gamma-linolenic-acid and Diabetic-Neuropathies

The essential fatty acid deficiency (EFA) gives rise to many pathologic states and may predispose for certain disease development. One of the most frequently deficient EFA is gamma-linolenic acid. The gamma-linolenic acid supplementation brings some hopeful effects in treatment of diabetic neuropathy, eczema, cyclic mastalgia, rheumatoid arthritis, osteoporosis and ADHD. Many double blind trials have been performed for defective assessment of GLA efficiency. Some of them have proved statistically significant efficacy, the others have led to some doubts. There is a necessity to perform more trials. The gamma-linolenic acid is completely safe, non-toxic, and non-cancerogenic substance. It can be an interesting alternative for supporting treatment.

Topics: Arthritis, Rheumatoid; Attention Deficit Disorder with Hyperactivity; Diabetic Neuropathies; Dietary Supplements; Eczema; gamma-Linolenic Acid; Humans; Osteoporosis; Treatment Outcome

Topics: Aldehyde Reductase; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Chronic Disease; Diabetic Neuropathies; Enzyme Inhibitors; gamma-Linolenic Acid; Glycation End Products, Advanced; Guanidines; Humans; Insulin; Oxidative Stress; Rhodanine; Thiazolidines

Diabetic neuropathy is a common complication of diabetes that is often associated both with considerable morbidity and mortality. The epidemiology and natural course of diabetic neuropathy is clouded with uncertainty, largely due to confusion regarding the definition and measurement of this disorder. The recent resurgence of interest in the vascular hypothesis, oxidative stress, the neurotrophic hypothesis and the possibility of the role of autoimmunity have opened up new avenues of investigation for therapeutic intervention. Paralleling our increased understanding of the pathogenesis of diabetic neuropathy, there must be refinements in our ability to measure quantitatively the different types of defects that occur in this disorder, so that appropriate therapies can be targeted to specific fibre types. These tests must be validated and standardised to allow comparability between studies and a more meaningful interpretation of study results. Our ability to manage successfully the many different manifestations of diabetic neuropathy depends ultimately on our success in uncovering the pathogenic processes underlying this disorder.

Topics: Aldehyde Reductase; Animals; Diabetic Neuropathies; Enzyme Inhibitors; gamma-Linolenic Acid; Guanidines; Humans; Immunoglobulins, Intravenous; Thioctic Acid

Impaired conversion of linoleic acid to gamma-linolenic acid (GLA) has been demonstrated in animal diabetes and inferred from blood fatty acid profiles in human diabetes. This impairment could theoretically lead to defective nerve function because metabolites of GLA are known to be important in nerve membrane structure, nerve blood flow, and nerve conduction. Administration of GLA corrects the impaired nerve function in animal models of diabetes. Two multicenter, randomized, placebo-controlled trials in humans with diabetic neuropathy have shown significant benefits of GLA as compared with placebo in neurophysiological parameters, thermal thresholds, and clinical sensory evaluations. Further work is needed to define the place of this therapeutic approach and its interactions with other treatment modalities.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Lipids; Rats

Topics: Animals; Diabetic Neuropathies; Eicosanoids; Erectile Dysfunction; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Linoleic Acids; Male; Nitric Oxide; Nucleotides, Cyclic; Oenothera biennis; Penile Erection; Penis; Plant Oils; Prostaglandins

A substantial disturbance of the metabolism of the n-6 essential fatty acids (EFAs) exists in both human and experimental diabetes mellitus. The process of conversion of dietary linoleic acid to gammalinolenic, dihomogammalinolenic and arachidonic acids, and other polyunsaturates is inadequate in diabetic patients. Disturbances of these EFAs and the 1- and 2-series prostaglandins derived from them cause a variety of microvascular, haemorheological, and other abnormalities leading to reduced blood flow and neural hypoxia. This will in turn produce an escalating cycle of further hypoxia through the generation of oxygen-free radicals and aggravation of neural capillary endothelial damage. Endoneurial hypoxia impairs axonal transport, produces demyelination, and reduces neural ATP-ase activity. Furthermore, depletion of polyunsaturated fatty acids derived from n-6 pathway may lead to abnormalities of myelin turnover, membrane-bound proteins (such as enzymes and receptors) and other axonal structural abnormalities. The disorders postulated here may synergistically interact with the metabolic changes described in both the glycosylation and the myoinositol hypotheses and may have important implications in the approach to treat diabetic neuropathy.

Topics: Diabetes Mellitus; Diabetic Neuropathies; Dietary Fats; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Models, Biological

Gamma-linolenic acid (GLA) has recently been found to be beneficial in the management of breast pain and of diabetic neuropathy. GLA is a precursor of unsaturated fatty acids which are important in membrane structures, as second messengers in their own right and as precursors of eicosanoids. While the mechanisms of GLA action are likely to be complex, non-eicosanoid effects are probably of substantial importance. These effects include modification of membrane fluidity and of the functions of lipid-associated receptors and changes in the inositol cycle.

