Exp Clin Endocrinol Diabetes 2020; 128(01): 59-65
DOI: 10.1055/a-0919-4614
Article
© Georg Thieme Verlag KG Stuttgart · New York

Tanshinone II A Affects Diabetic Peripheral Neuropathic Pain via Spinal Dorsal Horn Neuronal Circuitry by Modulating Endoplasmic Reticulum Stress Pathways

Dawei Kong
1   Department of Neurosurgery, Peking University, China-Japan Friendship School of Clinical Medicine, Beijing, China
,
Zhuangli Guo
2   Department of Rehabilitation, The Affiliated Hospital of Qingdao University, Qingdao, China
,
Wenqiang Yang
1   Department of Neurosurgery, Peking University, China-Japan Friendship School of Clinical Medicine, Beijing, China
,
Qi Wang
1   Department of Neurosurgery, Peking University, China-Japan Friendship School of Clinical Medicine, Beijing, China
,
Yanbing Yu
1   Department of Neurosurgery, Peking University, China-Japan Friendship School of Clinical Medicine, Beijing, China
,
Li Zhang
1   Department of Neurosurgery, Peking University, China-Japan Friendship School of Clinical Medicine, Beijing, China
› Author Affiliations
Acknowledgements: This work was financed by the National Natural Science Foundation of China (No. 81673793, 81373796, 81173424).
Further Information

Publication History

received 10 April 2019
revised 10 April 2019

accepted 14 May 2019

Publication Date:
11 July 2019 (online)

Abstract

Diabetic peripheral neuropathic pain (DPNP) is a common manifestation of diabetic peripheral neuropathy (DPN). Although the pathogenesis of DPNP remains unclear, the disinhibition of spinal dorsal horn neuronal circuitry mediated by endoplasmic reticulum stress (ERS) is an important mechanism underlying neuropathic pain (NP). Tanshinone II A is mainly used to treat cardiovascular diseases but has also been shown to relieve various types of neuralgia, including DPNP. This study investigated the effects of tanshinone II A in DPNP model rats. We divided animals into two groups: 1) the model (diabetic) group and 2) the tanshinone II A-treatment group. Our results demonstrated that diabetic rats exhibited a decrease in the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL), and that NMT is increased and TWL is prolonged in rats treated with tanshinone II A. Additionally, the levels of ERS-signaling pathway factors in the spinal dorsal horns of rats were lower in the tanshinone II A-treated group than in the diabetic group. Overall, our study demonstrated that the disinhibition of spinal dorsal horn neuronal circuitry mediated by endoplasmic reticulum stress underlies DPNP and is modulated by tanshinone II A treatment.

 
  • References

  • 1 International Diabetes Federation, IDF Diabetes Atlas. sixth ed. International Diabetes Federation; Brussels, Belgium: 2013
  • 2 Chan JC, Zhang Y, Ning G. Diabetes in China: a societal solution for a personal challenge. Lancet Diabetes Endocrinol 2014; 2: 969-979
  • 3 Cao FL, Xu M, Wang Y. et al. Tanshinone II A attenuates neuropathic pain via inhibiting glial activation and immune response, Pharmacol. Biochem. Behav 2015; 128: 1-7
  • 4 Tang J, Zhu C, Li ZH. et al. Inhibition of the spinal astrocytic JNK/M CP-1 pathway activation correlates with the analgesic effects of tanshinone II A sulfonate in neuropathic pain. J Neuro inflammation 2015; 12: 57
  • 5 Zhang E, Yi MH, Shin N. et al. Endoplasmic reticulum stress impairment in the spinal dorsal horn of a neuropathic pain model. Sci Rep 2015; 5: 11555
  • 6 Réthelyi M, Light AR, Perl E.R.. Synaptic complexes formed by functionally defined primary afferent units with fine myelinated fibers. J Comp Neurol 1982; 207: 381-393
  • 7 Lu Y, Dong H, Gao Y. et al. A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia. J Clin Invest 2013; 123: 4050-4062
  • 8 Torsney C, MacDermott AB. Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord. J Neurosci 2006; 26: 1833-1843
  • 9 Yan J, Feng J, Yang X. et al. Recent progress on pharmacological effects and therapeutic use of tanshinone II A. Practical Pharmacy and Clinical Remedies 2015; 18: 972-975
  • 10 Baba H, Ji RR, Kohno T. et al. Removal of GABAergic inhibition facilitates polysynaptic A fiber-mediated excitatory transmission to the superficial spinal dorsal horn. Mol Cell Neurosci 2003; 24: 818-830
  • 11 Zeilhofer HU, Wildner H, Yévenes GE. Fast synaptic inhibition in spinal sensory processing and pain control. Physiol Rev 2012; 92: 193-235
  • 12 Sardella TC, Polgár E, Watanabe M. et al. A quantitative study of neuronal nitric oxide synthase expression in laminae I-III of the rat spinal dorsal horn. Neuroscience 2011; 192: 708-720
  • 13 Polgár E, Hughes DI, Riddell JS. et al. Selective loss of spinal GABAergic or glycinergic neurons is not necessary for development of thermal hyperalgesia in the chronic constriction injury model of neuropathic pain. Pain 2003; 104: 229-239
  • 14 Zhang ZJ, Reynolds GP. A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr. Res 2002; 55: 1-10
  • 15 Haze K, Yoshida H, Yanagi H. et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 1999; 10: 3787-3799
  • 16 Yoshida H, Matsui T, Yamamoto A. et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001; 107: 881-891
  • 17 Lee K, Tirasophon W, Shen X. et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 2002; 16: 452-466
  • 18 Calfon M, Zeng H, Urano F. et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 2002; 415: 92-96
  • 19 Bertolotti Zhang Y, Hendershot LM. et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2000; 2 . 326-332
  • 20 Shen J, Chen X, Hendershot L. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3 2002; 99-111
  • 21 Kimata Y, Kimata YI, Shimizu Y. et al. Genetic evidence for a role of BiP/Kar2 that regulates Ire1 in response to accumulation of unfolded proteins. Mol Biol Cell 14 2003; 2559-2569
  • 22 Wang YS, Deng WL, Xue CS. Pharmacology and Application of Chinese Medicine. second ed. Beijing Peopleʼs Medical Publishing House; Beijing: 1998
  • 23 Jiy B, Zhang GM. Pharmacology and Application of Chinese Medicine on Effective Constituents of Anti-cancer. Haerbin Science and Technology Publishing House of Heilongjiang; 1995
  • 24 Shang Q, Xu H, Huang L. Tanshinone II A: A promising natural cardioprotective agent. Evid Based Complement Alternat Med 2012; 2012: 716459
  • 25 Ren BX, Ji Y, Tang JC. et al. Effect of Tanshinone II A intrathecal injections on pain and spinal inflammation in mice with bone tumors. Genet. Mol. Res 2015; 14: 2133-2138
  • 26 Hao W, Chen L, Wu LF. et al. Tanshinone II A Exerts an Antinociceptive Effect in Rats with Cancer-induced Bone Pain. Pain Physician 2016; 19: 465-476
  • 27 Tang J, Zhu C, Li ZH. et al. Inhibition of the spinal astrocytic JNK/MCP-1 pathway activation correlates with the analgesic effects of tanshinone II A sulfonate in neuropathic pain. J. Neuroinflammation 2015; 12: 57
  • 28 Liu Y, Wang L, Li X. et al. Tanshinone II A improves impaired nerve functions in experimental diabetic rats. Biochem. Biophys. Res. Commun 2010; 399: 49-54