DIABETIC NEUROPATHY: STILL A CHALLENGE IN PHARMACOLOGY.HTML Full Text
DIABETIC NEUROPATHY: STILL A CHALLENGE IN PHARMACOLOGY.
RAWAL SHRUTI*1, SHASHI ALOK2, MAHAJAN N1, MAHOR A3, JOSHI A1, SHARMA P4, SAROHA M. 5.
Department of Pharmaceutical Sciences, Lovely School of Pharmacy, Lovely Professional University*1, Phagwara, Punjab., India
Institute of Pharmacy, Bundelkhand University 2, Jhansi, U. P., India
Department of Pharmaceutical Sciences, Dr. H. S. Gour University 3, Sagar, M. P., India
- M. College of Pharmacy, M. M University4, Mullana, Haryana., India
Amity Institute of Biotechnology, Amity University 5, New Delhi, India
ABSTRACT: Diabetic neuropathy is one of the most serious microvascular complications of diabetes, which appears in about 50% of the patients suffering from diabetes. It is a nerve disorder caused by diabetes, characterized usually by numbness, pain or tingling in the feet or legs, which can lead to serious problems. Patients with diabetic neuropathy suffer from various types of pain. The underlying mechanisms include hyperglycaemia, insulin deficiency, oxidative stress, nitrosative stress, ischaemia, osmolyte accumulation, neurotropic factors deficiency, autoimmune-mediated nerve destruction, alterations in cellular signal pathways and gene expression of proteins. The factors leading to the development of peripheral neuropathy in diabetes are not understood completely, and multiple hypotheses have been advanced which include the polyol pathway, non-enzymatic glycation, oxidative stress, altered neurotropism and apoptosis. At present, there is no clinically proven efficacious drug specifically designated for the treatment of diabetic neuropathy; however, prevention or retardation of the progress of diabetic neuropathy is considered to depend on various antidiabetics, antioxidants, anti-depressants, anticonvulsants, NSAIDs, etc. The new advances in the development of neurotrophic factors and aldose reductase inhibitors herald the host of potentially combined treatments in the field of DN. The use of neurotrophic factors appears to be the most exciting approach because of the potential for the reversibility and regeneration of nerves
Diabetes mellitus is a conglomeration of metabolic and chronic inflammatory derangements characterized by hyperglycemia; altered metabolism of carbohydrates, fats and proteins1, 2.With the availability of new and improved drugs, the life expectancy in diabetes has increased considerably. But progress of the disease is often marred by complications including microvascular, macrovascular, and neuropathic disorders3. The macrovascular complications lead to pathological states such as stroke, large vessel ischaemia, etc and the microvascular complications include peripheral and autonomic neuropathies4.
Diabetic neuropathy is one of the most serious microvascular complications of diabetes, which appears in about 50% of the patients suffering from diabetes from 25 years5, 6, 7. It is a nerve disorder caused by diabetes, characterized usually by numbness, pain or tingling in the feet or legs, which can lead to serious problems. Patients with diabetic neuropathy suffer from various types of pain such as hyperalgesia and allodynia8. This develops in the early stages of diabetes. The underlying molecular mechanisms for diabetic neuropathy are still debatable but hyperglycaemia has been proposed as the major precipitating factor in various studies6. Other mechanisms include insulin deficiency, oxidative stress, nitrosative stress, ischaemia, osmolyte accumulation, neurotropic factors deficiency, autoimmune-mediated nerve destruction, alterations in cellular signal pathways and gene expression of proteins9. The cellular mechanism for hyperalgesic and allodynic pain in diabetic neuropathy includes the remodeling of voltage- and ligand-gated Ca2+ channels that can increase excitability of the sensory neurons10. In the past few decades, several experimental drugs have undergone clinical trials but none has been proved efficacious. This may be due to the fact that diabetic neuropathy is a multifactorial disease and no specific drug has yet been evolved which can herald the progression of the complication by acting on the multiple aetiological targets. Moreover, the biomarkers which can indicate the progression of a disease when it can be reversed is still lacking in case of diabetic neuropathy.
This review focus on (i) the various molecular and pathological basis for diabetic neuropathy (ii) the current therapeutic interventions in diabetic neuropathy (iii) the future prospects for the prevention and treatment of this dreaded complication of diabetes.
Epidemiology & risk factors of diabetic neuropathy: The incidence of diabetic patients affected with neuropathic complications is approximately 45-50%. Around 50% of people who have diabetes for more than 25 years will eventually develop diabetic neuropathy with an average prevalence of approximately 30% of the patients5, 7, 11. Pharmacoepidemiologic studies have suggested that 2.5% of the patients with diabetes develop diabetic foot ulcers every year and approximately 15% of the patients develop diabetic foot ulcers during their life time12.
