The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
James D Schmelzer - One of the best experts on this subject based on the ideXlab platform.
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Ischemia–reperfusion injury of peripheral nerve in Experimental Diabetic Neuropathy
Journal of the Neurological Sciences, 2004Co-Authors: Yanping Wang, James D Schmelzer, A. Schmeichel, Haruyasu IidaAbstract:Abstract The pathogenesis of human Diabetic Neuropathy likely involves the interplay of hyperglycemia, ischemia, and oxidative stress. Mild–moderate ischemia–reperfusion to streptozotocin (STZ)-induced diabetes results in florid fiber degeneration in Diabetic but not in normal nerves. Uncertainty exists as to the influence of duration of diabetes on this susceptibility. We therefore studied Diabetic tibial and sciatic nerves using a rat ischemia–reperfusion (IR) model after 1 month and 4 months of diabetes utilizing electrophysiological, behavioral, and neuropathological methods. Electrophysiological abnormalities were present in 1-month Diabetic rats (D) and persisted over 4 months. Behavioral scores were decreased markedly at 4 months (p
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ischemia reperfusion injury of peripheral nerve in Experimental Diabetic Neuropathy
Journal of the Neurological Sciences, 2004Co-Authors: Yanping Wang, James D Schmelzer, A. Schmeichel, Haruyasu IidaAbstract:Abstract The pathogenesis of human Diabetic Neuropathy likely involves the interplay of hyperglycemia, ischemia, and oxidative stress. Mild–moderate ischemia–reperfusion to streptozotocin (STZ)-induced diabetes results in florid fiber degeneration in Diabetic but not in normal nerves. Uncertainty exists as to the influence of duration of diabetes on this susceptibility. We therefore studied Diabetic tibial and sciatic nerves using a rat ischemia–reperfusion (IR) model after 1 month and 4 months of diabetes utilizing electrophysiological, behavioral, and neuropathological methods. Electrophysiological abnormalities were present in 1-month Diabetic rats (D) and persisted over 4 months. Behavioral scores were decreased markedly at 4 months (p
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oxidative injury and apoptosis of dorsal root ganglion neurons in chronic Experimental Diabetic Neuropathy
Diabetes, 2003Co-Authors: A. Schmeichel, James D SchmelzerAbstract:We evaluated the effects of chronic hyperglycemia on L5 dorsal root ganglion (DRG) neurons using immunohistochemical and electrophysiologic techniques for evidence of oxidative injury. Experimental Diabetic Neuropathy was induced by streptozotocin. To evaluate the pathogenesis of the Neuropathy, we studied peripheral nerve after 1, 3, and 12 months of diabetes. Electrophysiologic abnormalities were present from the first month and persisted over 12 months. 8-Hydroxy-2′-deoxyguanosine labeling was significantly increased at all time points in DRG neurons, indicating oxidative injury. Caspase-3 labeling was significantly increased at all three time points, indicating commitment to the efferent limb of the apoptotic pathway. Apoptosis was confirmed by a significant increase in the percentage of neurons undergoing apoptosis at 1 month (8%), 3 months (7%), and 12 months (11%). These findings support the concept that oxidative stress leads to oxidative injury of DRG neurons, with mitochondrium as a specific target, leading to impaired mitochondrial function and apoptosis, manifested clinically as a predominantly sensory Neuropathy.
