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Diabetic neuropathy is a peripheral nervous system disorder affecting both somatic and autonomic components of nervous system. A growing body of evidence have depicted that high glucose levels can induce activation of the Wnt/β-catenin pathway, however there are no studies targeting this pathway in DN. The intent of the present study was to investigate the effects of isoquercitrin (ISQ), a Wnt/β-catenin signaling pathway inhibitor, in diabetic neuropathy. Streptozotocin (50 mg/kg, i.p.) was used to induce diabetes in rats. 6-week diabetic rats were treated intrathecally with ISQ at 10 and 30 μM doses for 3 days. Furthermore, to confirm the results of the intrathecal study, a 2-week intraperitoneal treatment of ISQ was given to diabetic rats. After 6 weeks, diabetic rats developed neuropathy which was evident from reduced thermal and mechanical hyperalgesia thresholds and significant deterioration in motor nerve conduction velocity (MNCV), nerve blood flow (NBF). Sciatic nerves of diabetic neuropathy rats showed increased expression of Wnt pathway proteins namely β-catenin, c-myc and MMP2. Treatment with ISQ, both intrathecally (10 and 30 μM) and intraperitoneally (10 mg/kg), significantly ameliorated the alterations in behavioral pain thresholds and improved functional parameters in diabetic rats. Moreover, ISQ also downregulated the expression of Wnt/β-catenin pathway proteins significantly in diabetic rats as compared to vehicle-treated diabetic rats. Results of the present study suggest the neuroprotective potential of ISQ in the treatment of DN via inhibition of Wnt/β-catenin signaling pathway., (© 2020 International Union of Biochemistry and Molecular Biology.)

Wnt signaling pathway has been investigated extensively for its diverse metabolic and pain-modulating mechanisms; recently its involvement has been postulated in the development of neuropathic pain. However, there are no reports as yet on the involvement of Wnt signaling pathway in one of the most debilitating neurovascular complication of diabetes, namely, diabetic peripheral neuropathy (DPN). Thus, in the present study, involvement of Wnt signaling was investigated in DPN using Wnt signaling inhibitors namely LGK974 (porcupine inhibitor), NSC668036 (disheveled inhibitor), and PNU74654 (β-catenin inhibitor). Diabetes was induced by a single intraperitoneal injection of streptozotocin (50 mg/kg) to male Sprague-Dawley rats. Diabetic rats after 6 weeks of diabetes induction showed increased expression of Wnt signaling proteins in the spinal cord (L4-L6 lumbar segment), dorsal root ganglions and sciatic nerves. Subsequent increase in inflammation, endoplasmic reticulum stress and loss of intraepidermal nerve fiber density was also observed, leading to neurobehavioral and nerve functional deficits in diabetic rats. Intrathecal administration of Wnt signaling inhibitors (each at doses of 10 and 30 µmol/L) in diabetic rats showed improvement in pain-associated behaviors (heat, cold, and mechanical hyperalgesia) and nerve functions (motor, sensory nerve conduction velocities, and nerve blood flow) by decreasing the expression of Wnt pathway proteins, inflammatory marker, matrix metalloproteinase 2, endoplasmic reticulum stress marker, glucose-regulated protein 78, and improving intraepidermal nerve fiber density. All these results signify the neuroprotective potential of Wnt signaling inhibitors in DPN. PERSPECTIVE: This study emphasizes the involvement of Wnt signaling pathway in DPN. Blockade of this pathway using Wnt inhibitors provided neuroprotection in experimental DPN in rats. This study may provide a basis for exploring the therapeutic potential of Wnt inhibitors in DPN patients., (Copyright © 2019 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

