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Metformin attenuates increase of synaptic number in the rat spinal dorsal horn with painful diabetic neuropathy induced by type 2 diabetes: a stereological study

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Abstract

In our previous study, we have shown that number of synapses in the L5 segment of spinal dorsal horn increased significantly in a rat model of painful diabetic neuropathy (PDN) induced by high-dose of streptozotocin (an animal model of type 1 diabetes). The aims of this study were: (1) to determine whether high fat diet/low dose streptozotocin-diabetes, a rat model for type 2 diabetes, related PDN was also associated with this synaptic plasticity, (2) to reveal the range of this synaptic plasticity change occurred (in the whole length of spinal dorsal horn or only in the L5 lumbar segment of spinal dorsal horn) and (3) to discover whether treatment with metformin had effect on this synaptic plasticity. Male adult Sprague–Dawley rats were randomly allocated into the control group (n = 7), the PDN group (n = 6) and the PDN treated with metformin (PDN + M) group (n = 7), respectively. 28 days after medication, synaptic and neuronal numbers in the whole length of spinal dorsal horn or in 1 mm length of the L5 segment of spinal dorsal horn were estimated by the optical disector (a stereological technique). Compared to the control group and the PDN + M group, number of synapses in the L5 segment of spinal dorsal horn increased significantly in the PDN group (P < 0.05). There was no significant change between the control group and the PDN + M group in terms of the parameters in the L5 segment of the spinal dorsal horn (P > 0.05). Parameters of the whole length of spinal dorsal horn showed no significant changes (P > 0.05). Our results suggest that high fat diet/low dose streptozotocin diabetes related PDN is also associated with a numerical increase of synapses in the L5 segment of spinal dorsal horn but not in the whole length of spinal dorsal horn. Furthermore, the analgesic effect of metformin against PDN is related to its inhibition of numerical increase of synaptic number in the rat spinal dorsal horn.

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References

  1. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM et al (1993) The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester diabetic neuropathy study. Neurology 43(4):817–824

    Article  CAS  Google Scholar 

  2. Schreiber AK, Nones CF, Reis RC, Chichorro JG, Cunha JM (2015) Diabetic neuropathic pain: physiopathology and treatment. World J Diabetes 6(3):432–444

    Article  Google Scholar 

  3. Peltier A, Goutman SA, Callaghan BC (2014) Painful diabetic neuropathy. BMJ 348:g1799

    Article  Google Scholar 

  4. Bastyr EJ 3rd, Price KL, Bril V, MBBQ Study Group (2005) Development and validity testing of the neuropathy total symptom score-6: questionnaire for the study of sensory symptoms of diabetic peripheral neuropathy. Clin Ther 27(8):1278–1294

    Article  Google Scholar 

  5. Zieglar D, Gries FA, Spüler M, Lessmann F (1992) The epidemiology of diabetic neuropathy. Diabetic cardiovascular autonomic neuropathy multicenter study group. J Diabetes Complicat 6(1):49–57

    Article  Google Scholar 

  6. Fuchs D, Birklein F, Reeh PW, Sauser SK (2010) Sensitized peripheral nociception in experimental diabetes of the rat. Pain 151(2):496–505

    Article  CAS  Google Scholar 

  7. Lin J-Y, Huang X-L, Chen J, Yang Z-W, Lin J, Huang S, Peng B (2017) Stereological study on the number of synapses in the rat spinal dorsal horn with painful diabetic neuropathy induced by streptozotocin. Neuroreport 28(6):319–324

    Article  CAS  Google Scholar 

  8. Callaghan BC, Little AA, Feldman EL, Hughes RA (2012) Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev 13(6):CD007543

    Google Scholar 

  9. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M (1995) Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333(2):89–94

    Article  CAS  Google Scholar 

  10. Mao-Ying QL, Kavelaars A, Krukowski K et al (2014) The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PLoS ONE 9(6):e100701

    Article  Google Scholar 

  11. Ma J, Yu H, Liu J et al (2015) Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin. Eur J Pharmacol 764:599–606

    Article  CAS  Google Scholar 

  12. Taylor A, Westveld AH, Szkudlinska M et al (2013) The use of metformin is associated with decreased lumbar radiculopathy pain. J Pain Res 6:755–763

    PubMed  PubMed Central  Google Scholar 

  13. Russe OQ, Möser CV, Kynast KL et al (2013) Activation of the AMP-activated protein kinase reduces inflammatory nociception. J Pain 14(11):1330–1340

    Article  CAS  Google Scholar 

  14. Łabuzek K, Liber S, Suchy D, Okopień B (2013) A successful case of pain management using metformin in a patient with adiposis dolorosa. Int J Clin Pharmacol Ther 51(6):517–524

    PubMed  Google Scholar 

  15. Zuo ZF, Wang W, Niu L et al (2011) RU486 (mifepristone) ameliorates cognitive dysfunction and reverses the down-regulation of astrocytic N-myc downstream-regulated gene2 in streptozotocin-induced type-1 diabetic rats. Neuroscience 190:156–165

    Article  CAS  Google Scholar 

  16. Kou ZZ, Li CY, Tang J et al (2013) Down-regulation of insulin signaling is involved in painful diabetic neuropathy in type 2 diabetes. Pain Physician 16(2):E71–E83

    PubMed  Google Scholar 

  17. Chen SR, Pan HL (2002) Hypersensitivity of spinothalamic tract neurons associated with diabetic neuropathic pain in rats. J Neurophysiol 87(6):2726–2733

    Article  Google Scholar 

  18. Mei XP, Zhou Y, Wang W et al (2011) Ketamine depresses toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain. Neurosignals 19(1):44–53

    Article  CAS  Google Scholar 

  19. Chaplan SR, Bach FW, Pogrel JW et al (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53(1):55–63

    Article  CAS  Google Scholar 

  20. Peng B, Lin JY, Shang Y et al (2010) Plasticity in the synaptic number associated with neuropathic pain in the rat spinal dorsal horn: a stereological study. Neurosci Lett 486(1):24–28

    Article  CAS  Google Scholar 

  21. Morrow TJ (2004) Animal models of painful diabetic neuropathy: the STZ rat model. Curr Protoc Neurosci. https://doi.org/10.1002/0471142301.ns0918s29. (Chap. 9:Unit 9.18).