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morphometry of dorsal root ganglion in chronic Experimental Diabetic Neuropathy
Diabetes, 2002Co-Authors: Motoko Kishi, James Tanabe, James D SchmelzerAbstract:Chronic hyperglycemia results in a predominantly sensory Neuropathy. Recent studies suggest that dorsal root ganglion (DRG) neurons comprise a specific target and may be responsible for the important complication of Diabetic sensory Neuropathy, since hyperglycemia for longer than 6 months results in a vacuolar ganglionopathy with associated radiculopathy and distal sensory Neuropathy. We undertook morphometric analysis of L5 DRG neurons in seven Diabetic rats and six age- and sex-matched littermates. Nerve conduction studies were also performed, and Neuropathy was confirmed. Diabetes was induced with streptozotocin; duration of diabetes was 12 months. The DRG count for control rats was 15,304 ± 991 neurons. Two of seven Diabetic DRG counts were reduced, but the group mean count at 14,847 ± 1,524 was not significantly reduced. The number of small neurons (type B) considerably exceeded that of large neurons (type A), at a ratio of 71:29. The percentage of large cells was significantly reduced in Diabetic compared with control rats ( P = 0.01). The large-diameter population can be subdivided into two groups; with this subdivision, the number of neurons
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gene expression of antioxidant enzymes in Experimental Diabetic Neuropathy
Journal of The Peripheral Nervous System, 2000Co-Authors: Yutaka Kishi, Kim K Nickander, James D SchmelzerAbstract:Chronic hyperglycemia results in a large deficit in nerve blood flow. Both autoxidative- and ischemia-induced lipid peroxidation occurs, with resultant peripheral sensory Neuropathy in streptozotocin-induced diabetes in the rat. Free radical defenses, especially involving antioxidant enzymes, have been suggested to be reduced, but scant information is available on chronic hyperglycemia. We evaluated the gene expression of glutathione peroxidase, catalase, and superoxide dismutase (cuprozinc and manganese separately) in L4,5 dorsal root ganglion (DRG) and superior cervical ganglion, as well as enzyme activity of glutathione peroxidase in DRG and sciatic nerve in Experimental Diabetic Neuropathy of 3 months and 12 months durations. We also evaluated nerve electrophysiology of caudal, sciatic-tibial, and digital nerves. A nerve conduction deficit was seen in all nerves in Experimental Diabetic Neuropathy at both 3 and 12 months. Gene expression of glutathione peroxidase, catalase, cuprozinc superoxide dismutase, and manganese superoxide dismutase were not reduced in Experimental Diabetic Neuropathy at either 3 or 12 months. Catalase mRNA was significantly increased in Experimental Diabetic Neuropathy at 12 months. Glutathione peroxidase enzyme activity was normal in sciatic nerve. We conclude that gene expression is not reduced in peripheral nerve tissues in very chronic Experimental Diabetic Neuropathy. Changes in enzyme activity may be related to duration of diabetes or due to post-translational modifications.
Shyam S Sharma - One of the best experts on this subject based on the ideXlab platform.
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SNEDDS curcumin formulation leads to enhanced protection from pain and functional deficits associated with Diabetic Neuropathy: An insight into its mechanism for neuroprotection
Nanomedicine: Nanotechnology Biology and Medicine, 2013Co-Authors: Rayanta P. Joshi, Ashutosh Kumar, Geeta Negi, Yogesh B. Pawar, Bhushan Munjal, Arvind K. Bansal, Shyam S SharmaAbstract:Abstract 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- κ B, 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.
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suppression of nf κb and nf κb regulated oxidative stress and neuroinflammation by bay 11 7082 iκb phosphorylation inhibitor in Experimental Diabetic Neuropathy
Biochimie, 2012Co-Authors: Ashutosh Kumar, Geeta Negi, Shyam S SharmaAbstract: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.
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melatonin modulates neuroinflammation and oxidative stress in Experimental Diabetic Neuropathy effects on nf κb and nrf2 cascades
Journal of Pineal Research, 2010Co-Authors: Geeta Negi, Ashutosh Kumar, Shyam S SharmaAbstract:Abstract: 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.
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nf κb inhibitory action of resveratrol a probable mechanism of neuroprotection in Experimental Diabetic Neuropathy
Biochemical and Biophysical Research Communications, 2010Co-Authors: Ashutosh Kumar, Shyam S SharmaAbstract: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.
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neuroprotective potential of combination of resveratrol and 4 amino 1 8 naphthalimide in Experimental Diabetic Neuropathy focus on functional sensorimotor and biochemical changes
Free Radical Research, 2009Co-Authors: Shyam S Sharma, Manish Arora, Ashutosh Kumar, Ravinder K KaundalAbstract: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.
