Prostaglandin E1 Protects the Peripheral Nerve in Diabetics through Preventing Vascular Permeability Changes

Abstract

Objective The aims of this study were to investigate the effects of the vasodilator prostaglandin E1 on microvascular permeability, the expression of vascular endothelial growth factor (VEGF), as well as the structural and functional changes of the peripheral nerve in diabetic rats.

Methods Streptozotocin-induced diabetes mellitus were randomly divided into two groups and intraperitoneally received, once daily, an injection of prostaglandin E1 at 1.6 μg/kg in normal saline or the same volume of normal saline (diabetic control), respectively. Six rats were randomly selected as normal controls.

Results Diabetic controls exhibited a significant increase in the tail flick threshold temperature, water content of the sciatic nerve, serum VEGF level, and VEGF level in the sciatic nerve; in addition, a decrease in the sciatic nerve conduction velocity (NCV) was observed, compared with normal rats (P<0.01). Treatment with prostaglandin E1 resulted in similar changes but at a slower rate than in those without treatment. Diabetic control rats also showed histological and ultrastructural abnormalities of the sciatic nerve, whereas prostaglandin E1-treated rats exhibited similar but less severe injury. The serum VEGF level was negatively correlated with the sciatic NCV (r=−0.932, P<0.01) and positively correlated with the tail flick threshold temperature (r=0.835, P<0.01) as well as the water content of the sciatic nerve (r=0.901, P<0.01).

Conclusion Prostaglandin E1 could protect the peripheral nerve by improving sciatic nerve function, reducing the VEGF level, and decreasing the vascular permeability. This study provides an experimental proof that prostaglandin E1 has potential benefits in improving DPN in early stage.

Key words

prostaglandin E1 - diabetic rats - vascular endothelial growth factor - vascular permeability - peripheral nerve

