A lipoic acid-gamma linolenic acid conjugate is effective against multiple indices of experimental diabetic neuropathy

Hounsom, Luke; Horrobin, D. F.; Tritschler, Hans; Corder, Roger; Tomlinson, David R.

doi:10.1007/s001250050996

Cited by 101 publications

(64 citation statements)

References 39 publications

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“…In rats treated throughout their diabetes with a diester of a-lipoic acid and g-linolenic acid (GLA-LA), which has antioxidant properties, the ERK response was considerably attenuated but the JNK response was greatly enhanced. As GLA-LA is protective against a number of functional and biochemical defects in diabetic rats [97], these observations support the hypothesis that JNK activation is protective, with the exaggerated activation indicating increased antioxidant protection. The role of ERK remains ambiguous, in that reduction of its activation by an antioxidant could imply that phospho-ERK is damaging but it could also imply that it is a sensitive protective element and that its reduced activation shows the attenuated oxidative stress associated with the antioxidant treatment.…”

Section: Oxidative Stresssupporting

confidence: 72%

“…It is, therefore, possible that JNK activation could be pathogenic through neurofilament phosphorylation in several disease states. Obviously, it is difficult to reconcile these speculations with the finding that a drug with many beneficial effects in diabetic rats [97] appears to amplify activation of a MAP kinase that could be damaging. Our understanding of these phenomena is in its infancy.…”

Section: Diabetic Neuropathymentioning

confidence: 99%

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Mitogen-activated protein kinases as glucose transducers for diabetic complications

1999

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The results of the Diabetes Control and Complications Trial [1] emphatically confirmed the heroic studies of Jean Pirart [2±4], showing that poor control of glycaemia in Type I (insulin-dependent) diabetes mellitus predisposes patients to chronic complications. This has led to the tacit assumption that glucose, at supranormal concentrations, is the agent of damage. Participation of hypoinsulinaemia or other manifestations of poor control cannot be discounted but glucose itself certainly has the capacity to disturb biosystems. It can do this in a variety of ways, so that hypotheses to explain specific complications ± retinopathy, nephropathy and neuropathy ± starting from high glucose are tenable, testable and, therefore, useful.Figure 1 presents a simple generic plan by which complications develop. It usefully discriminates between metabolic effects of glucose on the target cells showing the complication and the exacerbating effect of independent accelerators, such as arterial hypertension in diabetic nephropathy. Not all independent accelerators have, however, as clearly defined a rela- Diabetologia (1999) AbstractThe damaging effects of glucose on the cells which contribute to the development of diabetic complications are ill-understood. There are three major hypotheses ± the sorbitol pathway, non-enzymatic glycation of proteins and increased oxidative stress ± and many examples illustrate inter-connections between the three. It is suggested that these pathways, together with other biochemical anomalies arising from hyperglycaemia, can synergise by sharing the capacity to activate mitogen-activated protein kinases (MAP kinases) and that these enzymes in actual fact form glucose transducers. The more recent hypothesis, namely that activation of a specific isoform of protein kinase C (PKC) underpin damaging changes in retinopathy and neuropathy, can also be related because protein kinase C is an effective activator of mitogen-activated protein kinases. These latter kinases phosphorylate transcription factors, which in turn alter the balance of gene expression. In this way they can alter cellular phenotype, promote division or increase production of extracellular material. In short, mitogen-activated protein kinases have the capacity to trigger all the cellular events necessary for the development of diabetic nephropathy, retinopathy and neuropathy and it is suggested that their pharmacological modulation might provide therapeutic control of these conditions. [Diabetologia (1999

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Section: Oxidative Stresssupporting

confidence: 72%

Section: Diabetic Neuropathymentioning

confidence: 99%

Mitogen-activated protein kinases as glucose transducers for diabetic complications

1999

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“…MNCV and SNCV. For measurement of MNCV and SNCV, the procedure commonly adopted for measuring M-waves and H-reflexes was used (23). In brief, all mice were anesthetized with isoflurane (Abbot) and placed on a thermostatically controlled heated mat to maintain the body temperature at 37°C.…”

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confidence: 99%

Effects of Polyol Pathway Hyperactivity on Protein Kinase C Activity, Nociceptive Peptide Expression, and Neuronal Structure in Dorsal Root Ganglia in Diabetic Mice