Topics: Breast Diseases; Diabetic Neuropathies; Drug Evaluation; Fatty Acids, Essential; Female; gamma-Linolenic Acid; Gonadal Steroid Hormones; Humans; Linoleic Acids; Linolenic Acids; Male; Membrane Fluidity; Models, Biological; Oenothera biennis; Pain; Plant Oils; Receptors, Cell Surface; Second Messenger Systems

Linoleic acid is the main dietary essential fatty acid (EFA). To be fully utilized by the body, it must be metabolized to a range of other substances. The first step in this pathway is delta-6-desaturation to gamma-linolenic acid (GLA). This step is slow and rate-limiting, particularly in humans. If delta-6-desaturation is impaired for any reason, the supply of further metabolites may be inadequate for normal function. If the consumption of further metabolites is excessive, then a normal rate of delta-6-desaturation may be inadequate. In these circumstances the direct supply of GLA or further metabolites may be of value. This concept is illustrated by atopic eczema and diabetes, which may represent inherited and acquired examples of inadequate delta-6-desaturation.

Topics: Dermatitis, Atopic; Diabetes Mellitus; Diabetic Neuropathies; Fatty Acid Desaturases; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Linoleic Acid; Linoleic Acids; Linolenic Acids; Linoleoyl-CoA Desaturase

EF4 is an entirely new approach to the management of diabetic neuropathy. EF4 (providing gamma-linolenic acid or gamolenic acid, GLA) has been shown to reverse existing diabetic neuropathy in trials in seven centres. Diabetic animals and humans have a reduced ability to convert dietary linoleic acid to GLA. GLA and its metabolites are required for normal neuronal structure and function and a normal microcirculation. The lack of GLA and its metabolites may play a major role in the development of the neuropathy. EF4 helps to correct the biochemical defects, restores levels of GLA metabolites towards normal and produces highly significant clinical and neurophysiological improvements in diabetic neuropathy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Diabetic Neuropathies; gamma-Linolenic Acid; Humans; Linolenic Acids

This study was a multicenter, parallel-group, double-blind, double-dummy, randomized, noninferiority trial to evaluate the efficacy and safety of γ-linolenic acid (GLA) relative to α-lipoic acid (ALA) over a 12-week treatment period in type 2 diabetes mellitus (T2DM) patients with painful diabetic peripheral neuropathy (DPN).. This study included 100 T2DM patients between 20 and 75 years of age who had painful DPN and received either GLA (320 mg/day) and placebo or ALA (600 mg/day) and placebo for 12 weeks. The primary outcome measures were mean changes in pain intensities as measured by the visual analogue scale (VAS) and the total symptom scores (TSS).. Of the 100 subjects who initially participated in the study, 73 completed the 12-week treatment period. Per-protocol analyses revealed significant decreases in the mean VAS and TSS scores compared to baseline in both groups, but there were no significant differences between the groups. The treatment difference for the VAS (95% confidence interval [CI]) between the two groups was -0.65 (-1.526 to 0.213) and the upper bound of the 95% CI did not exceed the predefined noninferiority margin (δ₁=0.51). For the TSS, the treatment difference was -0.05 (-1.211 to 1.101) but the upper bound of the 95% CI crossed the noninferiority margin (δ₂=0.054). There were no serious adverse events associated with the treatments.. GLA treatment in patients with painful DPN was noninferior to ALA in terms of reducing pain intensity measured by the VAS over 12 weeks.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; gamma-Linolenic Acid; Humans; Male; Middle Aged; Pain Measurement; Thioctic Acid

Impaired conversion of linoleic acid to gamma-linolenic acid (GLA) has been demonstrated in animal diabetes and inferred from blood fatty acid profiles in human diabetes. This impairment could theoretically lead to defective nerve function because metabolites of GLA are known to be important in nerve membrane structure, nerve blood flow, and nerve conduction. Administration of GLA corrects the impaired nerve function in animal models of diabetes. Two multicenter, randomized, placebo-controlled trials in humans with diabetic neuropathy have shown significant benefits of GLA as compared with placebo in neurophysiological parameters, thermal thresholds, and clinical sensory evaluations. Further work is needed to define the place of this therapeutic approach and its interactions with other treatment modalities.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Fatty Acids, Essential; gamma-Linolenic Acid; Humans; Lipids; Rats

To compare the effects of placebo and GLA on the course of mild diabetic neuropathy over 1 yr.. We entered 111 patients with mild diabetic neuropathy from seven centers into a randomized, double-blind, placebo-controlled parallel study of GLA at a dose of 480 mg/day. MNCV, SNAP, CMAP, hot and cold thresholds, sensation, tendon reflexes, and muscle strength were assessed by standard tests in upper and lower limbs.. For all 16 parameters, the change over 1 yr in response to GLA was more favorable than the change with placebo, and for 13 parameters, the difference was statistically significant. Sex, age, and type of diabetes did not influence the result, but treatment was more effective in relatively well-controlled than in poorly-controlled diabetic patients.. GLA had a beneficial effect on the course of diabetic neuropathy.

