Faruk Kılınç, Ramis Çolak, Mete Özcan, Ahmet Ayar

Investigation of effects of neurotrophic factors on painful diabetic neuropathy: an experimental study

Objective: We have studied the effects of neurotrophin-4 (NT-4) different doses on the pain levels ofstreptozocin-induced diabetic rats.Methods: Thirty-five 3-week-old male rats were used. After induction of diabetes in rats with streptozocin(nearly 4 weeks); diabetic animals were divided into 4 groups. The first group; healthy control group (n = 15),the second group; diabetic control group (n = 10 ), the third group; low dose (0.3 mg/ kg ) recombinant humanNT-4 was applied (n = 4 ) and the fourth group; high dose recombinant human NT-4 was applied (n = 6).Results: In the low-dose NT-4 group, the pain threshold values did not differ from the diabetic control andhealthy control groups. In the high dose NT-4 group, a rise was observed in the pain threshold values of hotplate in comparison with the healthy control group, diabetic control group and low dose applied group and thisrise reached at the level of statistical significance (p < 0.05).Conclusion: Neurotrophic factors (neurotrophin-4) have been shown to be effective on painful diabeticneuropathy in streptozocin-induced diabetic rats. However, there is a need for larger-scale and longer-termstudies for clinical use.

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[1] Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum. Indian J Endocrinol Metab 2016;20:546-51.
[2] Davon A. M, Chronic pain. A primary Care Guide to Practical Management, second ed., Human Pres: Totawa, NJ. 2005;114-5.
[3] Price RD, Milne SA, Sharkey J, Matsuoka N, Advances in small molecules promoting neurotrophic function. Pharmacol Ther 2007;115:292-306.
[4] Bennett DL. Neurotrophic factors important regulators of nociceptive function. Neuroscientist 2001;7:13-7.
[5] Skaper SD. The neurotrophin family of neurotrophic factors: an overview. Methods Mol Biol 2012;846:1-12.
[6] Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J, et al. Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci 1999;19:5138-48.
[7] Chen SQ, Cai Q, Shen YY, Cai XY, Lei HY. Combined use of NGF/BDNF/bFGF promotes proliferation and differentiation of neural stem cells in vitro. Int J Dev Neurosci 2014;38:74-8.
[8] Christianson JA, Ryals JM, McCarson KE, Wright DE. Beneficial actions of neurotrophin therapy on diabetes-induced hypoalgesia in mice. J Pain 2003;4:493-504.
[9] Christianson JA, Ryals JM, Johnson MS , Dobrowsky RT, Wright DE. Neurotrophic modulation of myelinated cutaneous innervation and mechanical sensory loss in diabetic mice. Neuroscience 2007;145:303-13.
[10] Handwerker HO, Kobal G. Psychophysiology of experimentally induced pain. Physiol Rev 1993;73:639-71.
[11] Deli G, Bosecyak E, Pusch G, Komoly S, Feher G. Diabetic neuropathies: diagnosis and management. Neuroendocrinology 2013;98:267-80.
[12] Vinik AI, Park TS, Stansberry K B, Pittenger GL. Diabetic neuropathies. Diabetologia 2000;43;957-73.
[13] Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol 2002;11:521-34.
[14] Rees DA, Alcolado JC. Animal models of diabetes mellitus. Diabet Med 2005;22:359-70.
[15] Malik RA. Current and future strategies for the management of diabetic neuropathy. Treat Endocrinol 2003;2:389-400.
[16] Ahlgren SC, Levine JD. Mechanical hyperlgesia in streptozocin diabetic rat is not sympathetically maintained. Brain Res 1993;616:171-5.
[17] Ahlgren SC, White DM, Levine JD. Increased responsiveness of sensory neurons in the saphenous nerve of the streptozotocin-diabetic rat. J Neurophysiol 1992;68:2077-85.
[18] Piercy V, Banner SE, Bhattacharyya A, Parsons AA, Sanger GJ, Smith SA, et al. Thermal but not mechanical, nociceptive behavior is altered in the Zucker Diabetic Fatty rat and is independent of glycemic status. J Diabetes Complications 1999;13:163-9.
[19] Zhuang HX, Secyder CK, Pu SF, Ishii DN. Insulin-like growth factors reverse or arrest diabetic neuropathy: effects on hyperalgesia and impaired nerve regeneration in rats. Exp Neurol 1996;140:198-205.
[20] Calcutt NA, Jorge MC, Yaksh TL, Chaplan SR. Tactile allodynia and formalin hyperalgesia in streptozotocin-diabetic rats: effects of insulin, aldose reductase inhibition and lidocaine. Pain 1996;68 293-9.
[21] Fox A, Eastwood C, Gentry C, Manning D, Urban L. Critical evaluation of the streptozotocin model in the rat. Pain 1999;81:307-16.
[22] Raz I, Hasdai D, Seltzer M, Melmed RN. Effect of hyperglycemia on pain perception and on efficacy of morphine analgesia in rats. Diabetes 1988;37:1253-9.
[23] Klitgaard H, Matagne A, Gobert J, Wülfert E. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol 1998;353:191-206.
[24] Apfel SC. Neurotrophic factors in the therapy of diabetic neuropathy. Am J Med 2000;107:34-42.
[25] Schuman EM. Neurotropin regulation of synaptic transmission. Curr Opin Neurobiol 1999;9:105-9.
[26] Apfel SC. Neurotrophic factors and diabetic peripheral neuropathy. Eur Neurol 1999;41:27-34.
[27] Akkina SK, Patterson CL, Wright DE. GDNF rescues nonpeptidergic unmyelinated primary afferents in streptozotocintreated diabetic mice. Exp Neurol 2001;167:173-82.
[28] Apfel SC, Kessler JA. Neurotrophic factors in the therapy of peripheral neuropathy, Baillieres Clin Neurol 1995;4:593-606.
[29] Wellmer A, Misra VP, Sharief MK, Kopelman PG, Anand P. A double-blind placebo-controlled clinical trial of recombinant human brain-derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy. J Peripher Nerv Syst 2001;6:204-10.
[30] Siuciak JA, Wong V, Pearsall D, Wiegand SJ, Lindsay RM. BDNF produces analgesia in the formalin test and modifies neuropeptide levels in rat brain and spinal cord areas associated with nociception. Eur J Neurosci 1995;7663-70.