Potential risk factors for painful diabetic neuropathy include hypertension, hyperglycaemia, smoking, obesity, hyperlipidemia and atherosclerosis13. Thus, risk factors apart from hyperglycaemia are probably involved in the evolution of neuropathic complications in diabetic patients.
Pathophysiological basis of diabetic neuropathy: The exact pathophysiological mechanism of diabetic neuropathy is yet to be understood completely. The various hypotheses proposed include the polyol pathway, non-enzymatic glycation, oxidative Stress, altered neurotropism and apoptosis (fig. 1).
Fig. 1: Pathophysiological mechanisms for Diabetic Neuropathy
Polyol pathway in diabetic neuropathy: Polyhydroxy alcohol pathway involves the conversion of glucose to sorbitol by aldose reductase. This sorbitol is further converted to fructose by sorbitol dehydrogenase which leads to depletion of organic osmolytes like taurine, glycerophosphoryl choline and myo-inositol14, 15, 16. Myo-inositol depletion in peripheral nerves results in insufficiency of diacylglycerol necessary to maintain protein kinase C which ultimately resulting in inactivation of Na+ /K+ATPase activity, Na+ retention, cellular oedema and cell lysis17, 18. These further results in nodal swelling, axonal degeneration and axonal atrophy16, 19, 20. Taurine is not only an osmolyte but also an antioxidant and a neurotrophic factor, depletion of which in peripheral nerves causes nerve degeneration21.
Non-enzymatic glycation & oxidative stress in diabetic neuropathy: Oxidative stress and oxidative damage to tissues are common end points of chronic diseases, such as atherosclerosis, diabetes, and rheumatoid arthritis. Oxidative stress can occur in diabetes via metabolic changes induced by hyperglycaemia such as activation of aldose reductase and the polyol pathway 20, production of advanced glycation end products and reduced recycling of the antioxidant glutathione by glutathione peroxidase due to depletion of its cofactor NADPH22. The increase in glycoxidation and lipidperoxidation products in plasma and tissue suggests that oxidative stress is increased in diabetes. Increased chemical modification of proteins by carbohydrates and lipids in diabetes is the result of overload on metabolic pathways involved in detoxification of reactive carbonyl species23. This leads to a general increase in steady-state levels of reactive carbonyl compounds formed by both oxidative and nonoxidative reactions. N epsilon-(carboxymethyl) lysine, N epsilon-(carboxymethyl) hydroxylysine, and the cross-linked pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins24. These glycoxidation products accumulate in tissue collagen with age and at an accelerated rate in diabetes25.
Oxidative stress is promoted by auto-oxidation of glucose26 and results in formation of glycoxidation products which generates reactive oxygen species, such as oxygen radicals such as superoxide (O2-), alkoxyl (RO.), peroxyl (ROO.), and hydroxyl radicals (OH.), and non-radical derivatives of oxygen, namely, hydrogen peroxide (H2O2) and ozone (O3) that contribute to apoptosis25. Reduced sugars like glucose, fructose or galactose react with free amino groups of proteins, lipids or nucleic acids and form reversible Schiff bases and Amadori products that undergo chemical rearrangements to form AGEs, i.e.
Advanced Glycation End Products24. The AGE pentosidine is formed by glucose auto-oxidation27, and Nε-(carboxymethyl) lysine (CML) is an AGE formed by both auto-oxidation and lipid peroxidation28. These AGEs binds to RAGE (receptor for AGE) and depletes intracellular reduced glutathione and Vit. C. Due to this, free radicals gets accumulated in nerves and other sites of the body and ultimately results in oxidative stress29. The extracellular matrix within a nerve trunk comprises of the fibrous collagens I and III, basal laminal sheaths and small quantities of connective tissue proteins. All these are required to maintain the normal growth and functioning of nerve cells. If connections between the axon and its end organs are damaged by glycation, it leads to alteration in transport and growth factor changes24.
The proteins, tubulin and actin that surround the nerve fibre which undergoes glycation and results in axonal atrophy while the protein laminin undergoes glycation resulting in nerve sprouting culminating in nerve fibre regeneration30, 31, 32, 33. Myelin components, myelin basic protein and proteolipid proteins are scavenged by macrophages via RAGE, receptor for advanced glycation end products by non-enzymatic glycation resulting in segmental demyelination34, 35, 36.