Diabetic neuropathy is a complex disorder induced by long standing diabetes. Many signaling pathways and transcription factors have been proposed to be involved in the development and progression of related processes. Years of research points to critical role of oxidative stress, neuroinflammation and apoptosis in the pathogenesis of neuropathy in diabetes. Heme oxygenase-1 (HO-1) is heat-shock protein induced under conditions of different kinds of stress and has been implicated in cellular defense against oxidative stress. HO-1 degrades heme to biliverdin, carbon monoxide (CO) and free iron. Biliverdin and CO are gaining particular interest because these two have been found to mediate most of anti-inflammatory, antioxidant and anti-apoptotic effects of HO-1. Although extensively studied in different kinds of cancers and cardiovascular conditions, role of HO-1 in diabetic neuropathy is still under investigation. In this paper, we review the unique therapeutic potential of HO-1 and its role in mitigating various pathological processes that lead to diabetic neuropathy. This review also highlights the therapeutic approaches such as pharmacological and natural inducers of HO-1, gene delivery of HO-1 or its reaction products that in future, could lead to progression of HO-1 activators through the preclinical stages of drug development to clinical trials., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Calpain plays an important role in the pathophysiology of neurological and cardiovascular complications, but its functional association in diabetic neuropathy is not yet elucidated. Therefore, we investigated the role of calpain in modulation of tetrodotoxin-resistant sodium channels (TTX-R Na(+) channels) in dorsal root ganglion (DRG) neurons using a pharmacological approach. The effects of a calpain inhibitor, MDL 28170 (3 and 10 mg/kg, i.p.) on TTX-R Na(+) channels in DRG neurons of streptozotocin-induced diabetic rats were assessed by using whole-cell patch-clamp technique. In addition to this biochemical, functional and behavioral deficits were also measured. Diabetic rats demonstrated the mechanical allodynia and thermal hyperalgesia with reduced nerve perfusion and conduction velocity as compared to control. MDL 28170 treatments significantly recovered these functional and nociceptive deficits. Moreover, diabetic rats exhibited increased calpain activation, lipid peroxidation and proinflammatory cytokines as compared to control. Drug treatment significantly improved these biochemical deficits. Additionally, DRG neurons from diabetic rats illustrated a significant increase in TTX-R sodium current (INa) density as compared to control. MDL 28170 treatments in diabetic rats significantly blocked the altered channel kinetics with hyperpolarizing shift in voltage-dependence of steady-state activation and inactivation curves. All together, our study provides evidence that calpain activation is directly associated with alterations in TTX-R Na(+) channels and triggers functional, nociceptive and biochemical deficits in experimental diabetic neuropathy. The calpain inhibitor, MDL 28710 have shown beneficial effects in alleviating diabetic neuropathy via modulation of TTX-R Na(+) channel kinetics and reduction of oxidative stress and neuro-inflammation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Nuclear factor-κB (NF-κB) has been reported as a critical component of signalling mechanisms involved in the pathogenesis of a number of inflammatory conditions. Previous reports have shown that anti-inflammatory agents have a protective role in experimental diabetic neuropathy. Here, we assessed whether the inhibition of NF-κB cascade via IκB kinase (IKK) exerts any neuroprotective effect in experimental diabetic neuropathy. IKK inhibitor SC-514 (1 and 3 mg/kg) was administered daily for 2 weeks starting after 6 weeks of streptozotocin-induced diabetes. Nerve conduction and blood flow were determined by Powerlab and LASER Doppler system, respectively. We evaluated the changes in NF-κB, iNOS, and COX-2 expression by Western blotting in sciatic nerve. We found that IKK inhibition with SC-514 increased nerve blood flow and conduction velocity and improved pain threshold in diabetic animals. SC-514 also reduced the expression of NF-κB and phosphorylation of IKKβ in the sciatic nerve. Treatment with SC-514 reduced the elevated levels of pro-inflammatory cytokines (TNF-α and IL-6), iNOS, and COX-2. SC-514 reduces the expression of NF-κB and its downstream inflammatory components which may be involved in the improvement in nerve functions and pain perception in diabetic neuropathy. From the data of the present study, we suggest that diminution in IKK can be exploited as a drug target to significantly reduce the development of long-term complications of diabetes, particularly neuropathy.

