death and survival, cellular response to stress, stem cell division, and pluripotency [5]. MiR-155 is upregulated in resident myeloid cells of the nervous systems, blood monocytes and activated microglia [15]

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