Altered neurotropism in diabetic neuropathy: Altered neurotropism is associated with diabetic neuronal dysfunction19, 20. Nerve growth factor (NGF) which is selectively trophic to small-fiber sensory and sympathetic ganglion neurons is reduced due to oxidative stress and this leads to neuronal damage37, 38, 39, 40. NGF, normally blocks induction of ROS and thus stabilizes mitochondrial membrane potentia41. Administration of NGF administration has been documented to prevent the reduction of neuropeptides such as substance P and Calcitonin gene- related peptide in dorsal root ganglion (DRG) and sciatic nerve of diabetic rats42, 43. These neuropeptides mediate nociceptive and thermoreceptive sensations and are vasodilators. NGF binds to high- and low- affinity NGF receptors. The high affinity NGF receptor is a tyrosine kinase transmembrane protein called TrkA and the low affinity receptor is a 75-kD glycoprotein known as p75. Both the receptors are located on small, unmyelinated fibres of sensory neurons in ANS, CNS and PNS.
In diabetes, the expression of TrkA is reduced while p75 is increased, which results in decreased NGF in DRG neurons44. IGF-I and II promotes nerve regeneration, astrocyte functions and also co-ordinates with glial cell neurotropic factor changes45. IGFs have neurotrophic actions on sensory, sympathetic and motor neurons. Reduction in IGF-1 levels and increased IGF-1 binding protein levels contributes to impaired IGF-1 activity and causes peripheral nerve damage 46.
Neurotropins (NT) promote development, survival and differentiation of neurons47. Tropomyosin related kinases (A, B, C) modulate nerve functions45. Reduced expression of TrkA in the respective neurons and decreased synthesis of the neurotrophin-3 contribute to nerve dysfunction in DPN39.
Role of apoptosis in diabetic neuropathy: Apoptosis is a cell suicide mechanism that enables tissues to control cell number. Certain cells have unique sensors, termed death receptors, on their surface. Death receptors detect the presence of extracellular death signals and, in response; they rapidly ignite the cell's intrinsic apoptosis machinery48.These caspases thenactivate death receptors, mitochondrial dysfunction, leading to endoplasmic reticulum (ER) abnormalities and alterations in calcium homeostasis and ultimately neuronal cell death20.
Therapeutic interventions in diabetic neuropathy: The exact pathophysiology of diabetic neuropathy is not clearly understood. Treating neuropathy is a difficult task for the physician and most of the conventional pain medications primarily mask symptoms.The most effective strategy currently available to prevent diabetic neuropathy is the strict glycaemic control11. Various other therapeutic strategies used in the management of neuropathic pain include non-pharmacological measures like monochromatic near-infrared treatment49, 50, 51, electrical nerve stimulators50, acupuncture therapy51 and application of Opsite which is a thin adhesive film50.
Surgical Management include pancreatic transplantation in patients with diabetic and end-stage renal disease can stabilize neuropathy and in some instances improve motor, sensory and autonomic function for as long as 48 months after uremia plateaus52. The pharmacological management of neuropathic pain includes antidepressants, anticonvulsants, NSAIDS, etc. Although these drugs provide symptomatic relief to the patients but are associated with a number of side-effects (Table 1).
The pharmacological treatment has been reported using antidepressants53. Tricyclic antidepressants are primarily considered as first line agents in the management of neuropathic pain which include duloxetine54, amitryptyline55 and now venlafaxine 56. Amitryptyline was the first drug that went under clinical trials for diabetic pain and is widely used but it carries a high incidence of anticholinergic side effects55. Venlafaxine has a combination of both norepinepherine and serotonin reuptake inhibiting effects without having anticholinergic side effects but it include other side effects like increased blood pressure, irritability, insomnia, constipation, vomiting 56. Selective Serotonin Reuptake Inhibitors (SSRIs) such as fluoxetine have been reported to reduce pain in depressed patients57. These agents increase the concentration of serotonin at the receptor site.
Several anticonvulsants like carbamazapine53, pregabalin58, 59, 60, gabapentin61, 62, 63, topiramate64, valproate65, 66, 67 and lamotrigine68, 69 are usually considered as second-line therapy in neuropathies but are mostly associated with anticholinergic side effects. Sodium channels blocking activity on the nerve fibres by these agents is the proposed mechanism for treating neuropathic pain53. Pregabalin has also been approved by the FDA for diabetic neuropathy58, 59, 60.It acts peripherally at the GABA receptor to block the perception of pain. Pregabalin is well tolerated in patients and causes less sedation than gabapentin. However, it is associated with other serious adverse effects, including rhabodmyolysis, acute renal failure, central nervous system effects, hyperthermia, and secondary acute-angle glaucoma54. Topiramate is another agent used in the treatment of diabetic neuropathy that is associated with weight loss64.