Ashutosh Kumar - One of the best experts on this subject based on the ideXlab platform.
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adenosine monophosphate activated protein kinase modulation by berberine attenuates mitochondrial deficits and redox imbalance in Experimental Diabetic Neuropathy
Neuropharmacology, 2018Co-Authors: Veera Ganesh Yerra, Aparna Areti, Anil Kumar Kalvala, Bhoomika Sherkhane, Ashutosh KumarAbstract:Abstract Adenosine monophosphate-activated protein kinase (AMPK) has been studied for its myriad metabolic and mitochondrial benefits in several chronic diseases. Recent studies have uncovered its therapeutic potential against mitochondrial dysfunction in cultured dorsal root ganglion (DRG) neurons isolated from streptozotocin (STZ) induced Diabetic rats. The present study is aimed at evaluating the pharmacological efficacy of berberine (BRB), a natural AMPK activator against Experimental Diabetic Neuropathy (DN) phenotype developed in STZ (55 mg/kg, i.p.) induced Diabetic rats and neurotoxicity in high-glucose (30 mM) stimulated neuro 2a (N2A) cells. Diabetic-rats have shown reduced expression of p-AMPK (Thr 172) in sciatic nerves with a consequent reduction in mitochondrial biogenesis and autophagy. BRB (50 & 100 mg/kg, po) administration to Diabetic rats for 2-weeks rescued mitochondrial functional deficits and autophagy impairment by increasing the p-AMPK expression. BRB administration also augmented the NEF-2 related factor 2 (Nrf2) mediated endogenous antioxidant defence systems to restrain neuronal damage and neuroinflammation. These effects after BRB administration resulted in enhanced conduction velocity, improved nerve blood flow and attenuated hyperalgesia. Similarly, BRB exposure (5 & 10 μM) to N2A cells attenuated high glucose induced ROS generation, mitochondrial membrane depolarization through the promotion of Nrf2 mediated antioxidant defence systems. BRB exposure augmented peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mediated mitochondrial biogenesis in neuronal cells. Results from this study signify the importance of mitoprotection conferred by BRB in DN and can be used as a preliminary basis for further molecular exploration.
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morin exerts neuroprotection via attenuation of ros induced oxidative damage and neuroinflammation in Experimental Diabetic Neuropathy
Biofactors, 2018Co-Authors: Pragna Bachewal, Veera Ganesh Yerra, Aparna Areti, Anil Kumar Kalvala, Chayanika Gundu, Ashutosh KumarAbstract:Morin, a bioflavonoid with diverse pharmacological effects against various diseases; in most cases morin protective effects were attributed to its detoxifying effect against reactive oxygen species (ROS). Diabetic Neuropathy (DN) is a chronic, debilitating neuronal pain associated with intense generation of free radicals and proinflammatory cytokine accumulation in peripheral neurons. We investigated the pharmacological effect of morin against metabolic excess mediated mitochondrial ROS generation and corresponding effect on Nrf2, NF-κB pathways in Streptozotocin (STZ)-induced Diabetic rats and in high glucose insulted Mouse neuroblastoma cell line, Neuro 2A (N2A). Animals were evaluated for nerve function parameters, motor and sensory nerve conduction velocities (MNCV and SNCV) and nerve blood flow (NBF) followed by TUNEL and immunoblot analysis. Mitochondrial function was evaluated by performing JC-1 and MitoSOX assays in high glucose (30 mM) incubated N2A cells. Diabetic animals showed significant impairment in MNCV, SNCV, and NBF as well as increased pain hypersensitivity. However, oral administration of morin at 50 and 100 mg/kg improved SNCV, MNCV, and NBF and reduced sensorimotor alterations (hyperalgesia and allodynia) in Diabetic animals. Studies in N2A cells have revealed that morin ameliorated the high glucose-induced mitochondrial superoxide production, membrane depolarization, and total ROS generation. Morin effectively counteracted NF-κB-mediated neuroinflammation by reducing ROS mediated IKK activation and increased Nrf2-mediated antioxidant defenses in high glucose-induced N2A cells. The results of our study suggest that morin has exquisite role in offering neuroprotection in Experimental DN and further clinical investigation may reward in finding better alternative for the management of DN. © 2017 BioFactors, 44(2):109-122, 2018.