Topics: Analysis of Variance; Anti-Inflammatory Agents, Non-Steroidal; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Female; gamma-Linolenic Acid; Humans; Linolenic Acids; Male; Middle Aged; Motor Neurons; Neural Conduction; Neurologic Examination; Neurons, Afferent; Reflex

Twenty-two patients with distal diabetic polyneuropathy confirmed both clinically and by objective nerve function studies, completed a double-blind, placebo-controlled study to assess the effect of dietary supplementation with gamma-linolenic acid on their neuropathy. Patients received either 360 mg gamma-linolenic acid (12 patients) or indistinguishable placebo capsules (10 patients) for 6 months. All patients were assessed at the beginning and end of the study period by neuropathy symptom and sign scoring, motor and sensory nerve conduction studies, and thermal threshold measurements. When compared with the placebo group, patients on gamma-linolenic acid showed statistically significant improvement in neuropathy symptom scores (p less than 0.001), median nerve motor conduction velocity (p less than 0.01) and compound muscle action potential amplitude (p less than 0.01), peroneal nerve motor conduction velocity (p less than 0.05) and compound muscle action potential amplitude (p less than 0.05), median (p less than 0.01) and sural (p less than 0.001) sensory nerve action potential amplitude and ankle heat threshold (p less than 0.001) and cold threshold (p less than 0.01) values. gamma-Linolenic acid therapy might have a useful role in the prevention and treatment of distal diabetic polyneuropathy.

Topics: Action Potentials; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Double-Blind Method; Fatty Acids, Essential; Female; Follow-Up Studies; gamma-Linolenic Acid; Humans; Linoleic Acids; Linolenic Acids; Male; Middle Aged; Neural Conduction; Neurons, Afferent; Oenothera biennis; Phospholipids; Placebos; Plant Oils; Random Allocation; Reference Values

Topics: Clinical Trials as Topic; Diabetic Neuropathies; Double-Blind Method; gamma-Linolenic Acid; Humans; Linolenic Acids; Random Allocation

Diabetic polyneuropathy is a serious complication of diabetes mellitus and the most frequent neuropathy worldwide.. This study was designed to investigate the possible beneficial effects of evening primrose oil (EPO) on histopathological changes of sciatic nerves in streptozotocin-induced diabetic rats.. The rats were randomly allotted into three experimental groups: A (control), B (diabetic untreated), and C (diabetic treated with EPO); each group contained 10 animals. Groups B and C received streptozotocin (STZ) to induce diabetes. The rats in group C were given EPO for 2 weeks after 6 weeks of STZ injection. Blood and tissue samples were obtained for biochemical and histopathological investigation.. STZ-treated diabetic rats showed reduction of the size of islets of Langerhans, fatty degeneration in the pancreatic acini with dilation, irregularity, and increased thickness of blood vessels. Electron micrography of sciatic nerves of diabetic rats showed multiple vaculations and partial separation of myelinated nerve fibers with axonal atrophy, endoneural edema, and increased collagen fibers. Compared with diabetic rats, EPO induced partial recovery from diabetes-induced pancreatic and nerve damage.. Histologic evaluation of the tissues in diabetic animals treated with EPO showed fewer morphologic alterations with significant decrease of myelin breakdown. Furthermore, the ultrastructural features of axons showed partial improvement. It is believed that further preclinical research into the utility of EPO may indicate its usefulness as a potential treatment on peripheral neuropathy in STZ-induced diabetic rats.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; gamma-Linolenic Acid; Linoleic Acids; Male; Microscopy, Electron; Oenothera biennis; Plant Oils; Rats; Sciatic Nerve

A deficiency in essential fatty acid metabolism has been reported in diabetes. Nutritional supplementations with (n-6) or (n-3) PUFA have differential efficiency on parameters of diabetic neuropathy, including nerve conduction velocity (NCV) and nerve blood flow (NBF). The aim of this study was to compare the neuroprotective effects of gamma-linolenic acid (GLA)-lipoic acid (LA) conjugate (GLA-LA) and docosahexaenoic acid (DHA)-enriched phospholipids (PL) supplementations on NCV and NBF. Streptozotocin-induced diabetic (D) and control (C) rats were supplemented for 8 wk with either DHA-enriched PL at a dose of 30 mg.kg-1.d-1 (DDHA and CDHA) or with corn oil enriched with GLA-LA at a dose of 30 mg.kg-1.d-1 (DGLA and CGLA). Moreover, a C and D group received no supplementation. After 8 wk, NCV (-30%) and NBF (-50%) were lower in the D group than in the C group. Supplementation with GLA-LA totally prevented the decrease in NCV and NBF in the DGLA group, in which values did not differ from group C. Supplementation with DHA only partially prevented the decrease in NCV in the DDHA group, in which value was different from groups C and D and did not affect NBF. We conclude that at the low doses used, supplementation with GLA-LA is more effective than supplementation with DHA in preventing experimental diabetic neuropathy. The difference could be due in part to an antioxidant protective effect of LA on GLA.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Docosahexaenoic Acids; Dose-Response Relationship, Drug; gamma-Linolenic Acid; Male; Neural Conduction; Phospholipids; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Thioctic Acid

Treatment with alpha-lipoic acid (LA) or evening primrose oil (EPO), individually, fails to prevent diabetes-induced changes in enteric nerves. Since synergy between these treatments has been reported, the aim was to investigate the effectiveness of combined LA/EPO treatment. LA and EPO were administered in the diet (approximately 80 and 200 mg/kg/day, respectively) to control and diabetic (induced by streptozotocin, 65 mg/kg, i.p.) rats. For prevention, treatment started after 1 week and lasted 7 weeks. For reversal, treatment lasted 4 weeks and was initiated after 8 weeks. Nerves supplying the ileum containing vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and noradrenaline (NA) were examined immunohistochemically or biochemically. Diabetes caused a significant increase in VIP-containing cell bodies (p<0.001), decrease in NA content (p<0.01) and loss of CGRP-immunoreactivity. LA/EPO treatment totally prevented diabetes-induced changes in VIP (p<0.001) and CGRP and partially reversed (p<0.05) these changes once they had been allowed to develop. In contrast, treatment had no effect on diabetes-induced changes in NA-containing nerves. Therefore, LA and EPO are only effective at treating diabetes-induced changes in some enteric nerves when administered in combination. However, diabetes-induced changes in NA-containing nerves are resistant to treatment.