    Article  PubMed  Google Scholar 

  22. Gheibi S, Kashfi K, Ghasemi A (2017) A practical guide for induction of type-2 diabetes in rat: incorporating a high-fat diet and streptozotocin. Biomed Pharmacother 95:605–613. https://doi.org/10.1016/j.biopha.2017.08.098

    Article  CAS  PubMed  Google Scholar 

  23. Lin JY, Peng B, Yang ZW, Min S (2011) Number of synapses increased in the rat spinal dorsal horn after sciatic nerve transection: a stereological study. Brain Res Bull 84(6):430–433

    Article  Google Scholar 

  24. Zhou X, Wu LF (2003) Spinal cord. In: Cheng LZ, Zhong CP, Cai WQ (eds) Contemporary histology. Shanghai Scientific and Technological Literature Publishing House, Shanghai, pp 425–427 (book in Chinese)

    Google Scholar 

  25. Gundersen HJ, Bagger P, Bendtsen TF et al (1988) The new stereological tools: disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 96(10):857–881

    Article  CAS  Google Scholar 

  26. Martin MM (1953) Diabetic neuropathy; a clinical study of 150 cases. Brain 76(4):594–624

    Article  CAS  Google Scholar 

  27. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P et al (2010) Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33(10):2285–2293

    Article  Google Scholar 

  28. Holland NR, Crawford TO, Hauer P, Cornblath DR, Griffin JW, McArthur JC (1998) Smallfiber sensory neuropathies: clinical course and neuropathology of idiopathic cases. Ann Neurol 44(1):47–59

    Article  CAS  Google Scholar 

  29. Shehab SA (2009) Acute and chronic sectioning of fifth lumbar spinal nerve has equivalent effects on the primary afferents of sciatic nerve in rat spinal cord. J Comp Neurol 517(4):481–492

    Article  Google Scholar 

  30. Abbott CA, Malik RA, van Ross ER, Kulkarni J, Boulton AJ (2011) Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the UK. Diabetes Care 34(10):2220–2224

    Article  Google Scholar 

  31. The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329(14):977–986

    Article  Google Scholar 

  32. Linn T, Ortac K, Laube H, Federlin K (1996) Intensive therapy in adult insulin dependent diabetes mellitus is associated with improved insulin sensitivity and reserve: a randomized, controlled, prospective study over 5 years in newly diagnosed patients. Metabolism 45(12):1508–1513

    Article  CAS  Google Scholar 

  33. Azad N, Emanuele NV, Abraira C, Henderson WG, Colwell J, Levin SR et al (1999) The effects of intensive glycemic control on neuropathy in the VA cooperative study on type II diabetes mellitus (VA CSDM). J Diabetes Complicat 13(5–6):307–313

    Article  CAS  Google Scholar 

  34. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD et al (2009) Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360(2):129–139

    Article  CAS  Google Scholar 

  35. Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J, Cohen RM et al (2010) Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 376(9739):419–430

    Article  Google Scholar 

  36. Tovi J, Svanborg E, Nilsson BY, Engfeldt P (1998) Diabetic neuropathy in elderly type 2 diabetic patients: effects of insulin treatment. Acta Neurol Scand 98(5):346–353

    Article  CAS  Google Scholar 

  37. Melemedjian OK, Khoutorsky A, Sorge RE, Yan J, Asiedu MN et al (2013) mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK. Pain 154(7):1080–1091

    Article  CAS  Google Scholar 

  38. Melemedjian OK, Yassine HN, Shy A, Price TJ (2013) Proteomic and functional annotation analysis of injured peripheral nerves reveals ApoE as a protein upregulated by injury that is modulated by metformin treatment. Mol Pain 9:14

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Guoyun Qin, Buming Wan, Shuai He and Mingyou Wang (undergraduates of North Sichuan Medical College) for their assistance in the lab work and animal care.

Funding

This research was supported by the Grant of the Education Department of Sichuan (No. 16ZA0238) and the Grant from Special Project of Municipal-school Cooperation (NSMC20170443).

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Author notes

  1. Jing-yan Lin and Yi-na He are co-first authors.

Authors and Affiliations

  1. Department of Anesthesiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan, China

    Jing-yan Lin, Yi-na He & Na Zhu

  2. Department of Anesthesiology, Nanchong Central Hospital, Nanchong, 637000, Sichuan, China

    Yi-na He

  3. Research Unit of Electron Microscopy Structures, North Sichuan Medical College, Nanchong, 637000, Sichuan, China

    Bin Peng

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  1. Jing-yan Lin
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Correspondence to Bin Peng.

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Lin, Jy., He, Yn., Zhu, N. et al. Metformin attenuates increase of synaptic number in the rat spinal dorsal horn with painful diabetic neuropathy induced by type 2 diabetes: a stereological study. Neurochem Res 43, 2232–2239 (2018). https://doi.org/10.1007/s11064-018-2642-4

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