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isoliquiritigenin reduces oxidative damage and alleviates mitochondrial impairment by sirt1 activation in Experimental Diabetic Neuropathy
Journal of Nutritional Biochemistry, 2017Co-Authors: Veera Ganesh Yerra, Anil Kumar Kalvala, Ashutosh KumarAbstract:Sirtuin (SIRT1) inactivation underlies the pathogenesis of insulin resistance and hyperglycaemia-associated vascular complications, but its role in Diabetic Neuropathy (DN) has not been yet explored. We have evaluated hyperglycaemia-induced alteration of SIRT1 signalling and the effect of isoliquiritigenin (ILQ) on SIRT1-directed AMP kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signalling in peripheral nerves of streptozotocin (STZ) (55 mg/kg, ip)-induced Diabetic rats and in high glucose (30 mM)-exposed neuro2a (N2A) cells. Diabetic rats and high glucose-exposed N2A cells showed reduction in SIRT1 expression with consequent decline in mitochondrial biogenesis and autophagy. ILQ (10 & 20 mg/kg, po) administration to Diabetic rats for 2 weeks and exposure to glucose-insulted N2A cells resulted in significant SIRT1 activation with concurrent increase in mitochondrial biogenesis and autophagy. ILQ administration also enhanced NAD+/NADH ratio in peripheral sciatic nerves which explains its possible SIRT1 modulatory effect. Functional and behavioural studies show beneficial effect of ILQ as it alleviated nerve conduction and nerve blood flow deficits in Diabetic rats along with improvement in behavioural parameters (hyperalgesia and allodynia). ILQ treatment to N2A cells reduced high glucose-driven ROS production and mitochondrial membrane depolarization. Further, ILQ-mediated SIRT1 activation facilitated the Nrf2-directed antioxidant signalling. Overall, results from this study suggest that SIRT1 activation by ILQ mimic effects of calorie restriction, that is, PGC-1α-mediated mitochondrial biogenesis, FOXO3a mediated stress resistance and AMPK mediated autophagy effects to counteract the multiple manifestations in Experimental DN.
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fisetin imparts neuroprotection in Experimental Diabetic Neuropathy by modulating nrf2 and nf κb pathways
Cellular and Molecular Neurobiology, 2016Co-Authors: Reddemma Sandireddy, Veera Ganesh Yerra, Prashanth Komirishetti, Aparna Areti, Ashutosh KumarAbstract:The current study is aimed to assess the therapeutic potential of fisetin, a phytoflavonoid in streptozotocin (STZ)-induced Experimental Diabetic Neuropathy (DN) in rats. Fisetin was administered (5 and 10 mg/kg) for 2 weeks (7th and 8th week) post STZ administration. Thermal and mechanical hyperalgesia were assessed by measuring tactile sensitivity to thermal and mechanical stimuli, respectively. Motor nerve conduction velocity (MNCV) was determined using power lab system and sciatic nerve blood flow (NBF) was determined using laser Doppler system. Nerve sections were processed for TUNEL assay and NF-κB, COX-2 immunohistochemical staining. Sciatic nerve homogenate was used for biochemical and Western blotting analysis. MNCV and sciatic NBF deficits associated with DN were ameliorated in fisetin administered rats. Fisetin treatment reduced the interleukin-6 and tumour necrosis factor-alpha in sciatic nerves of Diabetic rats (p < 0.001). Protein expression studies have identified that the therapeutic benefit of fisetin might be through regulation of redox sensitive transcription factors such as nuclear erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-κB). Our study provides an evidence for the therapeutic potential of fisetin in DN through simultaneous targeting of NF-κB and Nrf2.