Topics: Animals; Calcitonin Gene-Related Peptide; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Drug Synergism; Drug Therapy, Combination; Fatty Acids, Essential; gamma-Linolenic Acid; Ileum; Immunohistochemistry; Linoleic Acids; Male; Myenteric Plexus; Neuroprotective Agents; Norepinephrine; Oenothera biennis; Plant Oils; Rats; Rats, Wistar; Thioctic Acid; Vasoactive Intestinal Peptide

The aim of the study was to investigate antioxidant (alpha-lipoic acid [LA]) and gamma-linolenic acid treatments in the prevention of changes in autonomic nerves induced in streptozotocin-diabetic rats. Autonomic nerves supplying the heart, penis, and gut were examined using immunohistochemical and biochemical techniques. LA and gamma-linolenic acid (present in evening primrose oil [EPO]) were administered as dietary supplements ( approximately 80 and 200 mg. kg(-1). day(-1), respectively). LA treatment prevented the diabetes-induced decrease of norepinephrine (NA) in the heart and of type I nitric oxide synthase (NOS-I) expression in erectile tissue of the penis but failed to prevent diabetes-induced changes in NA-, vasoactive intestinal polypeptide-, or calcitonin gene-related peptide-containing nerves supplying the ileum. LA partially prevented and EPO totally prevented the increase in NOS-I activity induced by diabetes in the ileum. EPO treatment failed to prevent any other diabetes-induced changes in the heart, penis, or ileum. These results demonstrate that, whereas LA treatment is more effective than EPO in preventing diabetes-induced changes in autonomic nerves, the effectiveness of LA treatment varies with the target organ studied. Diabetes-induced changes in nerves supplying the ileum are more resistant to treatment than those of the heart and penis.

Topics: Animals; Antioxidants; Autonomic Nervous System Diseases; Autonomic Pathways; Calcitonin Gene-Related Peptide; Diabetic Neuropathies; gamma-Linolenic Acid; Heart Conduction System; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Norepinephrine; Penis; Rats; Rats, Wistar; Thioctic Acid; Vasoactive Intestinal Peptide

This study compared the effects of streptozotocin-induced diabetes in rats with those of two pro-oxidant interventions; a diet deficient in vitamin E and treatment with primaquine.. Measurements were made by the classic motor and sensory conduction velocity deficits and by indicators of the breakdown of small fibre phenotype i.e., sciatic nerve content of nerve growth factor and the neuropeptides, substance P and neuropeptide Y.. As with diabetes, the pro-oxidant interventions decreased conduction velocities (though the effect of vitamin E deficiency was not significant), the sciatic nerve content of nerve growth factor and the neuropeptides (all percentages refer to the mean value for the appropriate control groups). In diabetes, nerve growth factor was depleted to 50% in the control rats (p < 0.05); oxidative stress depleted nerve growth factor to 64% (primaquine; p < 0.05) and 81% (vitamin E deficient; not significant) of controls. Substance P was depleted to 51% in the control rats (p < 0.01) with depletions to 74% and 72% (both p < 0.01) by oxidative stress; equivalent depletions for neuropeptide Y were 38% controls in diabetes (p < 0.001) and 67% (primaquine; p < 0.001) and 74% (vitamin E deficient; p < 0.05) for oxidative stress.. The relative magnitudes of these changes suggest an effect in diabetes of oxidative stress, coupled with some other cellular event(s). This is supported by the effects of a diester of gamma-linolenic acid and alpha-lipoic acid, which completely prevented the effects on the pro-oxidant interventions on conduction velocity, nerve growth factor and neuropeptide contents, but was only partially preventative in diabetes.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; gamma-Linolenic Acid; Male; Nerve Growth Factor; Neural Conduction; Neurons; Neuropeptide Y; Oxidative Stress; Phenotype; Primaquine; Rats; Rats, Wistar; Sciatic Nerve; Substance P; Thioctic Acid; Vitamin E

The influence of diets containing gamma-linolenic acid (GLA; 18:3n-6) on sciatic nerve conduction velocity (NCV) was determined in diabetic rats. NCV was lower in diabetic rats fed diets supplemented with olive oil or sunflower seed oil than in nondiabetic rats; rats supplemented with GLA during a 5-wk diabetic period, however, did not exhibit significantly lower NCV. The mean proportion of the phospholipid fatty acid linoleic acid (18:2n-6) was higher in the sciatic nerves of diabetic rats than in the nondiabetic groups irrespective of dietary lipid treatment. Additionally, the proportion of linoleic acid was higher in the diabetic rats fed sunflower oil than in all other groups. Dietary GLA supplementation did not significantly influence the fatty acid composition of nerve membrane phospholipids and there was no obvious correlation between the fatty acid composition of nerve membrane phospholipids and NCV. The content of fructose and glucose in sciatic nerves was higher, whereas that of myo-inositol was lower, in diabetic rats than in nondiabetic rats; however, this was not significantly influenced by dietary GLA. GLA administration did not significantly influence Na(+)-K(+)-exchanging ATPase or ouabain binding activity in sciatic nerve preparations, both of which remained nonsignificantly different in the diabetic and nondiabetic groups. The results suggest that dietary GLA can prevent the deficit in NCV induced by diabetes and that this effect is independent of the nerve phospholipid fatty acid profile, sugar and polyol content, Na(+)-K(+)-exchanging ATPase activity, and ouabain binding. GLA may prevent the deficit in NCV indirectly, possibly by its role as a precursor of vasodilatory prostaglandins. These results confirm that GLA is the active component of evening primrose oil.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Centrifugation, Density Gradient; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electrophysiology; Fatty Acids, Essential; Fatty Acids, Unsaturated; gamma-Linolenic Acid; Glucose; Linoleic Acids; Male; Neural Conduction; Oenothera biennis; Ouabain; Phospholipids; Plant Oils; Rats; Rats, Wistar; Sciatic Nerve; Sodium-Potassium-Exchanging ATPase; Streptozocin