Painful diabetic neuropathy (PDN) is one of most common complication of diabetes, usually affecting 50% of diabetic patients and remains important cause of morbidity, mortality and deterioration of quality of life. PDN is well characterised by chronic hyperglycemia, alterations in expression and kinetics of voltage-gated sodium channels (VGSCs) and neuro-inflammation which together may result into sensorimotor deficits in peripheral nervous system. Peripheral nociceptive neurons express variety of sodium channel isoforms particularly Nav1.3, Nav1.7, Nav1.8 and Nav1.9, each play a key role in physiology of nociception by undergoing respective dynamic changes in expression and voltage-dependent gating properties. Thus, they are critical determinants of sensory neuronal excitability and associated neuropathic pain signal. Recent preclinical and clinical trial research has shed light on VGSCs as most compelling target in the treatment of PDN, a development that may open up new therapeutic approaches involving subtype selective sodium channel blockers to boost clinical efficacy, cost effectiveness, better tolerability and targeted treatment. In this review, we have summarized structure and functions of VGSCs and their involvement in the pathophysiology of neuropathic pain along with the current status of pharmacological interventions targeted at VGSCs in the treatment of diabetic neuropathy.

Curcumin has shown to be effective against various diabetes related complications. However major limitation with curcumin is its low bioavailability. In this study we formulated and characterized self nano emulsifying drug delivery system (SNEDDS) curcumin formulation to enhance its bioavailability and then evaluated its efficacy in experimental diabetic neuropathy. Bioavailability studies were performed in male Sprague Dawley rats. Further to evaluate the efficacy of formulation in diabetic neuropathy various parameters like nerve function and sensorimotor perception were assessed along with study of inflammatory proteins (NF-κB, IKK-β, COX-2, iNOS, TNF-α and IL-6). Nanotechnology based formulation resulted in prolonged plasma exposure and bioavailability. SNEDDS curcumin provided better results against functional, behavioural and biochemical deficits in experimental diabetic neuropathy, when compared with naive curcumin. Further western blot analysis confirmed the greater neuroprotective action of SNEDDS curcumin. SNEDDS curcumin formulation due to higher bioavailability was found to afford enhanced protection in diabetic neuropathy., From the Clinical Editor: In this study the authors formulated and characterized a self-emulsifying drug delivery system for formulation to enhance curcumin bioavailability in experimental diabetic neuropathy. Enhanced efficacy was demonstrated in a rat model., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The Nuclear factor-2 erythroid related factor-2 (Nrf2) is a redox regulated transcription factor involved in the regulation of antioxidant defence systems. It drives the production of endogenous antioxidant defences and detoxifying enzymes. Nuclear factor-kappa light chain enhancer of B cells (NF-κB) is a transcription factor, involved in proinflammatory cytokine production, in addition to its immunological function. Both Nrf2 and NF-κB regulation are co-ordinated in order to maintain redox homeostasis in healthy cells. However, during pathological conditions this regulation is perturbed offering an opportunity for therapeutic intervention. Diabetic neuropathy is a condition, in which change in expression pattern of Nrf2 and NF-κB has been reported. This review aims to focus on the role of the Nrf2 and NF-κB in diabetic neuropathy and summarizes the therapeutic outcomes of various pharmacological modulators targeted at the Nrf2-NF-κB axis in diabetic neuropathy.

Inflammation is an emerging patho-mechanism of diabetes and its complications. NF-κB pathway is one of the central machinery initiating and propagating inflammatory responses. The present study envisaged the involvement of NF-κB inflammatory cascade in the pathophysiology of diabetic neuropathy using BAY 11-7082, an IκB phosphorylation inhibitor. Streptozotocin was used to induce diabetes in Sprauge Dawley rats. BAY 11-7082 (1 & 3 mg/kg) was administered to diabetic rats for 14 days starting from the end of six weeks post diabetic induction. Diabetic rats developed deficits in nerve functions and altered nociceptive parameters and also showed elevated expression of NF-κB (p65), IκB and p-IκB along with increased levels of IL-6 & TNF-α and inducible enzymes (COX-2 and iNOS). Furthermore, there was an increase in oxidative stress and decrease in Nrf2/HO-1 expression. We observed that BAY 11-7082 alleviated abnormal sensory responses and deficits in nerve functions. BAY 11-7082 also ameliorated the increase in expression of NF-κB, IκB and p-IκB. BAY 11-7082 curbed down the levels of IL-6, TNF-α, COX-2 and iNOS in the sciatic nerve. Lowering of lipid peroxidation and improvement in GSH levels was also seen along with increased expression of Nrf2/HO-1. Thus it can be concluded that NF-κB expression and downstream expression of proinflammatory mediators are prominent features of nerve damage leading to inflammation and oxidative stress and BAY 11-7082 was able to ameliorate experimental diabetic neuropathy by modulating neuroinflammation and improving antioxidant defence., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