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SNEDDS curcumin formulation leads to enhanced protection from pain and functional deficits associated with Diabetic Neuropathy: An insight into its mechanism for neuroprotection
Nanomedicine: Nanotechnology Biology and Medicine, 2013Co-Authors: Rayanta P. Joshi, Ashutosh Kumar, Geeta Negi, Yogesh B. Pawar, Bhushan Munjal, Arvind K. Bansal, Shyam S SharmaAbstract:Abstract 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- κ B, 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.
James W Russell - One of the best experts on this subject based on the ideXlab platform.
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overexpression of sirtuin 1 protein in neurons prevents and reverses Experimental Diabetic Neuropathy
Brain, 2019Co-Authors: Krish Chandrasekaran, Mohammad Salimian, Sruthi R Konduru, Joungil Choi, Pranith Kumar, Aaron Long, Nina Klimova, Chengying Ho, Tibor Kristian, James W RussellAbstract:In Diabetic Neuropathy, there is activation of axonal and sensory neuronal degeneration pathways leading to distal axonopathy. The nicotinamide-adenine dinucleotide (NAD+)-dependent deacetylase enzyme, Sirtuin 1 (SIRT1), can prevent activation of these pathways and promote axonal regeneration. In this study, we tested whether increased expression of SIRT1 protein in sensory neurons prevents and reverses Experimental Diabetic Neuropathy induced by a high fat diet (HFD). We generated a transgenic mouse that is inducible and overexpresses SIRT1 protein in neurons (nSIRT1OE Tg). Higher levels of SIRT1 protein were localized to cortical and hippocampal neuronal nuclei in the brain and in nuclei and cytoplasm of small to medium sized neurons in dorsal root ganglia. Wild-type and nSIRT1OE Tg mice were fed with either control diet (6.2% fat) or a HFD (36% fat) for 2 months. HFD-fed wild-type mice developed Neuropathy as determined by abnormal motor and sensory nerve conduction velocity, mechanical allodynia, and loss of intraepidermal nerve fibres. In contrast, nSIRT1OE prevented a HFD-induced Neuropathy despite the animals remaining hyperglycaemic. To test if nSIRT1OE would reverse HFD-induced Neuropathy, nSIRT1OE was activated after mice developed peripheral Neuropathy on a HFD. Two months after nSIRT1OE, we observed reversal of Neuropathy and an increase in intraepidermal nerve fibre. Cultured adult dorsal root ganglion neurons from nSIRT1OE mice, maintained at high (30 mM) total glucose, showed higher basal and maximal respiratory capacity when compared to adult dorsal root ganglion neurons from wild-type mice. In dorsal root ganglion protein extracts from nSIRT1OE mice, the NAD+-consuming enzyme PARP1 was deactivated and the major deacetylated protein was identified to be an E3 protein ligase, NEDD4-1, a protein required for axonal growth, regeneration and proteostasis in neurodegenerative diseases. Our results indicate that nSIRT1OE prevents and reverses Neuropathy. Increased mitochondrial respiratory capacity and NEDD4 activation was associated with increased axonal growth driven by neuronal overexpression of SIRT1. Therapies that regulate NAD+ and thereby target sirtuins may be beneficial in human Diabetic sensory polyNeuropathy.
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mitochondrial transcription factor a regulation of mitochondrial degeneration in Experimental Diabetic Neuropathy
American Journal of Physiology-endocrinology and Metabolism, 2015Co-Authors: Krish Chandrasekaran, Joungil Choi, Tatsuya Inoue, Muragundla Anjaneyulu, Avinash Rao Sagi, Chen Chen, James W RussellAbstract:Oxidative stress-induced mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage in peripheral neurons is considered to be important in the development of Diabetic Neuropathy. Mitochondrial ...
