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Current Neurovascular Research

Author(s): Yingda Li, Xizhe Zhang, Zhimei Fu* and Qi Zhou

DOI: 10.2174/1567202616666191111104145

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MicroRNA-212-3p Attenuates Neuropathic Pain via Targeting Sodium Voltage-gated Channel Alpha Subunit 3 (NaV 1.3)

Page: [465 - 472] Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Purpose: To explore the role and potential mechanism of miR-212-3p in neuropathic pain regulation.

Methods: Adult male rats were used to establish chronic constriction injury (CCI) model to mimic the neuropathic pain. Then, paw withdrawal threshold (PWT) and paw withdrawal thermal latency (PWL) were determined. The concentrations of interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were measured with enzyme-linked immune sorbent assay (ELISA) kit and the expression of miR-212-3p was measured by real time quantitative PCR (RTqPCR). Besides, miR-212-3p agomir was intrathecally injected into CCI rats and the expression of key apoptotic proteins was determined by western blot. Furthermore, dual-luciferase reporter assay was used to determine the binding of miR-212-3p and 3’ untranslated regions (3’UTR) of NaV1.3 and the expression levels of NaV1.3 were measured by western blot and RT-qPCR.

Results: In the CCI group, the PWT and PWL were significantly decreased and IL-1β, IL-6 and TNF-α were increased. miR-212-3p was decreased in response to CCI. The intrathecal injection of miR-212-3p agomir into CCI rats improved the PWT and PWL, decreased the IL-1β, IL-6 and TNF-α, decreased the expression levels of BCL2 associated X, apoptosis regulator (Bax), cleaved caspase-3 and increased the expression levels of BCL2 apoptosis regulator (Bcl-2). The results of dual--luciferase reporter assay showed that miR-212-3p could directly bind with 3’UTR of NaV1.3. The expression of NaV1.3 was up-regulated in CCI rats who were intrathecally injected with miRctrl, whereas it decreased in CCI rats intrathecally injected with miR-212-3p agomir.

Conclusion: The expression of miR-212a-3p attenuates neuropathic pain by targeting NaV1.3.

Keywords: miR-212-3P, neuropathic pain, CCI rats, NaV1.3, TNF-α, chronic constriction injury.