Elevated oxidative stress and impaired n-6 essential fatty acid metabolism contribute to defective nerve conduction velocity (NCV) and perfusion in diabetic rats, which may be corrected by free radical scavenger and gamma-linolenic acid (GLA) treatments. Alpha-lipoic acid (LPA) has antioxidant actions and both LPA racemate (racLPA) and GLA treatments produced benefits in clinical neuropathy trials. The aims were to study LPA action on neurovascular function in diabetic rats and to investigate potential interactions for co-treatment with GLA and other essential fatty acids. After 6 weeks of diabetes, 2 weeks of racLPA treatment corrected 20% sciatic motor and 14% saphenous sensory NCV deficits. The ED50 for motor NCV restoration was approximately 38 mg kg(-1) day(-1). racLPA also corrected a 49% diabetic deficit in sciatic endoneurial blood flow. R and S-LPA enantiomers were equipotent in correcting NCV and blood flow deficits. Treatment of diabetic rats with low doses (20 mg kg(-1) day(-1)) of racLPA and GLA, while having modest effects on their own, showed evidence of marked synergistic action in joint treatment, completely correcting motor NCV and blood flow deficits. This was also noted for the novel compound, SOC0150, which contains equimolar proportions of LPA and GLA (ED50 9.3 mg kg(-1) day(-1), containing 3.5 mg LPA). NCV effects also showed marked synergism when racLPA:GLA ratios were varied over a 1:3-3:1 range. In contrast, a compound containing LPA and the n-3 component, docosahexaenoic acid, showed similar activity to LPA alone. Thus, LPA-GLA interactions yield drug combinations and compounds with an order of magnitude increase in efficacy against experimental diabetic neuropathy and are worthy of consideration for clinical trials.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Neuropathies; gamma-Linolenic Acid; Male; Neural Conduction; Rats; Rats, Sprague-Dawley; Saphenous Vein; Sciatic Nerve; Thioctic Acid

Untreated streptozotocin-diabetic (7 weeks duration) rats showed reductions (all p < 0.01; percentages in brackets) in motor and sensory nerve conduction velocity (MNCV; 14%, SNCV; 17%) and in sciatic nerve contents of nerve growth factor (NGF; 57%), substance P (SP; 53%) and neuropeptide Y (NPY; 39%). Treatment with a gamma-linolenic acid-alpha-lipoic acid conjugate (GLA-LA; 35 mg x day(-1) x rat(-1)) attenuated (p < 0.05) these reductions to MNCV (8%), SNCV (5%), NGF (19%), SP (23%), NPY (20%), such that the values in GLA-LA-treated diabetic rats did not differ significantly from those of control non-diabetic animals. Treatment with alpha-lipoic acid alone at 100 mg/kg i.p. was without effect on these variables except for NGF (33% reduction, p < 0.05) and treatment with the antioxidant, butylated hydroxytoluene (1.5% dietary supplement) did not affect any deficits. These data show that GLA-LA is effective in improving both electrophysiological and neurochemical correlates of experimental diabetic neuropathy.

Topics: Animals; Antioxidants; Butylated Hydroxytoluene; Diabetes Mellitus, Experimental; Diabetic Neuropathies; gamma-Linolenic Acid; Male; Motor Neurons; Nerve Growth Factors; Neural Conduction; Neurons, Afferent; Neuropeptide Y; Rats; Rats, Wistar; Sciatic Nerve; Substance P; Thioctic Acid

A reduction in nerve conduction velocity and an increase in resistance to ischemic conduction failure are early signs of neural dysfunction in both diabetic patients and animal models of diabetes. The effect of Bimoclomol (BRLP-42), a drug under clinical development for the treatment of diabetic complications, on experimental peripheral neuropathy was examined in rats made diabetic by injection of streptozotocin. Daily oral doses of Bimoclomol (10 or 20 mg/kg) or control dose of gamma-linolenic acid (260 mg/kg), an agent with known neuropathy-improving effects, were administered for 3 months. Treatments began 1 day after diabetes induction to assess the prophylactic efficacy of Bimoclomol. Neuropathy was evaluated electrophysiologically by measuring motor and sensory nerve conduction velocities and resistance to ischemic conduction failure of sciatic nerve in vivo. Bimoclomol significantly reduced nerve conduction slowing and retarded the typical elevated ischaemic resistance due to streptozotocin-induced neuropathy, suggesting that the drug might be a useful treatment for diabetic peripheral neuropathies.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electromyography; gamma-Linolenic Acid; Ischemia; Male; Neural Conduction; Piperazines; Pyridines; Rats; Rats, Wistar; Sciatic Nerve; Vascular Resistance; Vasodilator Agents