High glucose driven reactive oxygen intermediates production and inflammatory damage are recognized contributors of nerve dysfunction and subsequent damage in diabetic neuropathy. Sulforaphane, a known chemotherapeutic agent holds a promise for diabetic neuropathy because of its dual antioxidant and anti-inflammatory activities. The present study investigated the effect of sulforaphane in streptozotocin (STZ) induced diabetic neuropathy in rats. For in vitro experiments neuro2a cells were incubated with sulforaphane in the presence of normal (5.5 mM) and high glucose (30 mM). For in vivo studies, sulforaphane (0.5 and 1 mg/kg) was administered six weeks post diabetes induction for two weeks. Motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and pain behavior were improved and malondialdehyde (MDA) level was reduced by sulforaphane. Antioxidant effect of sulforaphane is derived from nuclear erythroid 2-related factor 2 (Nrf2) activation as demonstrated by increased expression of Nrf2 and downstream targets hemeoxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO-1) in neuro2a cells and sciatic nerve of diabetic animals. Nuclear factor-kappa B (NF-κB) inhibition seemed to be responsible for antiinflammatory activity of sulforaphane as there was reduction in NF-κB expression and IκB kinase (IKK) phosphorylation along with abrogation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and tumor necrosis factor-α (TNF-α) and interleukine-6 (IL-6) levels. Here in this study we provide an evidence that sulforaphane is effective in reversing the various deficits in experimental diabetic neuropathy. This study supports the defensive role of Nrf2 in neurons under conditions of oxidative stress and also suggests that the NF-κB pathway is an important modulator of inflammatory damage in diabetic neuropathy.

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Melatonin exhibits an array of biological activities, including antioxidant and anti-inflammatory actions. Diabetic neuropathy is one of the complications of diabetes with a prevalence rate of 50-60%. We have previously reported the protective effect of melatonin in experimental diabetic neuropathy. In this study, we investigated the role of nuclear factor-kappa B (NF-κB) and nuclear erythroid 2-related factor 2 (Nrf2) in melatonin-mediated protection against streptozotocin-induced diabetic neuropathy. Melatonin at doses of 3 and 10 mg/kg was administered daily in seventh and eighth week after diabetes induction. Motor nerve conduction velocity and nerve blood flow were improved in melatonin-treated animals. Melatonin also reduced the elevated expression of NF-κB, IκB-α, and phosphorylated IκB-α. Further, melatonin treatment also reduced the elevated levels of proinflammatory cytokines (TNF-α and IL-6), iNOS and COX-2 in sciatic nerves of animals. The capacity of melatonin to modulate Nrf2 pathway was associated with increased heme oxygenase-1 (HO-1) expression, which strengthens antioxidant defense. This fact was also established by decreased DNA fragmentation (because inhibition of excessive oxidant-induced DNA damage) in the sciatic nerve of melatonin-treated animals. The results of this study suggest that melatonin modulates neuroinflammation by decreasing NF-κB activation cascade and oxidative stress by increasing Nrf2 expression, which might be responsible at least in part, for its neuroprotective effect in diabetic neuropathy., (© 2010 The Authors. Journal of Pineal Research © 2010 John Wiley & Sons A/S.)

Resveratrol has shown array of biological actions, and is under clinical development for various disease conditions. The etiology of diabetic neuropathy revolves around oxidative stress, AGE formation, lipid peroxidation etc. All these stimulate inflammatory processes and NF-kappaB cascade is considered as one of the major players of inflammatory response. Activation of NF-kappaB results in elevated levels of inflammatory mediators. COX-2 and TNF-alpha activity have also been correlated with inflammatory damage in the pathophysiology of diabetic neuropathy (DN). Therefore we investigated the effect of resveratrol on NF-kappaB inflammatory cascade, COX-2, TNF-alpha and IL-6 levels in experimental DN. We found that resveratrol protected against various functional and behavioral deficits in diabetic neuropathy in line with our earlier published reports. In this study we found that the resveratrol treatment decreased the expression of p65 and IkappaB-alpha in treated rats. Treatment also ameliorated the elevated levels of TNF-alpha, IL-6 and COX-2. Resveratrol treatment produced significant decrease in nerve MDA levels in treated animals which may also be contributing to reduction in neuro-inflammation. This study confirms the NF-kappaB inhibitory activity and anti-inflammatory activity of resveratrol which may contribute to neuroprotection in diabetic neuropathy apart from its antioxidant effect., (2010 Elsevier Inc. All rights reserved.)