[1]
Colloca L, Ludman T, Bouhassira D, et al. Neuropathic pain. Nat Rev Dis Primers 2017; 3: 17002-02.
[http://dx.doi.org/10.1038/nrdp.2017.2] [PMID: 28205574]
[2]
Baron R, Maier C, Attal N, et al. Peripheral neuropathic pain: A mechanism-related organizing principle based on sensory profiles. Pain 2017; 158(2): 261-72.
[http://dx.doi.org/10.1097/j.pain.0000000000000753] [PMID: 27893485]
[3]
Zhou M, Chen N, He L, Yang M, Zhu C, Wu F. Oxcarbazepine for neuropathic pain. Cochrane Database Syst Rev 2017; 12(12)CD007963
[PMID: 29199767]
[4]
Sumitani M, Sakai T, Matsuda Y, et al. Executive summary of the Clinical Guidelines of Pharmacotherapy for Neuropathic Pain Second edition by the Japanese Society of Pain Clinicians. In: J Anesthesia. 2018; 32: pp. (3)463-78.
[5]
Cardoso FC, Lewis RJ. Sodium channels and pain: From toxins to therapies. Br J Pharmacol 2018; 175(12): 2138-57.
[http://dx.doi.org/10.1111/bph.13962] [PMID: 28749537]
[6]
Lee GH, Kim SS. Therapeutic strategies for neuropathic pain: Potential application of pharmacosynthetics and optogenetics. Mediators Inflamm 2016; 2016: 5808215-15.
[http://dx.doi.org/10.1155/2016/5808215] [PMID: 26884648]
[7]
Xu W, Zhang J, Wang Y, Wang L, Wang X. Changes in the expression of voltage-gated sodium channels Nav1.3, Nav1.7, Nav1.8, and Nav1.9 in rat trigeminal ganglia following chronic constriction injury. Neuroreport 2016; 27(12): 929-34.
[http://dx.doi.org/10.1097/WNR.0000000000000632] [PMID: 27327156]
[8]
Samad OA, Tan AM, Cheng X, et al. Virus-mediated shRNA knockdown of Na(v)1.3 in rat dorsal root ganglion attenuates nerve injury-induced neuropathic pain. Mol Ther 2013; 21(1): 49-56.
[9]
Tan AM, Samad OA, Dib-Hajj SD, Waxman SG. Virus-mediated knockdown of Nav1.3 in dorsal root ganglia of STZ-induced diabetic rats alleviates tactile allodynia. Mol Med 2015; 21(1): 544-52.
[http://dx.doi.org/10.2119/molmed.2015.00063] [PMID: 26101954]
[10]
Dai Z, Chu H, Ma J, Yan Y, Zhang X, Liang Y. The regulatory mechanisms and therapeutic potential of MicroRNAs: From chronic pain to morphine tolerance. Front Mol Neurosci 2018; 11: 80-0.
[http://dx.doi.org/10.3389/fnmol.2018.00080] [PMID: 29615865]
[11]
Tan P-H, Pao Y-Y, Cheng J-K, Hung KC, Liu CC. MicroRNA-based therapy in pain medicine: Current progress and future prospects. Acta Anaesthesiol Taiwan 2013; 51(4): 171-6.
[http://dx.doi.org/10.1016/j.aat.2013.11.001] [PMID: 24529673]
[12]
Ciszek BP, Khan AA, Dang H, et al. MicroRNA expression profiles differentiate chronic pain condition subtypes. Transl Res 2015; 166(6): 706-720.e11.
[http://dx.doi.org/10.1016/j.trsl.2015.06.008] [PMID: 26166255]
[13]
Chen HP, Zhou W, Kang LM, et al. Intrathecal miR-96 inhibits Nav1.3 expression and alleviates neuropathic pain in rat following chronic construction injury. Neurochem Res 2014; 39(1): 76-83.
[http://dx.doi.org/10.1007/s11064-013-1192-z] [PMID: 24234845]
[14]
Li T, Wan Y, Sun L, et al. Inhibition of MicroRNA-15a/16 Expression alleviates neuropathic pain development through upregulation of G protein-coupled receptor kinase 2. Biomol Ther (Seoul) 2019; 27(4): 414-22.
[http://dx.doi.org/10.4062/biomolther.2018.073] [PMID: 31189298]
[15]
Tu WZ, Li SS, Jiang X, et al. Effect of electro-acupuncture on the BDNF-TrkB pathway in the spinal cord of CCI rats. Int J Mol Med 2018; 41(6): 3307-15.
[http://dx.doi.org/10.3892/ijmm.2018.3563] [PMID: 29568892]
[16]
Zhao F, Tang Q, Xu J, Wang S, Li S, Zou X, et al. Dehydrocrenatidine inhibits voltage-gated sodium channels and ameliorates mechanic allodia in a rat model of neuropathic pain. Toxins 2019; 11(4): 229.https://www.ncbi.nlm.nih.gov/pubmed/31003411
[PMID: 31003411]
[17]
Challa SR. Surgical animal models of neuropathic pain: Pros and Cons. Int J Neurosci 2015; 125(3): 170-4.
[http://dx.doi.org/10.3109/00207454.2014.922559] [PMID: 24831263]
[18]
Eskildsen TV, Jeppesen PL, Schneider M, et al. Angiotensin II regulates microRNA-132/-212 in hypertensive rats and humans. Int J Mol Sci 2013; 14(6): 11190-207.
[http://dx.doi.org/10.3390/ijms140611190] [PMID: 23712358]
[19]
Wong HK, Veremeyko T, Patel N, et al. De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer’s disease. Hum Mol Genet 2013; 22(15): 3077-92.
[http://dx.doi.org/10.1093/hmg/ddt164] [PMID: 23585551]
[20]
Ucar A, Gupta SK, Fiedler J, et al. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat Commun 2012; 3: 1078.
[http://dx.doi.org/10.1038/ncomms2090] [PMID: 23011132]
[21]
Wu X, Chen H, Zhang G, et al. MiR-212-3p inhibits cell proliferation and promotes apoptosis by targeting nuclear factor IA in bladder cancer. J Biosci 2019; 44(4): 80.
[http://dx.doi.org/10.1007/s12038-019-9903-5] [PMID: 31502558]
[22]
Hou P, Kang Y, Luo J. Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a. Cancer Biol Ther 2018; 19(11): 984-93.
[http://dx.doi.org/10.1080/15384047.2018.1456608] [PMID: 29672195]
[23]
Chen W, Ma X, Zhang P, Li Q, Liang X, Liu J. MiR-212-3p inhibits LPS-induced inflammatory response through targeting HMGB1 in murine macrophages. Exp Cell Res 2017; 350(2): 318-26.
[http://dx.doi.org/10.1016/j.yexcr.2016.12.008] [PMID: 27940320]
[24]
Li D, Bai L, Wang T, et al. Function of miR-212 as a tumor suppressor in thyroid cancer by targeting SIRT1. Oncol Rep 2018; 39(2): 695-702.
[http://dx.doi.org/10.1007/s12094-017-1772-5] [PMID: 29207181]
[25]
Li L, Li Y, Huang Y, et al. Long non-coding RNA MIF-AS1 promotes gastric cancer cell proliferation and reduces apoptosis to upregulate NDUFA4. 2018; 109(12): 3714-25.
[http://dx.doi.org/10.1111/cas.13801]
[26]
Xie C, Chen B, Wu B, et al. LncRNA TUG1 promotes cell proliferation and suppresses apoptosis in osteosarcoma by regulating miR-212-3p/FOXA1 axis. Biomed Pharmacother 2018; 97: 1645-53.
[27]
Zhao JL, Zhang L, Guo X, et al. miR-212/132 downregulates SMAD2 expression to suppress the G1/S phase transition of the cell cycle and the epithelial to mesenchymal transition in cervical cancer cells. IUBMB Life 2015; 67(5): 380-94.
[http://dx.doi.org/10.1002/iub.1381] [PMID: 25988335]
[28]
Zhang J, Zhang Y, Li X, Wang H, Li Q, Liao X. MicroRNA 212 inhibits colorectal cancer cell viability and invasion by directly targeting PIK3R3. Mol Med Rep 2017; 16(5): 7864-72.
[http://dx.doi.org/10.3892/mmr.2017.7552] [PMID: 28944887]
[29]
Hains BC, Klein JP, Saab CY, Craner MJ, Black JA, Waxman SG. Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci 2003; 23(26): 8881-92.
[http://dx.doi.org/10.1523/JNEUROSCI.23-26-08881.2003] [PMID: 14523090]
[30]
Xie M-X, Yang J, Pang R-P, et al. Bulleyaconitine A attenuates hyperexcitability of dorsal root ganglion neurons induced by spared nerve injury: The role of preferably blocking Nav1.7 and Nav1.3 channels. Mol Pain 2018; 141744806918778491
[http://dx.doi.org/10.1177/1744806918778491] [PMID: 29783906]
[31]
Su S, Shao J, Zhao Q, et al. MiR-30b attenuates neuropathic pain by regulating voltage-gated sodium channel nav1.3 in rats. Front Mol Neurosci 2017; 10(126): 126.
[http://dx.doi.org/10.3389/fnmol.2017.00126] [PMID: 28529474]