Table 1: Current Therapeutic Drugs for Diabetic Neuropathy
|Dry mouth, sedation, dizziness, confusion, orthostatic hypotension, constipation, urinary retention, blurred vision, weight gain, arrhythmias|
|Headache, nausea, sedation, constipation, sexual MAO inhibitors dysfunction, somnolence, hypertension, seizures, SIADH (syndrome of inappropriate antidiuretic hormone secretion),hyponatremia|
|Agitation, dry mouth, sedation, ataxia, nausea, vomiting, blurred vision, confusion, fatigue, nystagmus, aplastic anemia, rhinitis, toxic epidermal necrolysis, Peripheral edema, diplopia, rhabdomyolysis, acute renal failure, thrombocytopenia|
|NSAIDs like ibuprofen and Sulindac||Renal dysfunction
|Opioids||Tolerance & dependence|
|Capsaicin cream||Localized burning and itching, cough, sneezing|
|Tramadol||Nausea, sedation, constipation, headache, dry mouth, urinary retention, confusion, tremor, seizures|
|Mexilitine||Dyspepsia, dizziness, tremor, ataxia, insomnia, diarrhea, constipation, headache, nervousness, hepatotoxicity, arrhythmia, agranulocytosis, toxic epidermal necrolysis
Lamotrigine acts peripherally to treat neuropathic pain but is found to be less efficacious than carbamazepine and is associated with aplastic anemia and toxic epidermal necrosis68, 69.
NSAIDS like ibuprofen and Sulindac offer some pain relief in diabetic neuropathy70. These agents are limited in use because they cause renal dysfunction54. Opioids and topical agents like capsaicin have been used for symptomatic relief of pain in diabetic neuropathy54, 71.
Other agents like tramadol which acts through both monoaminergic and opioidergic mechanisms to block the pain72 and mixeletine which is a class IB antiarrhythmic drug and acts peripherally as an ion channel blocker to prevent the perception of pain73, 74, 75 are also being used in the neuropathic therapy76.
Future Prospects for therapy: The study of neurotrophic factors and C-peptide growth factors on several animal models appears to be the most exciting approach because of the potential for the reversibility of nerve abnormalities associated with diabetes. These neurotrophic factors and C-peptide growth factors are still under clinical trials and may prove efficacious for the treatment of diabetic neuropathy (Table 2).
Nerve Growth Factor: This protein promotes survival of sympathetic and small-fiber neural crest–derived elements in the peripheral nervous system77. In animals with diabetes, both production and transport of NGF are impaired. Antioxidants have been used to enhance the effects of NGF. This includes combinations of growth factors like Brain Derived Neurotrophic factor (BDNF) so that large fibre neuropathy can also be targeted. NGF has indicated beneficial effects in treating dysfunction of small sensory fibres78.
Aldose Reductase Inhibitors: Drugs like alrestatin have been shown to improve sensory impairment by inhibiting the aldose reductase in polyol pathway79. Sorbinil, another aldose reductase inhibitor has been shown to improve both motor and sensory conduction velocities compared to placebo80. Tolrestat, an aldose reductase inhibitor improves the autonomic function tests as well as vibration perception in diabetic patients81. A large number of aldose reductase inhibitors are still under trials and may come out as a novel target approach for diabetic neuropathy.
Insulin or C-peptide Growth Factors: Insulin and C-peptide growth factors have been shown to improve nerve regeneration20. Administration of C-peptide improves autonomic nerve function. C-peptide stimulates nerve Na+ K+ ATPase activity, resulting in improved electrolyte and enzyme state. This improves endoneural blood flow, stimulates endothelial nitric oxide synthase with release of nitric oxide19. Proinsulin C-peptide is known to enhance the effects of insulin82.
Other Agents: Alpha lipoic acid is a strong anti-oxidant, acts as a coenzyme of hydrogen transfer in oxidative stress20. Acetyl- L- carnitine and gamma-linolenic acid have been useful in endothelial dysfunction83, 84.
Table 2: Future Prospects for Diabetic Neuropathy
|Novel Therapeutic Implications||Examples|
|Neurotrophins(NT)||Nerve growth factor
Brain- derived neurotrophic factor
NT - 3
NT - 6
|Insulin - like growth factors (IGF)||Insulin
IGF - I
IGF - II
|Epidermal growth factor (EGF)
Transforming growth factor (TGF) - α
|Haematopoietic cytokines||Ciliary neurotrophic factor
Granulocyte colony- stimulating factor
Interleukin (IL) - 1
IL - 3
IL - 6
IL - 7
IL - 9
IL - 11
|Heparin – binding Factors||Acdic fibroblast growth factor (FGF)
int - 2 onc
Keratinocyte growth factor
FGF - 4
FGF - 5
FGF - 6
|TGF – β Factors||TGF - β1
TGF - β2
TGF - β3
Glial - derived neurotrophic factor
|Tyrosine kinase - associated cytokines||Platelet - derived growth factor
Colony - stimulating factor - 1
Stem cell factor
Human Intravenous Immunoglobin (IVg)
Aminoguanidine which is an inhibitor of the formation of AGEs has been reported to improve the nerve conduction velocity85, 86. Gangliosides have been shown to improve nerve cell membranes87, 88, 89, 90. Myoionositol supplements in normal diets have been reported to improve neuropathy by Na+ K+ ATPase activity which improves the nerve growth91. Human Intravenous Immunoglobin (IVg) treatment potentially ameliorates neurologic disturbances in diabetic patients92. Recombinant nerve growth factor administration has been demonstrated to restore the neuropeptide levels towards normal and prevent the manifestations of sensory neuropathy in animals93.