Oxidative stress resulting in excessive generation of ROS is a compelling initiator of DNA damage along with damage to various cellular proteins and other macromolecules. Poly(ADP-ribose) polymerase (PARP) activation in response to DNA damage, stirs an energy-consuming cellular metabolic cycle; culminating into cell death. The present study was designed to determine the effect of combining an antioxidant, Melatonin and a PARP inhibitor, Nicotinamide on the hallmark deficits developing in diabetic neuropathy (DN). Streptozotocin (STZ, 55 mg/kg, i.p.) was administered to induce diabetes. Six weeks post diabetes induction, two week treatment with Melatonin (3 and 10 mg/kg) and Nicotinamide (100 and 300 mg/kg) either alone or in combination was given. Effect of these interventions on the functional, behavioral and biochemical changes caused by hyperglycemia were studied in treated animals. Melatonin and Nicotinamide alone as well as in combination ameliorated the functional deficits along with improvement in pain parameters. The combination also demonstrated an essential reversal of biochemical alterations. Nitrotyrosine and Poly ADP Ribose (PAR) immunopositivity was significantly decreased in sciatic nerve micro-sections of treatment group. The results of this study advocate that simultaneous inhibition of oxidative stress-PARP activation cascade may prove useful for the pharmacotherapy of DN., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Peroxynitrite mediated nitrosative stress, an indisputable initiator of DNA damage and overactivation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated after sensing DNA damage, are two crucial pathogenetic mechanisms in diabetic neuropathy. The intent of the present study was to investigate the effect of combination of a peroxynitrite decomposition catalyst (PDC), FeTMPyP and a PARP inhibitor, 4-ANI against diabetic peripheral neuropathy. The end points of evaluation of the study included motor nerve conduction velocity (MNCV) and nerve blood flow (NBF) for evaluating nerve functions; thermal hyperalgesia and mechanical allodynia for assessing nociceptive alterations, malondialdehyde and peroxynitrite levels to detect oxidative stress-nitrosative stress; NAD concentration in sciatic nerve to assess overactivation of PARP. Additionally immunohistochemical studies for nitrotyrosine and Poly(ADP-ribose) (PAR) was also performed. Treatment with the combination of FeTMPyP and 4-ANI led to significant improvement in nerve functions and pain parameters and also attenuated the oxidative-nitrosative stress markers. Further, the combination also reduced the overactivation of PARP as evident from increased NAD levels and decreased PAR immunopositivity in sciatic nerve microsections. Thus, it can be concluded that treatment with the combination of a PDC and PARP inhibitor attenuates alteration in peripheral nerves in diabetic neuropathy (DN)., (Copyright 2009 Elsevier Inc. All rights reserved.)

The present study investigated whether combination of resveratrol and 4-amino 1,8 naphthalimide (4-ANI) is effective in the development of diabetic neuropathy (DN). After 6 weeks of diabetes induction, rats were treated for 2 weeks with resveratrol and 4-amino 1,8 naphthalimide (4-ANI) either alone or in combination. Experimental end points included functional, behavioural and biochemical parameters along with PAR immunohistochemistry and were performed at the end of treatment. Combination of resveratrol (10 mg/kg) and 4-ANI (3 mg/kg) attenuated conduction and nerve blood flow deficits and resulted in amelioration of diabetic neuropathic pain. Significant reversal of biochemical alterations (peroxynitrite, MDA and NAD levels) were also observed, as well as PAR accumulation in the sciatic nerve. This study suggests the beneficial effect of combining resveratrol and 4-ANI in experimental diabetic neuropathy.