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pgc 1α regulation of mitochondrial degeneration in Experimental Diabetic Neuropathy
Neurobiology of Disease, 2014Co-Authors: Joungil Choi, Krish Chandrasekaran, Tatsuya Inoue, Anjaneyulu Muragundla, James W RussellAbstract:Mitochondrial degeneration is considered to play an important role in the development of Diabetic peripheral Neuropathy in humans. Mitochondrial degeneration and the corresponding protein regulation associated with the degeneration were studied in an animal model of Diabetic Neuropathy. PGC-1α and its-regulated transcription factors including TFAM and NRF1, which are master regulators of mitochondrial biogenesis, are significantly downregulated in streptozotocin Diabetic dorsal root ganglion (DRG) neurons. Diabetic mice develop peripheral Neuropathy, loss of mitochondria, decreased mitochondrial DNA content and increased protein oxidation. Importantly, this phenotype is exacerbated in PGC-1α (−/−) Diabetic mice, which develop a more severe Neuropathy with reduced mitochondrial DNA and a further increase in protein oxidation. PGC-1α (−/−) Diabetic mice develop an increase in total cholesterol and triglycerides, and a decrease in TFAM and NRF1 protein levels. Loss of PGC-1α causes severe mitochondrial degeneration with vacuolization in DRG neurons, coupled with reduced state 3 and 4 respiration, reduced expression of oxidative stress response genes and an increase in protein oxidation. In contrast, overexpression of PGC-1α in cultured adult mouse neurons prevents oxidative stress associated with increased glucose levels. The study provides new insights into the role of PGC-1α in mitochondrial regeneration in peripheral neurons and suggests that therapeutic modulation of PGC-1α function may be an attractive approach for treatment of Diabetic Neuropathy.
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transforming growth factor β induces cellular injury in Experimental Diabetic Neuropathy
Experimental Neurology, 2008Co-Authors: Muragundla Anjaneyulu, Joungil Choi, Tatsuya Inoue, Alison Berentspillson, Kay Cherian, James W RussellAbstract:Abstract The mechanism/s leading to Diabetic Neuropathy are complex. Transforming growth factor-β1 (TGF-β1) has been associated with Diabetic nephropathy and retinopathy but not Neuropathy. In this study, changes in TGF-β isoforms were examined in vivo and in vitro. Two groups of animals, streptozotocin Diabetic with Neuropathy and non-Diabetic controls were examined at 4 weeks (n = 10/group) and 12 weeks (n = 8/group). In Diabetic DRG using quantitative real-time PCR (QRT-PCR), TGF-β1 and TGF-β2 mRNA, but not TGF-β3, was increased at 4 and 12 weeks. In sciatic nerve TGF-β3 mRNA was primarily increased. Immunohistochemistry (DRG) and immunoblotting (sciatic nerve) showed similar differential protein expression. In sciatic nerve TGF-β formed homo- and hetero-dimers, of which β2/β3, β1/β1, and β1/β3 were significantly increased, while that of the TGF-β2/β2 homodimer was decreased, in Diabetic compared to non-Diabetic rats. In vitro, pretreatment of embryonic DRG with TGF-β neutralizing antibody prevents the increase in total TGF-β protein observed with high glucose using immunoblotting. In high glucose conditions, combination with TGF-β2 > β1 increases the percent of cleaved caspase-3 compared to high glucose alone and TGF-β neutralizing antibody inhibits this increase. Furthermore, consistent with the findings in Diabetic DRG and nerve, TGF-β isoforms applied directly in vitro reduce neurite outgrowth, and this effect is partially reversed by TGF-β neutralizing antibody. These findings implicate upregulation of TGF-β in Experimental Diabetic peripheral Neuropathy and indicate a novel mechanism of cellular injury related to elevated glucose levels. In combination, these findings indicate a potential new target for treatment of Diabetic peripheral Neuropathy.
Douglas W. Zochodne - One of the best experts on this subject based on the ideXlab platform.