Laminin has been shown to promote neurite extension by cultured neurons94. Laminin is a large, heteromeric, cruciform glycoprotein composed of a large A chain and two smaller B chains, B1 and B295. It has been reported that recombinant human erythropoietin (rhEPO) has efficacy in preventing and reversing nerve dysfunction in streptozotocin-induced diabetes in rats96.
Diabetic neuropathy accounts for the most serious microvascular complications in the diabetic patients. Although there are many useful therapeutical drugs to treat painful diabetic neuropathy, a growing body of evidence suggests that these drugs are effective only in early stages of diabetic neuropathy and are incapable to control the late stage symptoms of diabetic neuropathy. We are still lacking in the disease-modifying treatment strategies including the biomarkers for indicating the progression & reversal of the disease. It may be possible in future to depict the possible biomarkers not only to detect the manifestations of progression but also to predict the progression of the disease so that it can be reversed. Understanding the complete patho-physiological background of the disease will enable us to design appropriate therapeutic strategies to herald the progression of this devastating complication of diabetes in near future.
The authors express their gratitude to Dr. Monika Gulati, Dean, Department of Pharmaceutical Sciences, Lovely Professional University for her inspiration and continuous support in this review.
- Tang LQ, Wei W, Chen LM, Liu S: Effects of berberine on diabetes induced by alloxan and a high-fat/high-cholesterol diet in rats. Journal of Ethnopharmacology 2006; 108: 109–115.
- Gabra BH, Sirois P: Beneficial effect of chronic treatment with the selective bradykinin B1 receptor antagonists, R-715 and R-954, in attenuating Streptozotocin-diabetic thermal Hyperalgesia in mice. Peptides 2003; 24: 1131–1139.
- American Diabetes Association. Diabetes facts and figures. (2005). Available at: http://diabetes.org/diabetes-statistics.jsp.
- Yusuf V, Altan M, Nuray ARI: Diabetic Complications in Experimental Models. J. of Medical Sciences 1998; 22: 331-341.
- Pirart J: Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973. Diabete Metab 1977; 3: 97-107.
- Vinik AI: Advances in Diabetes for the Millennium: New Treatments for Diabetic Neuropathies. MedGenMed 2004; 6 (3): 13-16.
- Argoff CE, Cole BE, Fishbain DA, Irving GA: Diabetic peripheral neuropathic pain: clinical and quality of life issues. Mayo Clinic Proceedings 2006; 81 (l): 3-11.
- Honda K et al: Contribution of Ca2+- Dependent Protein Kinase C in the spinal Cord to the development of Mechanical Allodynia in Diabetic Mice. Biol. Pharm. Bull 2007; 30(5): 990-993.
- Kannan V: Mechanism of Diabetic Neuropathy. Int. J. Diab. Dev. Countries 2000; 20: 101-103.
- Woolf CJ, Mannion RJ: Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353: 1959–1964.
- Tesfaye S et al: Prevalence of diabetic peripheral neuropathy and to glycaemic control and potential risk factors: the EURODIAB IDDM Complication Study. Diabetologia 1996; 39: 1377-1384.
- Ribu L, Hanestad BR, Moum T, Birkeland K, Rustoen T: Health-related quality of life among patients with diabetes and foot ulcers: association with demographic and clinical characteristics. Journal of Diabetes and Its Complications 2007; 21: 227-236.
- Booya F, Bandarian F, Larijani B, Pajouhi M, Nooraei M, Lotfi J: Potential risk factors for diabetic neuropathy: a case control study. BMC Neurology 2005; 5(24): 1-5.
- Zhu X, Eichberg J: A myo-inositol pool utilized for phosphatidylinositol synthesis is depleted in sciatic nerve from streptozotocin-induced diabetic rats. Proc. Natl. Acad. Sci. USA 1999; 87: 9818-9822.
- Zhu X and Eichberg J: 1, 2-Diacylglycerol content and its arachidonyl-containing molecular species are reduced in sciatic nerve from streptozotocin-induced diabetic rats. J. Neurochem 1990; 55: 1087-1090.
- Greene, DA, Lattimer, SA, Sima, AAF: Sorbital, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. J. Med 1987; 316: 599–606.
