Neuroinflammation and Oxidative Stress in Diabetic Neuropathy: Futuristic Strategies Based on These Targets (original) (raw)
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Oxidative Stress in the Pathogenesis of Diabetic Neuropathy
Endocrine Reviews, 2004
Oxidative stress results from a cell or tissue failing to detoxify the free radicals that are produced during metabolic activity. Diabetes is characterized by chronic hyperglycemia that produces dysregulation of cellular metabolism. This review explores the concept that diabetes overloads glucose metabolic pathways, resulting in excess free radical production and oxidative stress. Evidence is presented to support the idea that both chronic and acute hyperglycemia cause oxidative stress in the peripheral nervous system that can promote the development of diabetic neuropathy. Proteins that are damaged by oxidative stress have decreased biological activity leading to loss of energy metabolism, cell signaling, transport, and, ultimately, to cell death. Examination of the data from animal and cell culture models of diabetes, as well as clinical trials of antioxidants, strongly implicates hyperglycemia-induced oxidative stress in diabetic neuropathy. We conclude that striving for superior antioxidative therapies remains essential for the prevention of neuropathy in diabetic patients. (Endocrine Reviews 25: 612-628, 2004) Ϫ. B. Hydrogen peroxide (H 2 O 2) C. Nitric oxide (NO) III. Cellular Injury through Excess ROS Production IV. Cellular Antioxidant Defense A. Dietary antioxidants B. GSH C. Trx D. Antioxidant enzymes V. Production of ROS in Diabetes A. Advanced glycosylated end product (AGE)-mediated ROS formation B. The polyol pathway C. Protein kinase C (PKC) activation D. MAPK activities E. ROS formation at the mitochondria VI. Neuronal Response to Oxidative Stress VII. Biomarkers of Oxidative Stress A. Antioxidant reserves B. Antioxidant enzymes C. Free radical generation D. Protein, lipid, and DNA adducts VIII. Antioxidant Therapy for Diabetes Complications A. Aldose reductase inhibitors B. Nerve growth factor (NGF)
Diabetic neuropathy and oxidative stress
Diabetes/Metabolism Research and Reviews, 2006
This review will focus on the impact of hyperglycemia-induced oxidative stress in the development of diabetes-related neural dysfunction. Oxidative stress occurs when the balance between the production of reactive oxygen species (ROS) and the ability of cells or tissues to detoxify the free radicals produced during metabolic activity is tilted in the favor of the former. Although hyperglycemia plays a key role in inducing oxidative stress in the diabetic nerve, the contribution of other factors, such as endoneurial hypoxia, transition metal imbalances, and hyperlipidemia have been also suggested. The possible sources for the overproduction of ROS in diabetes are widespread and include enzymatic pathways, auto-oxidation of glucose, and mitochondrial superoxide production. Increase in oxidative stress has clearly been shown to contribute to the pathology of neural and vascular dysfunction in diabetes. Potential therapies for preventing increased oxidative stress in diabetic nerve dysfunction will be discussed.
The Role of Oxidative Stress in Diabetic Vascular and Neural Disease
Free Radical Research, 2003
This review will focus on the impact of hyperglycemiainduced oxidative stress in the development of diabetesinduced vascular and neural dysfunction. Oxidative stress occurs when the balance between the production of oxidation products and the ability of antioxidant mechanisms to neutralize these products is tilted in the favor of the former. The production of reactive oxygen species has been shown to be increased in patients with diabetes. The possible sources for the overproduction of reactive oxygen species is widespread and include enzymatic pathways, autoxidation of glucose and the mitochondria. Increase in oxidative stress has clearly been shown to contribute to the pathology of vascular disease not only in diabetes but also in hypertension, stroke and ischemia. Since the etiology of diabetic neuropathy is considered to have a large vascular component, prevention of oxidative stress in diabetes is considered by many investigators to be a primary defense against the development of diabetic vascular disease. Potential therapies for preventing increased oxidative stress in diabetes and the neural vasculature will be discussed.
Biochemical and Biophysical Research Communications, 2011
Long-standing diabetes and complications thereof particularly, neuropathy stands for one of the major causes of morbidity across the globe. It is postulated that excessive production of reactive oxygen species is a key component in the development and progression of diabetic neuropathy. Oxidative damage is the most common concluding pathway for various pathogenetic mechanisms of neuronal injury in diabetic neuropathy. However despite optimistic preclinical data, it is still very ambiguous that why antioxidants have failed to demonstrate significant neuroprotection in humans. A growing body of evidences now suggests that strategies utilizing a more targeted approach like focusing on Nrf2 (a transcription factor modulating oxidative stress) may provide an enthralling avenue to optimize neuroprotection in diabetes and diabetic neuropathy. This review presents an emerging concept of Nrf2 in diabetic neuropathy; thus looking forward to newer strategies for combating the oxidant induced damage.
