Exp Clin Endocrinol Diabetes 2018; 126(10): 632-639
DOI: 10.1055/s-0044-100722
Article
© Georg Thieme Verlag KG Stuttgart · New York

Tanshinone IIA Improves Painful Diabetic Neuropathy by Suppressing the Expression and Activity of Voltage-Gated Sodium Channel in Rat Dorsal Root Ganglia

Ao Ri-Ge-le
1   Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
2   Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
,
Zhuang-Li Guo
3   Department of Rehabilitation, The Affiliated Hospital of Qingdao University, Qingdao, China
,
Qi Wang
1   Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
,
Bao-Jian Zhang
1   Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
,
Da-Wei Kong
1   Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
,
Wen-Qiang Yang
2   Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
,
Yan-Bing Yu
1   Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
2   Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
,
Li Zhang
1   Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
2   Department of Neurosurgery, China-Japan Friendship Hospital, Beijing, China
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 30. November 2017
revised 03. Januar 2018

accepted 10. Januar 2018

Publikationsdatum:
31. Januar 2018 (online)

Abstract

Painful diabetic neuropathy (PDN) is one of the intractable complications of diabetes mellitus, which manifest as exaggerated pain perception. Previous studies showed that Tanshinone IIA (TIIA), one of the major bioactive extracts of Salvia miltiorrhiza Bunge, have obvious analgesic effect on different types of pain process, and the underlying analgesic mechanisms are not fully understood. The present study combined the behavioral, electrophysiological and biochemical methods to elucidate the analgesic mechanism of TIIA, using streptozotocin (STZ)-induced PDN rat models. Intraperitoneal injection (i.p.) of TIIA for 3 weeks in PDN rats significantly improved mechanical allodynia and thermal hyperalgesia. Patch clamp recordings showed that the excitability of dorsal root ganglion (DRG) nociceptive neuron was increased in diabetic state, and TIIA treatment effectively recovered the subnormality, which was achieved by preventing augments of both Tetrodotoxin-sensitive (TTX-resistant) and Tetrodotoxin-sensitive (TTX-S) sodium currents. Further, the protein expressions of voltage-gated sodium channels (VGSCs) α-subunits Nav1.3, Nav1.7 and Nav1.9 increased in DRG of diabetic rats and were normalized by TIIA application. In conclusion, this study provides evidence that the TIIA attenuated PDN by effecting VGSCs activities and expressions, indicating that the TIIA could be a promising agent for PDN treatment.