• References

• 1 Adeshara KA, Diwan AG, Tupe RS. Diabetes and complications: Cellular signalling pathways, current understanding and targeted therapies. Curr Drug Targets 2015
• 2 Bansal D, Gudala K, Muthyala H. et al. Prevalence and risk factors of development of peripheral diabetic neuropathy in type 2 diabetes mellitus in a tertiary care setting. J Diabetes Investig 2014; 5: 714-721
• 3 Gordois A, Scuffham P, Shearer A. et al. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 2003; 26: 1790-1795
• 4 Peng L, Liu W, Zhai F. et al. Microvessel permeability correlates with diabetic peripheral neuropathy in early stage of streptozotocin-induced diabetes rats. J Diabetes Complications 2015; 29: 865-871
• 5 Li Z, Langhans SA. Transcriptional regulators of Na,K-ATPase subunits. Front Cell Dev Biol 2015; 3: 66
• 6 Kalix P. Prostaglandin E1 raises the cAMP content of peripheral nerve tissue. Neurosci Lett 1979; 12: 361-364
• 7 Kreutz RP, Nystrom P, Kreutz Y. et al. Inhibition of platelet aggregation by prostaglandin E1 (PGE1) in diabetic patients during therapy with clopidogrel and aspirin. Platelets 2013; 24: 145-150
• 8 Kogawa S, Yasuda H, Terada M. et al. Apoptosis and impaired axonal regeneration of sensory neurons after nerve crush in diabetic rats. Neuroreport 2000; 11: 663-667
• 9 Najafpour A, Mohammadi R, Faraji D. et al. Local administration of prostaglandin E1 combined with silicone chamber improves peripheral nerve regeneration. Int J Surg 2013; 11: 1010-1015
• 10 Akahori H, Takamura T, Hayakawa T. et al. Prostaglandin E1 in lipid microspheres ameliorates diabetic peripheral neuropathy: Clinical usefulness of Semmes-Weinstein monofilaments for evaluating diabetic sensory abnormality. Diabetes Res Clin Pract 2004; 64: 153-159
• 11 Couffinhal T, Kearney M, Witzenbichler B. et al. Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in normal and atherosclerotic human arteries. Am J Pathol 1997; 150: 1673-1685
• 12 Yla-Herttuala S, Rissanen TT, Vajanto I. et al. Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol 2007; 49: 1015-1026
• 13 Rosenstein JM, Krum JM, Ruhrberg C. VEGF in the nervous system. Organogenesis 2010; 6: 107-114
• 14 Guaiquil VH, Pan Z, Karagianni N. et al. VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions. Proc Natl Acad Sci U S A 2014; 111: 17272-17277
• 15 Like AA, Rossini AA. Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science 1976; 193: 415-417
• 16 Misra UK, Kalita J, Nair PP. Diagnostic approach to peripheral neuropathy. Ann Indian Acad Neurol 2008; 11: 89-97
• 17 Coste TC, Gerbi A, Vague P. et al. Neuroprotective effect of docosahexaenoic acid-enriched phospholipids in experimental diabetic neuropathy. Diabetes 2003; 52: 2578-2585
• 18 Zangiabadi N, Mohtashami H, Hojatipour M. et al. The effect of Angipars on diabetic neuropathy in STZ-induced diabetic male rats: a study on behavioral, electrophysiological, sciatic histological and ultrastructural indices. ScientificWorldJournal 2014; 2014: 721547
• 19 Yu JX, Yin XX, Shen JP. et al. Protective effects of bendazac lysine on diabetic peripheral neuropathy in streptozotocin-induced diabetic rats. Clin Exp Pharmacol Physiol 2006; 33: 1231-1238
• 20 Yasuda H, Sonobe M, Yamashita M. et al. Effect of prostaglandin E1 analogue TFC 612 on diabetic neuropathy in streptozocin-induced diabetic rats. Comparison with aldose reductase inhibitor ONO 2235. Diabetes 1989; 38: 832-838
• 21 Ward JD. Abnormal microvasculature in diabetic neuropathy. Eye (Lond) 1993; 7 Pt 2 223-226
• 22 Miranda-Massari JR, Gonzalez MJ, Jimenez FJ. et al. Metabolic correction in the management of diabetic peripheral neuropathy: Improving clinical results beyond symptom control. Curr Clin Pharmacol 2011; 6: 260-273
• 23 Yang S, Xia C, Li S. et al. Mitochondrial dysfunction driven by the LRRK2-mediated pathway is associated with loss of Purkinje cells and motor coordination deficits in diabetic rat model. Cell Death Dis 2014; 5: e1217
• 24 Kidd GJ, Ohno N, Trapp BD. Biology of Schwann cells. Handb Clin Neurol 2013; 115: 55-79
• 25 Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002; 20: 4368-4380
• 26 Deguchi T, Hashiguchi T, Horinouchi S. et al. Serum VEGF increases in diabetic polyneuropathy, particularly in the neurologically active symptomatic stage. Diabet Med 2009; 26: 247-252
• 27 Sakai K, Komai K, Yanase D. et al. Plasma VEGF as a marker for the diagnosis and treatment of vasculitic neuropathy. J Neurol Neurosurg Psychiatry 2005; 76: 296
• 28 Toshihiko S, Masazumi M, Kazuhisa T. Effects of lipo-prostaglandin E1 on blood flow and oxygen pressure in lumbo-sacral nerve roots. Journal of Orthopaedic Science 1997; 2: 289-294
• 29 Jiang DQ, Li MX, Wang Y. et al. Effects of prostaglandin E1 plus methylcobalamin alone and in combination with lipoic acid on nerve conduction velocity in patients with diabetic peripheral neuropathy: A meta-analysis. Neurosci Lett 2015; 594: 23-29
• 30 Mackenzie F, Ruhrberg C. Diverse roles for VEGF-A in the nervous system. Development 2012; 139: 1371-1380
• 31 Schratzberger P, Walter DH, Rittig K. et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest 2001; 107: 1083-1092