Impaired omega-6 essential fatty acid metabolism and exaggerated polyol pathway flux contribute to the neurovascular abnormalities in streptozotocin-diabetic rats. The potential interactions between these mechanisms were examined by comparing the effects of threshold doses of aldose reductase inhibitors and evening primrose oil, alone and in combination, on neurovascular deficits. In addition, high-dose aldose reductase inhibitor and evening primrose oil treatment effects were challenged by co-treatment with the cyclo-oxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Eight weeks of diabetes caused an 18.9% reduction in sciatic motor conduction velocity (p < 0.001). This was only modestly ameliorated by a 0.1% dietary supplement of evening primrose oil or the aldose reductase inhibitors ZD5522 (0.25 mg.kg-1.day-1 and WAY121 509 (0.2 mg.kg-1.day-1 for the final 2 weeks. However, joint treatment with primrose oil and ZD5522 or WAY121 509 caused marked 71.5 and 82.4% corrections, respectively, of the conduction deficit. Sciatic nutritive blood flow was 43.1% reduced by diabetes (p < 0.001) and this was corrected by 67.8% with joint ZD5522 and primrose oil treatment (p < 0.001). High-dose WAY121 509 (10 mg. kg-1.day-1 and primrose oil (10% dietary supplement) prevented sciatic conduction velocity and nutritive blood flow deficits in 1-month diabetic rats (p < 0.001). However, these effects were abolished by flurbiprofen (5 mg.kg(-1).day-1 and NG-nitro-L-arginine (10 mg.kg-1.day-1) co-treatment (p < 0.001). Thus, the data provide evidence for synergistic interactions between polyol pathway/nitric oxide and essential fatty acid/cyclo-oxygenase systems in the control of neurovascular function in diabetic rats, from which a potential therapeutic advantage could be derived.

Topics: Acetanilides; Aldehyde Reductase; Analysis of Variance; Animals; Arginine; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dietary Fats, Unsaturated; Enzyme Inhibitors; Erythropoietin; Fatty Acids, Essential; Flurbiprofen; Fructose; gamma-Linolenic Acid; Inositol; Linoleic Acids; Male; Neural Conduction; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oenothera biennis; Plant Oils; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Regression Analysis; Sciatic Nerve; Sorbitol; Sulfones

Essential fatty acid metabolism is impaired by diabetes mellitus and gamma-linolenic acid rich treatments such as evening primrose oil correct deficits in nerve conduction and endoneurial blood flow in diabetic rats. Other mechanistically unrelated treatments, such as antioxidants and aldose reductase inhibitors have a similar effect and there may be positive interactions with multiple treatments. Our aim was to compare the efficacy of a novel essential fatty acid derivative, ascorbyl gamma-linolenic acid, with that of gamma-linolenic acid in correcting diabetic neurovascular deficits. Eight weeks of diabetes caused 20.4 and 48.2% reductions in sciatic motor conduction velocity and nutritive endoneurial blood flow, respectively. Treatment was given for the last 2 weeks with gamma-linolenic acid (100 mg.kg-1.day-1) either in pure form or as ascorbyl gamma-linolenic acid, an equivalent dose of ascorbate (21 mg.kg-1.day-1) or jointly with ascorbate and gamma-linolenic acid. Conduction velocity was corrected by 39.8, 87.4, 13.2 and 66.8% with gamma-linolenic acid, ascorbyl gamma-linolenic acid, ascorbate and gamma-linolenic acid plus ascorbate, respectively. Corresponding ameliorations of the nutritive blood flow deficit were 44.0, 87.4, 87.4, 13.2 and 65.7%. For the gamma-linolenic acid plus ascorbate combinatin, and especially for ascorbyl gamma-linolenic acid, the magnitude of correction for conduction velocity and blood flow was greater than expected for simple addition of ascorbate and gamma-linolenic acid, indicating a synergistic interaction. Thus, with an efficacy 40 times that of evening primrose oil in rats, ascorbyl gamma-linolenic acid may be a suitable candidate for clinical trials of diabetic neuropathy.

Topics: Animals; Ascorbic Acid; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Neuropathies; gamma-Linolenic Acid; Male; Motor Neurons; Neural Conduction; Rats; Rats, Sprague-Dawley; Sciatic Nerve

The role of cyclo-oxygenase and or its substrate(s) on the neuroactivity of evening primrose oil was investigated on the basis that a blockade of cyclo-oxygenase activity using aspirin would inhibit neuroactivity of primrose oil if this effect was mediated by prostanoids. Streptozotocin diabetic rats and controls were all given large doses of aspirin, but only subgroups of them received primrose oil. Saphenous sensory A- and C-fibre, and sciatic motor conduction velocities were measured to assess neuroactivity of primrose oil. Aspirin enhanced the neuroactivity of primrose oil thus indicating that prostanoids are unlikely to mediate this neuroactivity, but also suggesting that substrates of cyclo-oxygenase are neuroactive. It is likely that cyclo-oxygenase antagonises neuroactivity of primrose oil by competing with the process for substrates. Thickly myelinated sensory A-fibres were most affected by primrose oil suggesting that the predominant sensory symptoms in diabetic neuropathy could be due to the sensitivity of sensory nerves to the metabolic aberration in diabetes. Normal nerve function is probably preserved by cyclo-oxygenase during an influx of neuroactive fatty acids from the gut, since inhibition of the enzyme rendered non-diabetic nerves vulnerable to dietary primrose oil.