- Brownlee, K: Complication of Diabetics. Endocrinol Metab Clin 1997; 27: 250-269.
- Brismar, T, Sima, AAF, Greene DA: Reversible and irreversible nodal dysfunction in diabetic neuropathy. Ann. Neurol 1987; 21: 504-507.
- Sima, AAF, Brismar, T: Reversible diabetic nerve dysfunction: structural correlates to electrophysiologic abnormalities. Neurol 1985; 18: 21-29.
- Sima, AAF: New insights into the metabolic and molecular basis for diabetic neuropathy. Cell. Mol. Life Sci 2003; 60: 2445-2464.
- Pop-Busui, R et al: Depletion of Taurine in Experimental Diabetic Neuropathy: Implications for Nerve Metabolic, Vascular, and Functional Deficits. 2001; 168: 259-272.
- Peppa, M, Uribarri, J, Vlassara, H : Glucose, Glycation End Products, and Diabetes Complications: What is New and What Works. Clinical Diabetes 2003, 21(4): 186-187.
- Baynes, JW, Thorpe, SR: Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999; 48(1): 1-9.
- King, RHM: The role of glycation in the pathogenesis of diabetic polyneuropathy. J Clin Pathol: Mol Pathol 2001; 54: 400-408.
- Baynes JW: Role of oxidative stress in the development of complications in diabetes. Diabetes 1992; 40: 405-412.
- Feldman EL: Oxidative stress and diabetic neuropathy: a new understanding of an old problem. Clin. Invest 2003; 111: 431–433.
- Sell DR et al: Pentosidine: a molecular marker for the cumulative damage to proteins in diabetes, aging, and uremia. Diabetes Metab Rev 1991; 7: 239-251.
- Fu M et al: The advanced glycation end-product, Nε-(carboxymethyl) lysine, is a product of both lipid peroxidation and glycoxidation reactions. J Biol Chem 1996, 271: 9982-9986.
- Maritim AC, Sanders RA, and Watkins JB: Diabetes, oxidative stress and antioxidants: a review. J Biochem Mol Toxicol 2003; 17(1): 24-38.
- Federoff HJ, Lawrence D, Brownlee M: Nonenzymatic glycosylation of Laminin and Laminin peptide CIK-VAVS inhibits neurite outgrowth. Diabetes 1993; 42: 509-513.
- Ryle C, Leow CK, Dnaghy M: Nonenzymatic glycation of peripheral and central nervous system proteins in experimental diabetes mellitus. Muscle nerve 1997; 20: 577-584.
- Cullum NA, Mahon J, Stringer K, Mclean WG: Glycation of rat sciatic nerve Tubulin in experimental diabetic mellitus. Diabetologia 1991; 34: 387-389.
- Pekiner C et al: Glycation of brain actin in experimental diabetes. J. Neurochem 1993; 61: 436-442.
- Vlassara H, Brownlee M, Cerami A: Excessive nonenzymatic glycosylation of peripheral and central nervous system myelin components in diabetic rats. Diabetes 1983; 32: 670-674.
- Weimbs T, Stoffel W: Topology of CNS myelin Proteolipid protein: Evidence for the nonenzymatic glycosylation of extracytoplasmic domains in normal and diabetic animals. Biochemistry 1994; 33: 10408-10415.
- Vlassara H, Brownlee M, Cerami A: Accumulation of diabetic rat peripheral nerve myelin by macrophages increase with the presence of advanced glycosylation end-products. J. Exp. Med 1984; 160: 197-207.
- Ebendal, T: Function and evolution in the NGF family and its receptors. J. Neurosci. Res 1992; 32: 461-470.
- Hellweg R, Hartung HD: Endogenous levels of nerve growth factor (NGF) are altered in experimental diabetes mellitus: a possible role for NGF in the pathogenesis of diabetic neuropathy. J. Neurosci. Res 1990; 26: 258-267.
- Tomlinson DR, Fernyhough P, Diemel LT: Role of neurotrophins in diabetic neuropathy and treatment with nerve growth factors. Diabetes 1997; 46(2): S43-S49.
- Obrosova IG: How does glucose generate oxidative stress in peripheral nerve? Int. Rev.Neurobiol 2002; 50: 3-35.
- Vincent AM, Brownlee M, Russel JW: Oxidative stress and programmed cell death in diabetic neuropathy. Ann N.Y. Acad. Sci 2002; 959: 368-383.
- Apfel SC et al: Nerve growth factor administration protects against experimental diabetic sensory neuropathy. Brain. Res 1994; 634: 7-12.
- Diemel LT, Brewster WJ, Fernyhough P, and Tomlinson DR: Expression of neuropeptides in experimental diabetes: effects of treatment with nerve growth factor or brain-derived neurotrophic factor. Brain. Res 1994; 21: 171-175.