et al. 2004

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We explored the specific impact of polyol pathway hyperactivity on dorsal root ganglia (DRG) using transgenic mice that overexpress human aldose reductase because DRG changes are crucial for the development of diabetic sensory neuropathy. Littermate mice served as controls. Half of the animals were made diabetic by streptozotocin injection and followed for 12 weeks. After diabetes onset, diabetic transgenic mice showed a significant elevation of pain sensation threshold after transient decrease and marked slowing of motor and sensory nerve conduction at the end of the study, while these changes were modest in diabetic littermate mice. Protein kinase C (PKC) activities were markedly reduced in diabetic transgenic mice, and the changes were associated with reduced expression of membrane PKC-␣ isoform that was translocated to cytosol. Membrane PKC-␤II isoform expression was contrariwise increased. Calcitonin gene-related peptide-and substance P-positive neurons were reduced in diabetic transgenic mice and less severely so in diabetic littermate mice. Morphometric analysis disclosed neuronal atrophy only in diabetic transgenic mice. Treatment with an aldose reductase inhibitor (fidarestat 4 mg ⅐ kg -1 ⅐ day -1, orally) corrected all of the changes detected in diabetic transgenic mice. These findings underscore the pathogenic role of aldose reductase in diabetic sensory neuropathy through the altered cellular signaling and peptide expressions in DRG neurons. Diabetes 53:3239 -3247, 2004 P olyol pathway hyperactivity has been extensively studied for the mechanisms of diabetic neuropathy, where aldose reductase is a key regulating enzyme (1,2). In animal models, diabetes-induced peripheral nerve conduction deficits, neurometabolic imbalances, altered nerve blood flow, and morphologic abnormalities are prevented by structurally diverse aldose reductase inhibitors (ARIs) (3-5). Past clinical trials of ARIs were not, however, convincingly successful (6,7), and specific effects of polyol pathway hyperactivity on the clinical and structural aspects of diabetic sensory neuropathy is yet to be clear (8,9). The development of a transgenic animal model provides an ideal tool to identify the specific role of single molecules in disease mechanisms. We have established a strain of transgenic mice that overexpress human aldose reductase (10 -12). In this model, we confirmed that polyol pathway hyperactivity was indeed related to the severity of motor nerve conduction delay and nerve fiber atrophy. More recently, a new transgenic model that overexpresses aldose reductase, specifically in Schwann cells by use of myelin protein Po promoter, has enabled researchers to address more precise mechanisms of polyol pathway in the development of neuropathy in diabetes (13). Nevertheless, from these studies, it was not shown which measures were comparable with those found in human diabetic neuropathy, and it still remains obscure what could be the most appropriate target for the intervention with a potent and specific inhibitor for human aldos...

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“…Nerve energy status is closely associated with the redox state of free motochondrial and cytosolic NAD-couples, active transport and biosynthetic activity and directly correlates with nerve conduction [42±44]. Oxidative stress has been implicated in the impairment of neurotrophic support and nerve dysfunction in diabetes [26,45]. We compared our variables in control and diabetic rats treated with or without SDI.…”

mentioning

confidence: 99%

Evaluation of a sorbitol dehydrogenase inhibitor on diabetic peripheral nerve metabolism: a prevention study

Obrosova

Fathallah

Lang³

et al. 1999

Diabetologia

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Numerous studies in experimental models of diabetes [1±5] as well as a few clinical trials [6±9] have shown a reduction of peripheral nerve conduction deficit and morphological abnormalities by structurally different aldose reductase inhibitors thus implicating increased activity of the sorbitol pathway in the pathogenesis of diabetic neuropathy. The mechanisms leading from increased sorbitol pathway activity to complex functional, metabolic and morphological changes in the peripheral nervous system in diabetes are not com- Diabetologia (1999) AbstractAims/hypothesis. Studies of the role of sorbitol dehydrogenase in nerve functional deficits induced by diabetes reported contradictory results. We evaluated whether sorbitol dehydrogenase inhibition reduces metabolic abnormalities and enhances oxidative stress characteristic of experimental diabetic neuropathy. Methods. Control and streptozotocin-diabetic rats were treated with or without sorbitol dehydrogenase inhibitor (SDI)-157 (100 mg × kg ±1 × day ±1 , in the drinking water, for 3 weeks). Sciatic nerve free mitochondrial (cristae and matrix) and cytosolic NAD + : NADH ratios were calculated from the b-hydroxybutyrate, glutamate and lactate dehydrogenase systems. Concentrations of metabolites, e. g. sorbitol pathway intermediates and variables of energy state were measured in individual nerves spectrofluorometrically by enzymatic procedures. Results. The flux through sorbitol dehydrogenase (manifested by nerve fructose concentrations) was inhibited by 53 % and 74 % in control and diabetic rats treated with SDI compared with untreated control and diabetic groups. Free NAD + :NADH ratios in mitochondrial cristae, matrix and cytosol were decreased in diabetic rats compared with controls and reduction in either of the three variables was not prevented by sorbitol dehydrogenase inhibitor. Phosphocreatine concentrations and phosphocreatine:creatine ratios were decreased in diabetic rats compared with controls and were further reduced by the inhibitor. Malondialdehyde plus 4-hydroxyalkenals concentration was increased and reduced gluthathione concentration was reduced in diabetic rats compared with the control group, and changes in both variables were further exacerbated by sorbitol dehydrogenase inhibitor. Neither NAD-redox and energy states nor lipid aldehyde and reduced gluthathione concentrations were affected by treatment with the inhibitor in control rats. Conclusion/interpretation. Inhibition of sorbitol dehydrogenase does not offer an effective approach for prevention of oxidation and metabolic imbalances in the peripheral nerve that is induced by diabetes and is adverse rather than beneficial. [Diabetologia (1999

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A lipoic acid-gamma linolenic acid conjugate is effective against multiple indices of experimental diabetic neuropathy

Cited by 101 publications

References 39 publications

Mitogen-activated protein kinases as glucose transducers for diabetic complications

Mitogen-activated protein kinases as glucose transducers for diabetic complications

Effects of Polyol Pathway Hyperactivity on Protein Kinase C Activity, Nociceptive Peptide Expression, and Neuronal Structure in Dorsal Root Ganglia in Diabetic Mice

Evaluation of a sorbitol dehydrogenase inhibitor on diabetic peripheral nerve metabolism: a prevention study

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