Topics: Animals; Aspirin; Blood Glucose; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Fatty Acids, Essential; Female; gamma-Linolenic Acid; Linoleic Acids; Nerve Fibers; Nerve Fibers, Myelinated; Neural Conduction; Neurons, Afferent; Oenothera biennis; Plant Oils; Prostaglandin Antagonists; Prostaglandin Endoperoxides; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Rats, Sprague-Dawley

The interval between oral intake of evening primrose oil and its effect in peripheral nerves of rats was studied 35 days after induction of streptozotocin diabetes. Myelinated and unmyelinated sensory nerve conduction velocities were measured in the saphenous nerve and motor nerve conduction velocity was measured in the sciatic nerve to assess neuroactivity of primrose oil. The severity of diabetes was assessed by levels of HbA1 and plasma glucose. The diabetic state remained constant between 35 and 70 days post induction. Plasma glucose increased by 133%, and HbA1 by 122% in diabetic rats. Myelinated sensory and motor nerves had conduction deficits of 13 and 16%, respectively, 35 days post induction. Unmyelinated nerves had no conduction deficit until 45 days post induction. Primrose oil did not affect nerve conduction velocity in the first 12 h of its administration, but significantly increased it 24 h later (p < 0.001). Daily treatment with primrose oil caused oscillation of nerve conduction velocity in diabetic rats needing 10 days to stabilise. The latency suggests that neuroactivity of primrose oil may be mediated by its metabolic products synthesised in the body, and not by ready made constituents of the oil.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Electrophysiology; Fatty Acids, Essential; Feedback; Female; gamma-Linolenic Acid; Linoleic Acids; Nerve Fibers; Nerve Fibers, Myelinated; Neural Conduction; Oenothera biennis; Peripheral Nerves; Plant Oils; Rats; Rats, Sprague-Dawley; Reaction Time

Evening primrose oil (EPO) is rich in the omega-6 essential fatty acid component, gamma-linolenic acid. The aim of the investigation was to determine whether EPO treatment prevented a reduction in sciatic nerve perfusion and oxygenation in streptozotocin-diabetic rats. Rats were treated from diabetes induction with 10 g EPO kg-1 day-1. Sciatic blood flow was measured by microelectrode polarography and hydrogen clearance. Diabetes caused 47.7% +/- 3.4% (P < 0.001) and 58.8% +/- 4.8% (P < 0.001) reduction in the nutritive (capillary) and the non-nutritive (large vessel) components of endoneurial blood flow, respectively, which were prevented by EPO. Treatment had no significant effect on nutritive flow in non-diabetic rats; however, the rate of non-nutritive flow increased by 97.7% +/- 38.9% (P < 0.01). Sciatic endoneurial oxygen tension was measured by microelectrode polarography. Diabetes resulted in a 44.7% +/- 3.4% reduction in mean oxygen tension (P < 0.001), which was largely (82.3% +/- 10.2%) prevented by EPO treatment (P < 0.001). Thus, EPO prevents impairment of blood flow and endoneurial oxygenation in experimental diabetes. It is likely that this neurovascular action accounts for the beneficial effects of treatment on nerve function in diabetic rats and patients.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Fatty Acids, Essential; gamma-Linolenic Acid; Linoleic Acids; Male; Microcirculation; Oenothera biennis; Oxygen; Peripheral Nerves; Plant Oils; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Sciatic Nerve

Essential fatty acid metabolism is impaired by diabetes mellitus and this may be important in the aetiology of peripheral nerve dysfunction. The effects of gamma-linolenic acid (omega-6) and fish oil (omega-3) alone, and in combination, on nerve function and capillarization were examined in 2-month streptozotocin-diabetic rats. Diabetes resulted in approximately 15% and 23% decreases in saphenous sensory and sciatic motor nerve conduction velocities, respectively (p < 0.001). Motor and sensory conduction velocities were in the non-diabetic range after both preventive and reversal omega-6 treatment of diabetic rats (p < 0.001). No significant changes occurred in omega-6 treated non-diabetic rats. Preventive omega-3 treatment was largely ineffective. Reversal treatment with a combination of omega-6 and omega-3 fatty acids was marginally effective and improved motor (p < 0.05), but not sensory conduction velocity. In vitro measurement of sciatic nerve resistance to hypoxic conduction failure in diabetic rats revealed a 56% increase in the time taken for the compound action potential amplitude to be reduced by 80% (p < 0.01) compared to non-diabetic rats. This was partially prevented by omega-6 treatment (29% increase, p < 0.01). Reversal omega-6 treatment had a lesser effect (37% increase, p < 0.05 compared to untreated diabetic rats). omega-3 treatment had no significant effect on conduction failure time. Sciatic endoneurial capillary density increased by 11% with preventive omega-6 treatment (p < 0.05), but was unaffected by reversal omega-6 and by omega-3 treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Capillaries; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Fatty Acids, Omega-3; Fish Oils; gamma-Linolenic Acid; Hypoxia; Male; Motor Neurons; Muscle, Smooth, Vascular; Neural Conduction; Neurons, Afferent; Peripheral Nerves; Rats; Rats, Sprague-Dawley; Reference Values; Sciatic Nerve; Time Factors

