Oxidative stress participates in the breakdown of neuronal phenotype in experimental diabetic neuropathy

Hounsom, Luke; Corder, Roger; Patel, Jyoti; Tomlinson, David R.

doi:10.1007/s001250051638

Cited by 54 publications

(30 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This link supports the findings of other studies in experimental and clinical diabetes (Cameron et al, 1993;Low et al, 1997;Cameron et al, 1998;Hounsom et al, 2001). The current study explores the hypothesis that accelerating the accumulation of ROS in the peripheral nervous system will in turn accelerate the development of DN.…”

Section: Discussionsupporting

confidence: 88%

“…The idea that oxidative stress contributes to diabetic complications is widely acknowledged (Cameron et al, 1998;Vincent et al, 2004c;Low et al, 1997;Cameron et al, 1993;Hounsom et al, 2001;Brownlee, 2001). Our work focuses on understanding how hyperglycemia-induced oxidative stress contributes to diabetic neuropathy (DN).…”

Section: Introductionmentioning

confidence: 99%

“…Work in clinical diabetes supports this concept. Measures of oxidative stress including TRAP (Total Radical Antioxidant Potential), thiobarbituric acid reactive substances (TBARS, a measure of oxidized lipids), and advanced glycation end products (AGEs) are all elevated in diabetic patients (Rosenson, 2004;Matteucci et al, 2004;Siemionow and Demir, 2004) and in experimental models of diabetes (Toth et al, 2004;Hounsom et al, 2001). …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Vincent

Russell

Sullivan

et al. 2007

Experimental Neurology

102

View full text Add to dashboard Cite

Hyperglycemia-induced oxidative stress is an inciting event in the development of diabetic complications including diabetic neuropathy. Our observations of significant oxidative stress and morphological abnormalities in mitochondria led us to examine manganese superoxide dismutase (SOD2), the enzyme responsible for mitochondrial detoxification of oxygen radicals. We demonstrate that over expression of SOD2 decreases superoxide (O 2 •− ) in cultured primary dorsal root ganglion (DRG) neurons and subsequently blocks caspase-3 activation and cellular injury. Under expression of SOD2 in dissociated DRG cultures from adult SOD2 +/− mice results in increased levels of O 2 •− , activation of caspase-3 cleavage and decreased neurite outgrowth under basal conditions that are exacerbated by hyperglycemia. These profound changes in sensory neurons led us to explore the effects of decreased SOD2 on the development of diabetic neuropathy (DN) in mice. DN was assessed in SOD2 +/− C57BL/6J mice and their SOD2 +/+ litter mates following streptozotocin (STZ) treatment. These animals, while hyperglycemic, do not display any signs of DN. DN was observed in the C57BL/6Jdb/db mouse, and decreased expression of SOD2 in these animals increased DN. Our data suggest that SOD2 activity is an important cellular modifier of neuronal oxidative defense against hyperglycemic injury.

show abstract

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Vincent

Russell

Sullivan

et al. 2007

Experimental Neurology

102

View full text Add to dashboard Cite

show abstract

“…5A, 1,2,3,5,6 and B, 1,3,4,5). 16,20), and pro-oxidants (18,19) support the central role for oxidative stress in NBF and conduction deficits, metabolic changes, impaired neurotropism, and morphologic abnormalities characteristic for PDN. Oxidative injury is manifested by 1) accumulation of lipid peroxidation products; depletion of GSH, ascorbate, and taurine; changes in the glutathione and ascorbate redox states; downregulation of superoxide dismutase; and catalase activities in the peripheral nerve (4,5,8,(12)(13)(14)(15); 2) increased production of superoxide and nitrotyrosine (a marker of peroxynitriteinduced injury) in vasa nervorum (16,17); and 3) elevated concentrations of 8-hydroxy-2Ј-deoxyguanosine (a marker of DNA oxidative damage) in dorsal root ganglion of STZ-induced diabetic rats (30).…”