Diabetic neuropathy, a major complication of diabetes, affects more than 60% of diabetic patients. Recently, involvement of peroxynitrite has been postulated in diabetic neuropathy. In the present study, we have studied the effects of peroxynitrite decomposition catalysts (PDC's)-5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrinato iron(III) [FeTPPS] and 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrinato iron(III) [FeTMPyP]-in experimental diabetic neuropathy. Male Sprague-Dawley rats, with six weeks of untreated diabetes were treated for two weeks with peroxynitrite decomposition catalysts. Diabetic animals showed a significant decrease in motor nerve conduction velocity and nerve blood flow, nociception as evident from decreased tail flick latency (hyperalgesia) and increased paw withdrawal pressure (mechanical allodynia) along with elevation in peroxynitrite and reduction in nerve glutathione levels. Two weeks treatment with PDC's significantly improved all the above stated functional and biochemical deficits. Aftermath of this study advocates the beneficial effects of peroxynitrite decomposition catalysts in experimental diabetic neuropathy.

Diabetic neuropathic pain is generally considered to be one of the most troublesome complications affecting diabetic patients and current therapy provides inadequate pain relief. In the present study, the effect of adenosine was investigated in a model of diabetic neuropathic pain. Diabetes was induced by streptozotocin (65 mg/kg, ip) in male Sprague Dawley rats and subjected to thermal (cold and hot) and chemical (formalin) stimuli. Diabetic rats developed hyperalgesia by the end of six weeks in thermal and chemical stimuli test. Adenosine (100, 200 and 500 mg/kg, ip) produced significant reversal of responses to thermal and chemical stimuli in diabetic rats. 8-Cyclopentyl-1, 3-dipropylxanthine (DPCPX 1 mg/kg, ip), an adenosine A1-receptor antagonist, but not 3,7-dimethyl-1-propargylxanthine (DMPX 1 mg/kg, ip), an adenosine A2A-receptor antagonist, reversed the protective effect of adenosine. These results indicate that adenosine is an effective analgesics in a model of diabetic neuropathy, and the protection produced by adenosine is via stimulation of adenosine A1-receptors.

Peripheral diabetic neuropathy is a heterogeneous group of disorders, and is known to affect 50-60% of diabetic patients. Poly (ADP-ribose) polymerase (PARP) activation has been identified as one of the key components in the pathogenesis of diabetic neuropathy. In the present study we have targeted PARP overactivation in diabetic neuropathy using a known PARP inhibitor, 4 amino 1, 8-napthalimide (4-ANI). Streptozotocin induced diabetic rats developed neuropathy within 6 weeks, which was evident from significant reduction in motor nerve conduction velocity (MNCV), nerve blood flow (NBF) along with neuropathic pain and abnormal sensory perception. Six weeks after diabetes induction Sprague Dawley rats were treated with 4-ANI (3 and 10 mg/kg, p.o.) for a period of two weeks (seventh and eighth weeks). Two week treatment with 4-ANI showed improvement in nerve conduction, nerve blood flow and reduction in tail flick responses and mechanical allodynia in diabetic animals. 4-ANI also attenuated PAR immunoreactivity and NAD depletion in nerves of diabetic animals. Results of present study suggest the potential of PARP inhibitors like 4-ANI in the treatment of diabetic neuropathy.

Oxidative stress has been implicated in pathophysiology of diabetic neuropathy. All the pathways responsible for development of diabetic neuropathy are linked to oxidative stress in one way or the other. In the present study, we have targeted oxidative stress in diabetic neuropathy using resveratrol, a potent antioxidant. Eight weeks streptozotocin-diabetic rats developed neuropathy which was evident from significant reduction in motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and increased thermal hyperalgesia. The 2-week treatment with resveratrol (10 and 20 mg/kg, i.p.) started 6 weeks after diabetes induction significantly ameliorated the alterations in MNCV, NBF, and hyperalgesia. Resveratrol also attenuated enhanced levels of malondialdehyde (MDA), peroxynitrite and produced increase in catalase levels in diabetic rats. There was marked reduction in DNA fragmentation observed after resveratrol treatment in diabetic rats as evident from decrease in Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells in sciatic nerve sections. Results of the present study suggest the potential of resveratrol in treatment of diabetic neuropathy and its protective effect may be mediated through reduction in oxidative stress and DNA fragmentation.