Evaluation of oxidative stress markers in pathogenesis of diabetic neuropathy
Molecular Biology Reports, 2012
Experimental evidences suggest that hyperglycaemia-induced overproduction of reactive oxygen species and subsequent damage to proteins, lipids and DNA may play a key role in the development of distal symmetric polyneuropathy (DSPN)-the most common complication of diabetes mellitus. The study population consisted of 51 individuals aged 52-82 years classified into 3 groups: 16 patients diagnosed with type 2 diabetes mellitus (T2DM) with DSPN, 16 T2DM patients without DSPN and 19 control subjects without diabetes and neuropathy. The study was conducted to determine the activity of antioxidant enzymes: catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX) and total antioxidant status (TAS) in the examined groups. An alkaline comet assay was used to determine the extent of DNA damage of oxidized purines as glicosylo-formamidoglicosylase (Fpg) sites, and oxidized pyrimidines as endonuclease III (Nth) sites. A significant decrease of SOD (P \ 0.05), GPX (P \ 0.05) and nonsignificant decrease of CAT (P [ 0.05), and TAS status (P [ 0.05) were seen in T2DM patients with neuropathy compared to T2DM patients as well as controls. T2DM patients with or without neuropathy revealed significantly lower (P \ 0.05) plasma concentration of nitrous oxide compared to the control subjects. Endogenous level of oxidative DNA damage in T2DM patients with DSPN was significantly higher compared both to the controls and T2DM patients without DSPN (P \ 0.001). Moreover, lymphocytes isolated from T2DM patients with DSPN were more susceptible to oxidative DNA lesions induced by hydrogen peroxide than from T2DM patients without DSPN (P \ 0.001). Our results confirm hypothesis that oxidative stress may play a substantial role in the development and progression of diabetic distal symmetric polyneuropathy.
Mechanisms of Diabetic Neuropathies and Antioxidant Therapy
Journal of Pharmaceutical Research International
Background: Diabetic neuropathy is very common and affects half of patients with either type 1 or type 2 diabetes mellitus. It is the leading cause of diabetes-related hospital admissions and nontraumatic amputations. Currently, the keys to management are maintaining blood glucose concentration within the normal range and treatment of symptoms. Despite many studies of chronic pain associated with diabetic neuropathy, few improvements have been made. Main Finding: This is a review of the classification of diabetic neuropathy, molecular mechanisms, and treatment options focusing on antioxidants. Conclusion: As oxidative stress may play a significant role in the pathophysiology of diabetic neuropathy, the study of molecular mechanisms by which hyperglycemia induces oxidative stress is important. New targets for disease-modifying drugs could be elucidated.
Oxidative Stress in Diabetic Neuropathy – Sources of Reactive Oxygen Species
a pro-inflammatory shift in both, peripheral insulin-responsive tissues and HC astroglia and microglia. These changes were absent in 18 mo MGmice. In conclusion, chronic exposure to orally delivered highly reactive AGEs present in food simultaneously destabilizes metabolic and inflammatory processes, via overt OS/Infl and a severe depletion in central defense mechanisms including AGER1 and SIRT1. Since AGE-restriction improves IR in T2D, targeting the presence and/or absorption of food-derived AGEs may hold significant therapeutic potential for both these conditions.
The role of oxidative stress and endothelial injury in diabetic neuropathy and neuropathic pain
Neuro endocrinology letters, 2010
The roles of endothelin-1 (ET-1) and oxidative stress causing vascular injury in the pathogenesis of diabetic neuropathy are debatable. The present study was undertaken to clarify the possible effects of oxidative stress and ET-1 in diabetic patients with and without peripheric neuropathy. We studied plasma ET-1, nitric oxide (NO), catalase, glutathione (GSH) levels of fifty (22 females, 28 males) patients with Type 2 diabetes in order to evaluate endothelial dysfunction and oxidative stress. The neuropathy types (motor, sensorial and sensorimotor), comorbid diseases, antidiabetic treatments, smoking, diabetes duration were also considered. Short McGill Pain Questionnaire (SF-MPQ) was also performed for patients with neuropathy. There were no significant differences between patients with (n=23) and without (n=27) neuropathy with regards to demographic features except diabetic disease duration. The statistical analysis was done considering this difference. Although NO and ET-1 levels...