Section: Fig 1 Blood Glucose Concentrations In Control (Solid Blackmentioning

confidence: 87%

Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy

et al. 2004

View full text Add to dashboard Cite

Oxidative and nitrosative stress play a key role in the pathogenesis of diabetic neuropathy, but the mechanisms remain unidentified. Here we provide evidence that poly(ADP-ribose) polymerase (PARP) activation, a downstream effector of oxidant-induced DNA damage, is an obligatory step in functional and metabolic changes in the diabetic nerve. PARP-deficient (PARP ؊/؊ ) mice were protected from both diabetic and galactose-induced motor and sensory nerve conduction slowing and nerve energy failure that were clearly manifest in the wild-type (PARP ؉/؉ ) diabetic or galactose-fed mice. Two structurally unrelated PARP inhibitors, 3-aminobenzamide and 1,5-isoquinolinediol, reversed established nerve blood flow and conduction deficits and energy failure in streptozotocin-induced diabetic rats. Sciatic nerve immunohistochemistry revealed enhanced poly(ADP-ribosyl)ation in all experimental groups manifesting neuropathic changes. Poly(ADP-ribose) accumulation was localized in both endothelial and Schwann cells. Thus, the current work identifies PARP activation as an important mechanism in diabetic neuropathy and provides the first evidence for the potential therapeutic value of PARP inhibitors in this devastating complication of diabetes. Diabetes 53: 711-720, 2004 D iabetic distal symmetric sensorimotor polyneuropathy affects up to 60 -70% of diabetic patients and is the leading cause of foot ulceration and amputation (1). Improved blood glucose control reduces the risk of peripheral diabetic neuropathy (PDN), thereby implicating hyperglycemia as a leading causative factor. Diabetic hyperglycemia causes PDN via several mechanisms, among which increased aldose reductase (AR) activity (2-5), nonenzymatic glycation/glycoxidation (6,7), and activation of protein kinase C (2,8) are the best studied. All three mechanisms contribute to enhanced oxidative and nitrosative stress (4,5,7,9 -11) resulting from imbalance between production and neutralization of reactive oxygen species. Enhanced oxidative stress has been documented in peripheral nerve (4,5,8,(12)(13)(14), dorsal root and sympathetic ganglia (15), and vasculature (16,17) of the peripheral nervous system and has been implicated in neurovascular dysfunction and motor and sensory nerve conduction velocity (MNCV and SNCV) deficits, impaired neurotrophic support, nerve metabolic and signal transduction changes, and morphologic abnormalities characteristic for diabetes (4,5,12,14,16 -20). Evidence for the pathophysiologic role of reactive nitrogen species in PDN is also emerging (16,21).The question of how oxidative and nitrosative stress causes PDN remains open. We explored the role for poly(ADP-ribose) (PAR) polymerase (PARP-1; EC 2.4.2.30), a nuclear enzyme that is activated by oxidant-induced DNA single-strand breakage and transfers ADP-ribose residues from NAD ϩ to nuclear proteins (22-25). PARP-1 is present in both endothelial cells (22,23) and Schwann cells of the peripheral nerve (26). PARP-1 activation is clearly manifest in diabetes and contributes to diabetic end...

show abstract

“…In our previous study [17], use of the vasodilator α 1 -adrenoceptor antagonist prazosin to prevent diabetes-induced nerve perfusion deficit as manifested by normal vascular conductance failed to preserve normal mitochondrial oxidative capacity. The latter is quite understandable in light of recent findings suggesting the dependence of inner mitochondrial membrane potential on insulin-dependent neurotrophic support [40], which is likely to be unrelated to the state of perfusion, but which is affected by intracellular oxidative stress [26,41]. Our present findings demonstrate that inhibition of diabetes-induced PARP activation, which is known to be responsible for NAD depletion [1,3] and downregulation of glyceraldehyde 3-phosphate dehydrogenase (or insufficient up-regulation as in the peripheral nerve) [7], as well as for decreased rates of glycolysis and mitochondrial oxidation [1], restores normal nerve energy state, the metabolic variable that correlates best with nerve conduction [5,17,18,20].…”

Section: Resultsmentioning

confidence: 98%

Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy

Szabó

Pacher

et al. 2004

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis. Poly(ADP-ribose) polymerase activation depletes NAD + and high-energy phosphates, activates protein kinase C, and affects gene expression in various tissues. This study was designed to characterise the effects of the potent, orally active poly(ADP-ribose) polymerase inhibitor PJ34 in the Wistar rat model of early diabetic neuropathy. Methods. Control and streptozotocin-diabetic rats were maintained with or without PJ34 treatment (30 mg·kg −1 ·day −1 ) for two weeks, after two weeks without treatment. Endoneurial blood flow was assessed by hydrogen clearance; metabolites and highenergy phosphates were assayed by enzymatic spectrofluorometric methods; and poly(ADP-ribose) was detected by immunohistochemistry.Results. Blood glucose concentrations were increased to a similar extent in untreated and PJ34-treated diabetic rats compared with controls. Intense poly(ADPribose) immunostaining was observed in the sciatic nerve of diabetic rats, but not in other groups. Final sciatic motor nerve conduction velocity and digital sensory nerve conduction velocity were reduced by 24% and 22% respectively in diabetic rats compared with controls (p<0.01 for both), and both were 98% corrected by PJ34 (p<0.01 vs diabetic group for both).In contrast, with PJ34 treatment, nerve blood flow showed a modest (17%) increase, and vascular conductance showed a tendency to increase. Free mitochondrial and cytosolic NAD + :NADH ratios, assessed from the glutamate and lactate dehydrogenase systems, phosphocreatine concentrations, and phosphocreatine:creatine ratios were decreased in diabetic rats and essentially normalised by PJ34. In both untreated and PJ34-treated diabetic rats, nerve glucose, sorbitol and fructose were increased to a similar extent. PJ34 did not affect any variables in control rats. Conclusions/interpretation. Short-term poly(ADP-ribose) polymerase inhibitor treatment reverses functional and metabolic abnormalities of early diabetic neuropathy. Complete normalisation of nerve blood flow is not required for correction of motor or sensory nerve conduction velocities, provided that a therapeutic agent can restore nerve energy state via direct action on Schwann cells.Keywords Energy state · Motor and sensory nerve conduction · Nerve blood flow · Oxidative and nitrosative stress · Peripheral diabetic neuropathy · PJ34 · Poly(ADP-ribose) polymerase · Rat · Sorbitol pathway of glucose metabolism · Streptozotocindiabetes

show abstract

Oxidative stress participates in the breakdown of neuronal phenotype in experimental diabetic neuropathy

Cited by 54 publications

References 6 publications

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy

Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy

Contact Info

Product

Resources

About