1. Diabetic neuropathy is one of the most common complications of diabetes and oxidative stress has been implicated to play a major role in its pathophysiology. 2. In the present study, we targeted oxidative stress using trolox, an anti-oxidant, in streptozotocin-induced diabetic neuropathy in rats. 3. Compared with control rats, diabetic rats showed significant deficits in motor nerve conduction velocity (MNCV; 49.91 +/- 1.94 vs 42.77 +/- 1.39 m/s, respectively) and nerve blood flow (NBF; 107.98 +/- 8.22 vs 38.9 +/- 2.7 arbitarary perfusion units, respectively) after 8 weeks of diabetes. Tail flick latencies for cold and hot immersion tests were also significantly reduced in diabetic rats, indicating thermal hyperalgesia. These observations indicate development of diabetic neuropathy. 4. A significant decrease in the activity of anti-oxidant enzymes (superoxide dismutase and catalase) and an increase in lipid peroxidation were observed in sciatic nerves from diabetic rats compared with age-matched control rats. Alterations in the activity of anti-oxidant enzymes and lipid peroxidation in diabetic rats indicate oxidative stress in diabetic neuropathy. 5. Two weeks treatment with trolox (10 and 30 mg/kg, i.p.) started on completion of the 6th week of diabetes significantly improved MNCV, NBF and inhibited thermal hyperalgesia. Trolox treatment also improved the activity of anti-oxidant enzymes and inhibited lipid peroxidation in sciatic nerves of diabetic rats. 6. The results of the present study suggest the beneficial effects of trolox in experimental diabetic neuropathy.

Oxidative stress has been implicated to play an important role in the pathogenesis of diabetic neuropathy, which is the most common complication of diabetes mellitus affecting more than 50% of diabetic patients. In the present study, we have investigated the effect of U83836E [(-)-2-((4-(2,6-Di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl)methyl)-3,4-dihydro-2,3,7,8-tetramethyl-2H-1-benzopyran-6-ol, 2HCl], a potent free radical scavenger in streptozotocin (STZ)-induced diabetic neuropathy in rats. STZ-induced diabetic rats showed significant deficit in motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and thermal hyperalgesia after 8 weeks of diabetes induction, indicating development of diabetic neuropathy. Antioxidant enzyme (superoxide dismutase and catalase) levels were reduced and malondialdehyde (MDA) levels were significantly increased in diabetic rats as compared to the age-matched control rats, this indicates the involvement of oxidative stress in diabetic neuropathy. The 2-week treatment with U83836E (3 and 9 mg/kg, i.p.) started 6 weeks after diabetes induction significantly ameliorated the alterations in MNCV, NBF, hyperalgesia, MDA levels and antioxidant enzymes in diabetic rats. Results of the present study suggest the potential of U83836E in treatment of diabetic neuropathy.

This study examined the effects of chronic administration of adenosine and CGS 21680 hydrochloride (adenosine A2A receptor agonist) on motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and histology of sciatic nerve in animal model of diabetic neuropathy. Adenosinergic agents were administered for 2 weeks after 6 weeks of streptozotocin-induced (50 mg/kg i.p.) diabetes in male Sprague–Dawley rats. Significant reduction in sciatic MNCV and NBF were observed after 8 weeks in diabetic animals in comparison with control (non diabetic) rats. Adenosine (10 mg/kg, i.p.) significantly improved sciatic MNCV and NBF in diabetic rats. The protective effect of adenosine on MNCV and NBF was completely reversed by theophylline (50 mg/kg, i.p.), a non-selective adenosine receptor antagonist, suggesting that the adenosine effect was mediated via adenosinergic receptors. CGS 21680 (0.1 mg/kg, i.p.) significantly improved NBF; however, MNCV was not significantly improved in diabetic rats. At a dose of 1 mg/kg, neither MNCV nor NBF was improved by CGS 21680 in diabetic rats. ZM 241385 (adenosine A2A receptor antagonist) prevented the effect of CGS 21680 (0.1 mg/kg, i.p.). Histological changes observed in sciatic nerve were partially improved by the adenosinergic agents in diabetic rats. Results of the present study, suggest the potential of adenosinergic agents in the therapy of diabetic neuropathy. [ABSTRACT FROM AUTHOR]