 
  • References

  • 1 Rosenberg CJ, Watson JC. Treatment of painful diabetic peripheral neuropathy. Prosthetics and orthotics international 2015; 39: 17-28
  • 2 Spallone V, Greco C. Painful and painless diabetic neuropathy: one disease or two?. Current diabetes reports 2013; 13: 533-549
  • 3 Peltier A, Goutman SA, Callaghan BC. Painful diabetic neuropathy. Bmj 2014; 348: g1799
  • 4 Chen X, Levine JD. Hyper-responsivity in a subset of C-fiber nociceptors in a model of painful diabetic neuropathy in the rat. Neuroscience 2001; 102: 185-192
  • 5 Chahine M, Ziane R, Vijayaragavan K. et al. Regulation of Na v channels in sensory neurons. Trends in pharmacological sciences 2005; 26: 496-502
  • 6 Elliott AA, Elliott JR. Characterization of TTX-sensitive and TTX-resistant sodium currents in small cells from adult rat dorsal root ganglia. The Journal of physiology 1993; 463: 39-56
  • 7 Kharatmal SB, Singh JN, Sharma SS. Voltage-Gated Sodium Channels as Therapeutic Targets for Treatment of Painful Diabetic Neuropathy. Mini reviews in medicinal chemistry 2015; 15: 1134-1147
  • 8 Zhou L, Zuo Z, Chow MS. Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. Journal of clinical pharmacology 2005; 45: 1345-1359
  • 9 Hao W, Chen L, Wu LF. et al. Tanshinone IIA Exerts an Antinociceptive Effect in Rats with Cancer-induced Bone Pain. Pain physician 2016; 19: 465-476
  • 10 Sun S, Yin Y, Yin X. et al. Anti-nociceptive effects of Tanshinone IIA (TIIA) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. Brain research bulletin 2012; 88: 581-588
  • 11 Wang YS, Li YY, Wang LH. et al. Tanshinone IIA attenuates chronic pancreatitis-induced pain in rats via downregulation of HMGB1 and TRL4 expression in the spinal cord. Pain physician 2015; 18: E615-E628
  • 12 Cao FL, Su XJ, Wang Y. et al. Antinociceptive effects of systemic tanshinone IIA on visceral and somatic persistent nociception and pain hypersensitivity in rats. Pharmacology, biochemistry, and behavior 2014; 124: 74-80
  • 13 Cao FL, Xu M, Wang Y. et al. Tanshinone IIA attenuates neuropathic pain via inhibiting glial activation and immune response. Pharmacology, biochemistry, and behavior 2015; 128: 1-7
  • 14 Liu Y, Wang L, Li X. et al. Tanshinone IIA improves impaired nerve functions in experimental diabetic rats. Biochemical and biophysical research communications 2010; 399: 49-54
  • 15 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 IIA sulfonate in neuropathic pain. Journal of neuroinflammation 2015; 12: 57
  • 16 Chaplan SR, Bach FW, Pogrel JW. et al. Quantitative assessment of tactile allodynia in the rat paw. Journal of neuroscience methods 1994; 53: 55-63
  • 17 Hargreaves K, Dubner R, Brown F. et al. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988; 32: 77-88
  • 18 Chen X, Pang RP, Shen KF. et al. TNF-alpha enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury. Experimental neurology 2011; 227: 279-286
  • 19 Heng LJ, Qi R, Yang RH. et al. Docosahexaenoic acid inhibits mechanical allodynia and thermal hyperalgesia in diabetic rats by decreasing the excitability of DRG neurons. Experimental neurology 2015; 271: 291-300
  • 20 Sun W, Miao B, Wang XC. et al. Gastrodin inhibits allodynia and hyperalgesia in painful diabetic neuropathy rats by decreasing excitability of nociceptive primary sensory neurons. PloS one 2012; 7: e39647
  • 21 Abdulla FA, Smith PA. Axotomy- and autotomy-induced changes in the excitability of rat dorsal root ganglion neurons. Journal of neurophysiology 2001; 85: 630-643
  • 22 Liu B, Li H, Brull SJ. et al. Increased sensitivity of sensory neurons to tumor necrosis factor alpha in rats with chronic compression of the lumbar ganglia. Journal of neurophysiology 2002; 88: 1393-1399
  • 23 Rush AM, Cummins TR, Waxman SG. Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. The Journal of physiology 2007; 579: 1-14
  • 24 Renganathan M, Cummins TR, Waxman SG. Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. Journal of neurophysiology 2001; 86: 629-640
  • 25 Hong S, Morrow TJ, Paulson PE. et al. Early painful diabetic neuropathy is associated with differential changes in tetrodotoxin-sensitive and -resistant sodium channels in dorsal root ganglion neurons in the rat. The Journal of biological chemistry 2004; 279: 29341-29350
  • 26 Craner MJ, Klein JP, Renganathan M. et al. Changes of sodium channel expression in experimental painful diabetic neuropathy. Annals of neurology 2002; 52: 786-792
  • 27 He WY, Zhang B, Xiong QM. et al. Intrathecal administration of rapamycin inhibits the phosphorylation of DRG Nav1.8 and attenuates STZ-induced painful diabetic neuropathy in rats. Neuroscience letters 2016; 619: 21-28
  • 28 Herzog RI, Cummins TR, Waxman SG. Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons. Journal of neurophysiology 2001; 86: 1351-1364
  • 29 Baker MD, Chandra SY, Ding Y. et al. GTP-induced tetrodotoxin-resistant Na+ current regulates excitability in mouse and rat small diameter sensory neurones. The Journal of physiology 2003; 548: 373-382
  • 30 Tan AM, Samad OA, Dib-Hajj SD. et al. Virus-Mediated Knockdown of Nav1.3 in Dorsal Root Ganglia of STZ-Induced Diabetic Rats Alleviates Tactile Allodynia. Molecular medicine 2015; 21: 544-552
  • 31 Emery EC, Luiz AP, Wood JN. Nav1.7 and other voltage-gated sodium channels as drug targets for pain relief. Expert opinion on therapeutic targets 2016; 20: 975-983
  • 32 Chattopadhyay M, Zhou Z, Hao S. et al. Reduction of voltage gated sodium channel protein in DRG by vector mediated miRNA reduces pain in rats with painful diabetic neuropathy. Molecular pain 2012; 8: 17
  • 33 King GF, Vetter I. No gain, no pain: NaV1.7 as an analgesic target. ACS chemical neuroscience 2014; 5: 749-751
  • 34 Dib-Hajj SD, Yang Y, Black JA. et al. The Na(V)1.7 sodium channel: From molecule to man. Nature reviews Neuroscience 2013; 14: 49-62
  • 35 Dib-Hajj SD, Estacion M, Jarecki BW. et al. Paroxysmal extreme pain disorder M1627K mutation in human Nav1.7 renders DRG neurons hyperexcitable. Molecular pain 2008; 4: 37