Topics: Diabetic Neuropathies; Drug Contamination; gamma-Linolenic Acid; Humans; Linoleic Acid; Linoleic Acids

Early effects of insulin and essential fatty acids on nerve conduction were studied. Insulin-dependent diabetes was induced in rats using streptozocin (65 mg/kg, i.p.); control rats were treated with buffer. Five weeks later, diabetic rats were divided into 5 groups. Two groups were given oral essential fatty acids (75% linoleic and 9% gamma-linolenic acids) for a further 3 and 5 days, respectively. Two other groups received subcutaneous insulin for a further 3 or 5 days. A group of diabetic rats were left without further treatment. Motor nerve conduction velocity was measured terminally in all rats by stimulating the sciatic nerve and recording EMGs in the gastrocnemius muscle under urethane anaesthesia. Sensory nerve conduction velocity was measured by stimulating and recording from the saphenous nerve trunk. Diabetic rats had significantly slowed motor and sensory nerve conduction velocities after 5 weeks (16.7%, P less than 0.001). Three days treatment with either insulin or fatty acids corrected the slowed motor nerve conduction velocity to a normal level. Conduction velocity in myelinated sensory nerves was still 10% slower in diabetic rats treated with insulin for 3 days (P less than 0.01). It was above the control level by 11% in diabetic rats treated with fatty acids for the same period (P less than 0.01). Conduction velocities in both sensory and motor nerves were normal in diabetic rats treated with either insulin or fatty acids for 5 days. It was concluded that both insulin and essential fatty acids had early effects on nerve conduction in diabetic rats. The speed of their actions, and the magnitudes of responses were different in sensory and motor nerves.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Female; gamma-Linolenic Acid; Insulin; Linoleic Acid; Linoleic Acids; Linolenic Acids; Motor Neurons; Neural Conduction; Neurons, Afferent; Rats; Rats, Inbred Strains; Streptozocin

Effects of essential fatty acids on nerve conduction, hypoxic resistance, skeletal muscle contractile properties, and capillary density were examined in streptozocin-induced diabetic rats. Nondiabetic and diabetic controls and three diabetic groups treated with 10% supplements of corn oil, evening primrose oil (Efamol), or a mixture of 80% evening primrose oil and 20% fish oil (Efamol Marine) for 2 mo were used. Efamol and Efamol Marine increased plasma gamma-linolenic acid levels, but arachidonic acid was elevated only with Efamol. Diabetes resulted in 15-29% reductions in sciatic motor and sensory saphenous nerve conduction velocity. Efamol prevented conduction deficits more effectively than Efamol Marine, and corn oil had no effect. In vitro measurement of sciatic nerve hypoxic resistance revealed a 49% increase in the time taken for action potential amplitude to decline by 50% with diabetes. Corn oil had no significant effect. With Efamol, hypoxic resistance was within the nondiabetic range. Efamol Marine produced intermediate results. Functional improvements may relate to enhanced vasa nervorum perfusion, because endoneurial capillary density increased by 22% with Efamol, angiogenesis perhaps resulting from eicosanoid production from arachidonic acid. Soleus muscle contractions were prolonged by diabetes. This was partially corrected by treatment, Efamol being most effective. Extensor digitorum longus muscle had reduced tetanic tension with diabetes, and this was prevented by all treatments. Soleus showed a modest increase in capillarization with Efamol, which may have contributed to reduced susceptibility to fatigue. The data suggest involvement of abnormal fatty acid metabolism in the etiology of diabetic neuropathy and myopathy.

Topics: Animals; Capillaries; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Fatty Acids, Essential; Fish Oils; Food, Fortified; gamma-Linolenic Acid; Linoleic Acids; Male; Muscle Contraction; Muscles; Neural Conduction; Oenothera biennis; Plant Oils; Rats; Rats, Inbred Strains; Reference Values; Regional Blood Flow; Sciatic Nerve

This study was designed to examine the effect of dietary supplementation with essential fatty acids (evening primrose oil--5% weight:weight added to the diet) on acute neurophysiological and neurochemical defects in streptozotocin-diabetic rats. Diabetic rats, which were not given evening primrose oil, showed highly significant elevations of nerve sorbitol and fructose combined with a depletion of nerve myo-inositol. In those animals there was also a 40% reduction (p less than 0.02) in the accumulation of axonally transported substance P-like immunoreactivity proximal to a 12 h sciatic nerve ligature together with reduced motor nerve conduction velocity (13% [p less than 0.001] and 20% [p less than 0.001] in two separate experiments). Treatment of other diabetic rats with evening primrose oil prevented completely the development of the motor nerve conduction velocity deficit without affecting sorbitol, fructose or myo-inositol levels or the deficit in axonal transport of substance P. In a second experiment, treatment of diabetic rats with evening primrose oil was associated with significant attenuation of the conduction velocity deficit, but not complete prevention.

Topics: Animals; Axonal Transport; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Fatty Acids, Essential; Fructose; gamma-Linolenic Acid; Glucose; Hypolipidemic Agents; Inositol; Linoleic Acids; Male; Motor Neurons; Neural Conduction; Oenothera biennis; Plant Oils; Rats; Rats, Inbred Strains; Reference Values; Sciatic Nerve; Sorbitol