Exp Clin Endocrinol Diabetes 2012; 120(03): 132-138
DOI: 10.1055/s-0031-1291248
Article
© Georg Thieme Verlag KG Stuttgart · New York

Treatment with Actovegin® Improves Sensory Nerve Function and Pathology in Streptozotocin-Diabetic Rats via Mechanisms Involving Inhibition of PARP Activation

A. Dieckmann
1   Nycomed GmbH, 78467 Konstanz, Germany
,
M. Kriebel
2   Natural and Medical Sciences Institute, 72770 Reutlingen, Germany
,
E. Andriambeloson
3   Neurofit SAS, Illkirch, France
,
D. Ziegler
4   Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich Heine University, Department of Metabolic Diseases, University Hospital, Düsseldorf, Germany
,
M. Elmlinger
5   Nycomed International Management GmbH, Pipeline Sourcing, 8152 Zürich, Switzerland
› Author Affiliations
Further Information

Publication History

received 21 July 2011
first decision 22 August 2011

accepted 29 September 2011

Publication Date:
21 October 2011 (online)

Abstract

Background:

Diabetic neuropathy is one of the most severe complications of diabetes, affecting approximately one-third of diabetic patients. We investigated the potential neuroprotective effect of Actovegin®, a deproteinized hemoderivative of calf blood, in an animal model of diabetic neuropathy.

Methods:

A single intravenous injection of streptozotocin (STZ, 55 mg/kg) was used to induce experimental diabetes in male Sprague-Dawley rats. Actovegin® (200 or 600 mg/kg) was administered intraperitoneally from day 11 to day 40 post-STZ exposure. N-acetylcysteine (NAC) was used as a positive control and was added to drinking water (0.2 g/l) from day 2 until day 40. Measurements to assess efficacy included sensory nerve conduction velocity (SNCV), intraepidermal nerve fiber density (IENFD), and poly(ADP-ribose) content.

Results:

A decrease (35%) in sensory nerve conduction velocity (SNCV) was seen in STZ-induced diabetic rats from day 10 post-STZ administration and persisted at days 25 and 39. At study completion (day 41), a decrease (32%) in intraepidermal nerve fiber density (IENFD) was found in hind-paw skin biopsies from STZ-rats. Reduced SNCV and IENFD were significantly ameliorated by both doses of Actovegin®. More­over, 600 mg/kg Actovegin® markedly decreased poly(ADP-ribose) polymerase (PARP) activity in sciatic nerves from STZ-diabetic rats as assessed by poly(ADP-ribose) content.

Conclusion:

Actovegin® improved several para­meters of experimental diabetic neuropathy via mechanisms involving suppression of PARP activation, providing a rationale for treatment of this disease in humans.

 
  • References

  • 1 Andriambeloson E, Baillet C, Vitte PA et al. Interleukin-6 attenuates the development of experimental diabetes-related neuropathy. Neuropathology 2006; 26: 32-42
  • 2 Bordet T, Buisson B, Michaud M et al. Specific antinociceptive activity of cholest-4-en-3-one, oxime (TRO19622) in experimental models of painful diabetic and chemotherapy-induced neuropathy. J Pharmacol Exp Ther 2008; 326: 623-632
  • 3 Boulton AJ, Vinik AI, Arezzo JC et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 2005; 28: 956-962
  • 4 Buchmayer F, Pleiner J, Elmlinger M et al. Actovegin: a biological drug for more than 5 decades. Wien Med Wochenschr 2011; 161 (3-4) 80-88
  • 5 Cameron NE, Eaton SE, Cotter MA et al. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia 2001; 44: 1973-1988
  • 6 Cameron NE, Tuck Z, McCabe L et al. Effect of the hydroxyl radical scavenger, dimethylthiourea, on peripheral nerve tissue perfusion, conduction velocity and nociception in experimental diabetes. Diabetologia 2001; 44: 1161-1169
  • 7 Chong MS, Hester J. Diabetic painful neuropathy: current and future treatment options. Drugs 2007; 67: 569-585
  • 8 Drel VR, Lupachyk S, Shevalye H et al. New therapeutic and biomarker discovery for peripheral diabetic neuropathy: PARP inhibitor, nitrotyrosine, and tumor necrosis factor-{alpha}. Endocrinology 2010; 151: 2547-2555
  • 9 Francis G, Martinez J, Liu W et al. Intranasal insulin ameliorates experimental diabetic neuropathy. Diabetes 2009; 58: 934-945
  • 10 Garcia SF, Virag L, Jagtap P et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med 2001; 7: 108-113
  • 11 Holland NR, Stocks A, Hauer P et al. Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology 1997; 48: 708-711
  • 12 Ilnytska O, Lyzogubov VV, Stevens MJ et al. Poly(ADP-ribose) polymerase inhibition alleviates experimental diabetic sensory neuropathy. Diabetes 2006; 55: 1686-1694
  • 13 Kellogg AP, Wiggin TD, Larkin DD et al. Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fiber loss in experimental diabetes. Diabetes 2007; 56: 2997-3005
  • 14 Kuninaka T, Senga Y, Senga H et al. Nature of enhanced mitochondrial oxidative metabolism by a calf blood extract. J Cell Physiol 1991; 146: 148-155
  • 15 Lauria G, Lombardi R, Borgna M et al. Intraepidermal nerve fiber density in rat foot pad: neuropathologic-neurophysiologic correlation. J Peripher Nerv Syst 10 2005; 10: 202-208
  • 16 Obrosova IG, Drel VR, Pacher P et al. Oxidative-nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation in experimental diabetic neuropathy. Diabetes 2005; 54: 3435-3441
  • 17 Obrosova IG, Xu W, Lyzogubov VV et al. PARP inhibition or gene deficiency counteracts intraepidermal nerve fiber loss and neuropathic pain in advanced diabetic neuropathy. Free Radic Biol Med 2008; 44: 972-981
  • 18 Sagara M, Satoh J, Wada R et al. Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine. Diabetologia 1996; 39: 263-269
  • 19 Tesfaye S, Boulton AJ, Dyck PJ et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010; 33: 2285-2293
  • 20 Toth C, Brussee V, Zochodne DW.. Remote neurotrophic support of epidermal nerve fibres in experimental diabetes. Diabetologia 2006; 49: 1081-1088
  • 21 Vareniuk I, Pavlov IA, Drel VR et al. Nitrosative stress and peripheral diabetic neuropathy in leptin-deficient (ob/ob) mice. Exp Neurol 2007; 205: 425-436
  • 22 Ziegler D, Movsesyan L, Mankovsky B et al. Treatment of Symptomatic Polyneuropathy with Actovegin in Type 2 Diabetic Patients. Diabetes Care 2009; 32: 1479-1484