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new molecules for an irreversible disorder mrnas and mirnas in Experimental Diabetic Neuropathy s44 003
Neurology, 2016Co-Authors: Douglas W. Zochodne, Chu Cheng, Masaki KobayashiAbstract:OBJECTIVE: Our hypothesis is that novel molecular alterations in sensory neurons targeted by diabetes mellitus (DM) offer therapeutic targets to arrest or reverse Diabetic polyNeuropathy (DPN). The objective was to examine differential expression of mRNAs and miRNAs in the sensory ganglia (DRGs) of a long term model of Experimental DPN and to test whether their changes influence the phenotype of the disorder. BACKGROUND: Diabetic sensory neurodegeneration, or polyNeuropathy (DPN) is a common, progressive but irreversible neurological disorder. Given the failure of several therapeutic trials for human DPN, new molecular ideas are required. Understanding the differential regulation of mRNAs and their supraregulatory partners, noncoding miRNAs, in long term Experimental models may identify new and relevant molecular directions toward understanding the disorder. The long term outbred mouse model of Experimental DPN expresses features of the human disease: motor and sensory conduction slowing, loss of epidermal axons and loss of sensation. DESIGN/METHODS: Gene expression microarray and miRNA array in mice with long term Experimental DPN or littermates. RESULTS: We examined 28,869 DRG genes and identified 24 mRNAs (5 downregulated and 19 upregulated) differentially regulated. In the same ganglia, of 1042 targets we identified 19 (12 downregulated and 7 upregulated) high abundance and 123 (56 down and 67 up) low abundance miRNAs differentially regulated. Among the mRNAs, upregulation of CWC22, a spliceosome protein influenced growth properties of sensory neurons and features of Experimental DPN. A downregulated miRNA, mmu-let-7i was expressed in sensory neurons, supported enhanced outgrowth in sensory neurons and improved DPN when repleted. CONCLUSIONS: Sensory neurodegeneration generates a series of subtle neurodegenerative alterations including impacts on supraregulatory miRNA expression. The latter alters sensory neurons by epigenetic mechanisms. New molecular pathways identified here offer new directions to explore DPN therapy [Results previously reported in JNEN 74:804, 2015]. Study Supported by: CIHR, CDA and AIHS Disclosure: Dr. Zochodne has nothing to disclose. Dr. Cheng has nothing to disclose. Dr. Kobayashi has nothing to disclose.
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Evidence for Epigenetic Regulation of Gene Expression and Function in Chronic Experimental Diabetic Neuropathy.
Journal of neuropathology and experimental neurology, 2015Co-Authors: Chu Cheng, Hilarie Ng, Joanna J. Moser, Jose A. Martínez, Marvin J. Fritzler, Xiuling Wang, Masaki Kobayashi, Vandana Singh, Douglas W. ZochodneAbstract:Diabetic polyNeuropathy (DPN) is a common but irreversible neurodegenerative complication of diabetes mellitus. Here we show that features of sensory neuron damage in mice with chronic DPN may have altered epigenetic micro RNA (miRNA) transcriptional control. We profiled sensory neuron messenger RNA and miRNA profiles in mice with type I diabetes mellitus and findings of DPN. Diabetic sensory dorsal root ganglia neurons showed a pattern of altered messenger RNA profiles associated with upregulated cytoplasmic sites of miRNA-mediated messenger RNA processing (GW/P bodies). Dorsal root ganglia miRNA microarray identified significant changes in expression among mice with diabetes, the most prominent of which were a 39% downregulation of mmu-let-7i and a 255% increase in mmu-miR-341; both were identified in sensory neurons. To counteract these alterations, we replenished let-7i miRNA by intranasal administration; in a separate experiment, we added an anti-miR that antagonized elevated mmu-341 after 5 months of diabetes. Both approaches independently improved electrophysiologic, structural, and behavioral abnormalities without altering hyperglycemia; control sequences did not have these effects. Dissociated adult sensory neurons exposed to an exogenous mmu-let-7i mimic displayed enhanced growth and branching, indicating a trophic action. These findings identify roles for epigenetic miRNA alterations and enhanced GW/P expression in Diabetic dorsal root ganglia that contribute to the complex DPN phenotype.
