Neurovascular disease, antioxidants and glycation in diabetes

Dickinson, Peter J.; Carrington, Anne L.; Frost, Gary; Boulton, Andrew J.M.

doi:10.1002/dmrr.305

Cited by 61 publications

(41 citation statements)

References 198 publications

(236 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, little work has been done on the effects of radical traps on AGE chemistry. Ascorbic acid and ␣-tocopherol have been examined to some degree (48,49,50), but both of these bioantioxidants have significant disadvantages for understanding protein glycation chemistry. The lipophilic antioxidant ␣-tocopherol is only sparingly soluble in aqueous protein solutions and is unlikely to be associated with the highly polar protein or glycation residues.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Culbertson

Vassilenko

Morrison

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

The inhibition of post-Amadori advanced glycation end product (AGE) formation by three different classes of AGE inhibitors, carbonyl group traps, chelators, and radical-trapping antioxidants, challenge the current paradigms that: 1) AGE inhibitors will not increase the formation of any AGE product, 2) transition metal ions are required for oxidative formation of AGE, and 3) screening AGE inhibitors only in systems containing transition metal ions represents a valid estimate of potential in vivo mechanisms. This work also introduces a novel multifunctional AGE inhibitor, 6-dimethylaminopyridoxamine (dmaPM), designed to function as a combined carbonyl trap, metal ion chelator, and radicaltrapping antioxidant. Other AGE inhibitors including pyridoxamine, aminoguanidine, o-phenylenediamine, dipyridoxylamine, and diethylenetriaminepentaacetic acid were also examined. The results during uninterrupted and interrupted ribose glycations show: 1) an unexpected increase in the yield of pentosidine in the presence of radical-trapping phenolic antioxidants such as Trolox and dmaPM, 2) significant formation of N ⑀ -carboxymethyllysine (CML) in the presence of strong chelators and phenolic antioxidants, which implies that there must be nonradical routes to CML, 3) prevention of intermolecular cross-links with radical-trapping inhibitors, and 4) that dmaPM shows excellent inhibition of AGE. Glucose glycations reveal the expected inhibition of pentosidine and CML with all compounds tested, but in a buffer free of trace metal ions the yield of CML in the presence of radical-trapping antioxidants was between the metal ion-free and metal ion-containing controls. Protein molecular weight analyses support the conclusion that Amadori decomposition pathways are constrained in the presence of metal ion chelators and radical traps.Nonenzymatic protein glycation by reducing sugars, such as glucose or ribose, is a complicated cascade of condensations, rearrangements, fragmentations, and oxidative modifications that lead to a plethora of compounds collectively called advanced glycation end products (AGEs) 1 (1). AGE products slowly build up and contribute to the age-dependent chemical modification of long-lived tissue proteins. Once formed, AGE products may prevent normal protein function and recognition or stimulate potentially detrimental interactions in signaling pathways (2, 3). Glycation reactions are believed to have a significant role in the progression of diabetic complications largely because of elevated levels of glucose. Indeed, the formation of AGE has been increasingly implicated in pathogenesis of diabetic complications, atherosclerosis, and Alzheimer's disease (4 -6). Inhibitors that act to reduce AGE formation may prove useful for limiting nonenzymatic protein modification associated in the pathology of these and other chronic agerelated diseases. The reaction of amino compounds, such as lysine, with reducing sugars is known as the Maillard reaction (7, 8). The "classical" or Hodge pathway begins with reversible formation of...

show abstract

Section: Discussionmentioning

confidence: 99%

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Culbertson

Vassilenko

Morrison

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Formation of some AGEs (ie, pentosidine and N ε -[carboxymethyl]-lysine) combines both the glycation and oxidative steps in a process termed "glycooxidation." In the past several years, the role for glycation or glycoxidation in diabetic complications, including diabetic neuropathy, has been extensively reviewed [30,31].…”

Section: Role For Nonenzymatic Glycationmentioning

confidence: 99%

Update on the pathogenesis of diabetic neuropathy

Obrosova

2003

Curr Diab Rep

View full text Add to dashboard Cite

Peripheral diabetic neuropathy (PDN) affects up to 60% to 70% of diabetic patients, and is the leading cause of foot amputation. The pathogenesis of PDN involves multiple mechanisms. The findings obtained in 1999 to 2003 support the role of previously established mechanisms such as increased aldose reductase activity, nonenzymatic glycation or glyco-oxidation, activation of protein kinase C, enhanced oxidative stress, impaired neurotrophic support, and reveal the importance of new downstream effectors of oxidative injury. Those include mitogen-activated protein kinases and poly (ADP-ribose) polymerase that are activated by diabetes, and contribute to such neuropathic changes as motor and sensory nerve conduction deficits, decreased nerve blood flow, and energy failure. Further studies are needed to understand the role of other signaling pathways as well as interactions among previously discovered mechanisms in the pathogenesis of PDN.

show abstract

“…The role for methylglyoxal in advanced glycation end product formation is well established (7). Advanced glycation end products, in turn, exacerbate oxidative stress during interaction with their receptors (10), thus creating a "vicious cycle" and contributing to the pathogenesis of PDN via several mechanisms (6,7).…”

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

confidence: 99%

“…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)(3)(4)(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.…”

mentioning

confidence: 99%

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

Neurovascular disease, antioxidants and glycation in diabetes

Cited by 61 publications

References 198 publications

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Paradoxical Impact of Antioxidants on Post-Amadori Glycoxidation

Update on the pathogenesis of diabetic neuropathy

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

Contact Info

Product

Resources

About