Targeting aurora kinase B alleviates spinal microgliosis and neuropathic pain in a rat model of peripheral nerve injury.

Abstract

Peripheral nerve injury elicits spinal microgliosis, contributing to neuropathic pain. The aurora kinases A (AURKA), B (AURKB), and C (AURKC) are potential therapeutic targets in proliferating cells. However, their role has not been clarified in microglia. The aim of this study was to examine the regulation of aurora kinases and their roles and druggability in spinal microgliosis and neuropathic pain. Sprague-Dawley rats received chronic constriction injury (CCI). Gene expression of aurora kinases A-C was evaluated by quantitative RT-PCR and western blot, respectively, in spinal cords at 1, 3, 7, and 14 days after CCI. AURKB gene and protein expression was up-regulated concomitantly with the development of spinal microgliosis and neuropathic pain. Using lentiviral over-expression and adeno-associated viral knockdown approaches, the function of AURKB was further investigated by western blot, immunohistochemistry, RNA sequencing, and pain behavior tests. We found that AURKB over-expression in naive rats caused spinal microgliosis and pain hypersensitivity, whereas AURKB knockdown reduced microgliosis and alleviated CCI-induced neuropathic pain. Accordingly, RNA sequencing data revealed down-regulation of genes critically involved in signaling pathways associated with spinal microgliosis and neuropathic pain after AURKB knockdown in CCI rats. To examine its therapeutic potential for treatment of neuropathic pain, animals were treated intrathecally with the pharmacological AURKB inhibitor AZD1152-HQPA resulting in the alleviation of CCI-induced pain. Taken together, our findings indicated that AURKB plays a critical role in spinal microgliosis and neuropathic pain. Targeting AURKB may be an efficient method for treatment of neuropathic pain subsequent to peripheral nerve injury.

• Authors: Yu Shen, Zhuofeng Ding, Shengyun Ma, Yu Zou, Xin Yang, Zijin Ding, Yu Zhang, Xiaoyan Zhu, Michael K E Schäfer, Qulian Guo, Changsheng Huang
• Journal: Journal of neurochemistry (J Neurochem) Vol. 152 Issue 1 Pg. 72-91 (01 2020) ISSN: 1471-4159 [Electronic] England
• PMID: 31563141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 International Society for Neurochemistry.

Chemical References

• Enzyme Inhibitors
• Aurora Kinase B

Topics

• Animals
• Aurora Kinase B (antagonists & inhibitors, genetics, physiology)
• Disease Models, Animal
• Down-Regulation
• Enzyme Inhibitors (therapeutic use)
• Gene Expression
• Gene Knockdown Techniques
• Male
• Microglia (enzymology, pathology, physiology)
• Neuralgia (enzymology, therapy)
• Peripheral Nerve Injuries (enzymology, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Spinal Cord (enzymology, pathology)