- Schmidt RE, Dorsey DA, Roth KA, Parvin CA, Hounsom L, Tomlinson DR: Effect of streptozotocin-induced diabetes on NGF, P75NTR and TrkA content of prevertebral and paravertebral rat sympathetic ganglia. Brain Reseach 2000; 867(1-2): 149-156.
- Chiarelli F, Santilli F, Mohn A: Role of Growth Factors in the Development of Diabetic Complications. Horm Res 2000; 53: 53-67.
- Ishii DN: Implication of insulin-like growth factors in the pathogenesis of diabetic neuropathy. Brain Res. Rev 1995; 20: 47-67.
- Agerman K, Canlon B, Duan M, Ernfors P: Neurotrophins, NMDA Receptors, and Nitric Oxide in Development and Protection of the Auditory System. Annals of the New York Academy of Sciences 1999; 884: 131-142.
- Ashkenazi A, Dixit VM: Death Receptors: Signaling and Modulation. Science1998; 281(5381): 1305-1308.
- Leonard DR, Farooqi MH, Myers S: Restoration of Sensation, Reduced Pain, and Improved Balance in Subjects with Diabetic Peripheral Neuropathy. Diabetes Care 2004; 27: 168–172.
- Watkins PJ: Diabetic complications: cause and prevention. In: ABC of Diabetes. BMJ Publishing Group, London Edn 3, 2003: 42-65.
- Andrew CA, Bennani T, Freeman R, Hamdy O, Kaptchuk TJ: Two styles of acupuncture for treating painful diabetic neuropathy – a pilot randomised control trial. Acupuncture in Medicine 2007; 25(1-2): 11-17.
- Aszmann OC, Kress KM, Dellon AL: Results of decompression of peripheral nerves in diabetics: a prospective, blinded study. Plast Reconstr Surg 2000; 106(4): 816-22.
- Galer BS: Neuropathic pain of peripheral origin. Neurology 1995; 45: S17-S25.
- Huizinga MM, Peltier A: Painful Diabetic Neuropathy: A Management-Centered Review. Clinical Diabetes 2007; 25(1): 6-15.
- Davis JL, Lewis SB, Gerich JE, Kaplan RA, Schultz TA, Wallin JD: Peripheral diabetic neuropathy treated with amitriptyline and fluphenazine. JAMA 1977; 238: 2291–2292.
- Davis JL, Smith RL: Painful peripheral diabetic neuropathy treated with venlafaxine HCl extended release capsules. Diabetes Care 1999; 22: 1909–1910.
- Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner B: Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 1992; 326: 1250-1256.
- Richter RW et al: Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain 2005; 6: 253–260.
- Rosenstock J, Tuchman M, LaMoreaux L, Sharma U: Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 2004; 110: 628–638.
- Lesser H, Sharma U, LaMoreaux L, and Poole RM: Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 2004; 63: 2104–2110.
- Backonja M et al: Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998; 280: 1831–1836.
- Simpson D: Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromusc Dis 2001; 3: 53–62.
- DeToledo JC, Toledo C, DeCerce J, and Ramsay RE: Changes in body weight with chronic, high dose gabapentin therapy. Ther Drug Monit 1997; 19: 394–396.
- Vanina Y et al: Body weight changes associated with psychopharmacology. Psychiatr Serv 2002; 53: 842–847.
- Kochar DK, Jain N, Agarwal RP, Srivastava T, Agarwal P, Gupta S: Sodium valproate in the management of painful neuropathy in type 2 diabetes: a randomized placebo controlled study. Acta Neurol Scand 2002; 106: 248–252.
- Kochar DK et al: Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study. Q J Med 2004; 97: 33–38.
- Otto M, Bach FW, Jensen TS, Sindrup SH: Valproic acid has no effect on pain in polyneuropathy: a randomized, controlled trial. Neurology 2004; 62: 285–288.
- Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A: Lamotrigine reduces painful diabetic neuropathy: a randomized, controlled study. Neurology 2001; 57: 505–509.
- Eisenberg E, Alon N, Ishay A, Daoud D, Yarnitsky D: Lamotrigine in the treatment of painful diabetic neuropathy. Eur J Neurol 1998; 5: 167–173.
- Cohen KL, Haris S. (1987). Efficacy and safety of nonsteroidal anti-inflammatory drugs in the therapy of diabetic neuropathy. Arch Intern Med 1987; 147(8): 1442-1444.
- Tandan R, Lewis GA, Krusinski PB, Badger G.B, Fries TJ. (1992). Topical capsaicin in painful diabetic neuropathy: controlled study with long-term follow-up. Diabetes Care 1992; 15: 8–14.
- Sindrup SH, Andersen G, Madsen C, Smith T, Brosen K, Jensen TS. (1999). Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial. Pain 1999; 83: 85–90.