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intranasal insulin ameliorates Experimental Diabetic Neuropathy diabetes 2009 58 934 945 doi 10 2337 db08 1287
Diabetes, 2014Co-Authors: George Francis, Douglas W. Zochodne, Jose A. Martínez, Thuhien M Nguyen, Amit Ayer, Jared M Fine, Leah R Hanson, William H Frey, Cory TothAbstract:The corresponding author has formally requested to retract the above-titled paper, which was published online on 9 January 2009. Table 1 has been duplicated from a prior publication …
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intranasal insulin ameliorates Experimental Diabetic Neuropathy
Diabetes, 2009Co-Authors: George Francis, Douglas W. Zochodne, Jose A. Martínez, Thuhien M Nguyen, Amit Ayer, Jared M Fine, Leah R Hanson, William H Frey, Cory TothAbstract:OBJECTIVE We hypothesized that intranasal insulin (I-I) delivery targets the nervous system while avoiding potential adverse systemic effects when compared with subcutaneous insulin (S-I) for Experimental streptozotocin-induced Diabetic peripheral Neuropathy (DPN). RESEARCH DESIGN AND METHODS I-I or S-I at 0.87 IU daily or placebo were delivered in separate cohorts of Diabetic and nonDiabetic CD1 mice during 8 months of diabetes. Radiolabeled insulin detection was used to compare delivery and biodistribution for I-I and S-I. Biweekly behavioral testing and monthly electrophysiological and quantitative studies assessed progression of DPN. At and before end point, morphometric analysis of DRG, peripheral nerve, distal epidermal innervation, and specific molecular markers were evaluated. RESULTS Radiolabeled I-I resulted in more rapid and concentrated delivery to the spinal cord and DRG with less systemic insulin exposure. When compared with S-I or intranasal placebo, I-I reduced overall mouse mortality and sensory loss while improving neuropathic pain and electrophysiological/morphological abnormalities in Diabetic mice. I-I restored mRNA and protein levels of phosphoinositide 3-kinase/Akt, cyclic AMP response element–binding protein, and glycogen synthase kinase 3β to near normal levels within Diabetic DRGs. CONCLUSIONS I-I slows the progression of Experimental DPN in streptozotocin mice, avoids adverse effects associated with S-I treatment, and prolongs lifespan when compared with S-I. I-I may be a promising approach for the treatment of DPN.
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Experimental Diabetic Neuropathy with spontaneous recovery is there irreparable damage
Diabetes, 2005Co-Authors: James Kennedy, Douglas W. ZochodneAbstract:Progressive Diabetic Neuropathy has hitherto been irreversible in humans. New approaches raise the question of whether islet cell reconstitution rendering euglycemia can reverse specific features of Neuropathy. We evaluated physiological and structural features of Experimental Neuropathy in a long-term murine model of diabetes induced by streptozotocin. By serendipity, a subset of these Diabetic mice spontaneously regained islet function and attained near-euglycemia. Our hypotheses were that this model might better reflect axon loss observed in human disease and that spontaneous recovery from diabetes might identify the features of Neuropathy that are reversible. In this model, Experimental Neuropathy closely modeled that in humans in most critical aspects: declines in motor conduction velocities, attenuation of compound muscle (M waves) and nerve action potentials, axon atrophy, myelin thinning, loss of epidermal axons, and loss of sweat gland innervation. Overt sensory neuron loss in dorsal root ganglia was a feature of this model. In mice with recovery, there was robust electrophysiological improvement, less myelin thinning, and remarkable epidermal and sweat gland reinnervation. There was, however, no recovery of populations of lost sensory neurons. Our findings identify a robust model of human Diabetic Neuropathy and indicate that overt, irretrievable loss of sensory neurons is one of its features, despite collateral reinnervation of target organs. Sensory neurons deserve unique protective strategies irrespective of islet cell reconstitution.