- Oskarsson P, Ljunggren JG, Lins PE: Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. Diabetes Care 1997; 20: 1594–1597.
- Dejgard A, Petersen P, Kastrup J. (1988). Mexiletine for treatment of chronic painful diabetic neuropathy. Lancet1988; 1: 9–11.
- Wright JM, Oki JC, Graves L 3rd: Mexiletine in the symptomatic treatment of diabetic peripheral neuropathy. Ann Pharmacother 1997; 31: 29–34.
- Stracke H et al: Mexiletine in treatment of painful diabetic neuropathy. Med Klin (Munich) 1994; 89: 124–131.
- Pittenger G, Vinik A: Nerve Growth Factor and Diabetic Neuropathy. Experimental Diab. Res 2003; 4: 271–285.
- Rask C, Sanders C, Häussier J: Positive results of phase II recombinant human nerve growth factor (rhNGF) triggers two phase III trials to confirm efficacy and safety in diabetic neuropathy. J Neurol 1998; 245: 447-449.
- Fagius J, Jameson S: Effect of aldose reductase inhibitor treatment in diabetic polyneuropathy: A clinical and Neurophysiological study. J Neurol Neurosurg Psychiatry 1981; 44: 991-1001.
- Judzewitsch R, Jaspan J, Polonsky J: Aldose reductase inhibition improves nerve conduction velocity in diabetic patients. N Engl J Med 1983; 308: 119-125.
- Boulton A: Effect of Tolrestat, a new aldose reductase inhibitor, on nerve conduction and paraesthetic symptoms in diabetic neuropathy. Diabetologia 1986; 29: 521-526.
- Johansson BL, Kernell A, Sjoberg S, Wahren J: Influence of combined C-peptide and insulin administration on renal function and metabolic control in diabetes type 1. J. Clin. Endocrinol. Metab 1993; 77: 976-981.
- Hotta N et al: Effect of propionyl-L-carnitine on oscillatory potentials in electroretinogram in streptozotocin-diabetic rats. Eur J Pharmacol 1996; 311(2-3): 199-206.
- Keen H et al: Treatment of diabetic neuropathy with gamma- Linolenic acid: The Gamma- Linolenic Acid Multicenter Trial Group. Diabetes Care 1993; 16: 8-15.
- Miyauchi Y et al: Slowing of peripheral motor nerve conduction was ameliorated by Aminoguanidine in streptozotocin-induced diabetic rats. Eur J Endocrinol 1996; 134: 467-473.
- Schmidt RE, Dorsey DA, Beudet LN, Reiser KM, Williamson JR, Tilton RG: Effect of Aminoguanidine on the frequency of neuroaxonal dystrophy in superior messentric sympathetic autonomic ganglia of rats with streptozotocin-induced diabetes. Diabetes 1996; 45: 284-290.
- Abraham R, Wynn V: A double- blind placebo–controlled trial of mixed Gangliosides in diabetic peripheral and autonomic neuropathy. Adv Exp Med Biol 1984; 174: 607-624.
- Crepaldi G, Fedele D, Tiengo A: Ganglioside treatment in diabetic peripheral neuropathy: A multicenter trial. Acta Diabetol 1983; 10: 265-276.
- Horowitz S: Ganglioside therapy in diabetic neuropathy. Muscle nerve 1986; 9: 531-536.
- Naarden A et al: Treatment of painful diabetic polyneuropathy with mixed Gangliosides. Adv Exp Med Biol 1983; 174: 581-592.
- Greene DA et al: Complications: Neuropathy, pathogenetic consideration. Diabetes Care 1992; 15: 1902-25.
- Krendel DA, Costigan DA, Hopkins LC: Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol 1995; 52: 1053-1061.
- Apfel SC, Kessler JA: Neurotrophic factors in the therapy of peripheral neuropathy. Bailliere’s Clinical Neuropathy 1995; 4: 593-606.
- Lander AD, Fujii DK, Reichardt LF: Laminin is associated with the “neurite outgrowth-promoting factors” found in conditioned media. Proc Natl Acad Sci USA 1985; 82: 2183-2187.
- Timple R: Structure and biological activity of basement membrane proteins. Eur J Biochem 1989; 180: 487-502.
- Bianchi R et al: Erythropoietin both protects from and reverses experimental diabetic neuropathy. PNAS 2004; 101(3): 823-828.
RAWAL SHRUTI*, SHASHI ALOK, MAHAJAN N, MAHOR A, JOSHI A, SHARMA P, SAROHA M.
Department of Pharmaceutical Sciences, Lovely School of Pharmacy, Lovely Professional University*, Phagwara, Punjab., India
03 December, 2009
10 December, 2009
26 December, 2009
01 January, 2010