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© 2007 The American Society for Nutrition J. Nutr. 137:368-372, February 2007

Nutrition and Disease

At Low Doses, a {gamma}-Linolenic Acid-Lipoic Acid Conjugate Is More Effective Than Docosahexaenoic Acid-Enriched Phospholipids in Preventing Neuropathy in Diabetic Rats1

Séverine Pitel2, Denis Raccah2, Alain Gerbi3, Gérard Pieroni3, Philippe Vague2 and Thierry C. Coste2,*

2 UPRES EA 2193, Aix-Marseille Université, Faculté de Médecine, IPHM-IFR 125, Marseille, F-13385 France; 3 INSERM U476, Nutrition Humaine et Lipides, Marseille, F-13385, France; INRA UMR 1260, Marseille, F-13385, France; and Aix-Marseille Université, Faculté de Médecine, IPHM-IFR 125, Marseille, F-13385 France

* To whom correspondence should be addressed. E-mail: thierry.coste{at}medecine.univ-mrs.fr.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
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.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Diabetes mellitus is a chronic metabolic disorder that leads to long-term complications affecting some tissues such as heart, kidney, retina, and peripheral nerves. Neuropathy is the most common complication among diabetic patients (1). Diabetic neuropathy harms the patient's quality of life by the occurrence of pains in the lower limbs and plantar ulcers. Though mechanisms of this complication have been the subject of extensive research during the last decades, primary treatment trials have not yet provided effective therapies. Physiopathology of diabetic neuropathy includes activation of the polyol pathway, increases in oxidative stress and advanced glycosylation end products, perturbation in neurotrophism, and abnormalities in essential fatty acids metabolism (2). Among these, particular interest has been focused on the abnormalities of essential fatty acids metabolism (3,4).

Mammals synthesize the long chain PUFA from linoleic acid [18:2(n-6)] and {alpha}-linolenic acid [18:3(n-3)], which are the 2 precursors of (n-6) and (n-3) fatty acids families provided by the diet. Specific enzymes, desaturases and elongases, are involved in this pathway, but the conversion of precursors to long chain PUFA is generally low in humans. Moreover, diabetes impairs the desaturases activities (5,6). Consequently, the decrease in bioavailability of PUFA affects the fatty acid composition of membrane phospholipids (PL)4 with repercussions on membrane protein functionality (7), eicosanoid production (8,9), and PPAR regulation (10,11). Many studies have described the supplementation of the diet of diabetic (D) rats with some PUFA to shunt these limiting steps (3,4). Among these supplementations, {gamma}-linolenic acid [(GLA) 18:3(n-6)] as well as GLA-lipoic acid (LA), arachidonic acid [(AA) 20:4(n-6)], and docosahexaenoic acid [(DHA) 22:6(n-3)] totally improve some parameters of diabetic neuropathy, including nerve conduction velocity (NCV) and nerve blood flow (NBF) (12–16).

In this study, we compared the neuroprotective effects of equivalent and small doses (30 mg · kg–1 · d–1) of GLA-LA, in the form of triglycerides, and DHA, in the form of PL, on NCV and NBF in D rats.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Animals. The study was conducted according to the guidelines of the French Ministry of Agriculture on the experimental use of laboratory animals with agreement number A 13823. The principles of laboratory animal care (NIH) were followed. Male Sprague-Dawley rats, 6–7 wk old (n = 66; Iffa Credo), started the study after acclimatization for 1 wk. Their body weight at the beginning of the study was 228 ± 12 g (mean ± SD) and they were randomly assigned to 6 age- and weight-matched groups (n = 11). For the 3 D groups, diabetes was induced by a single intravenous injection of streptozotocin (STZ; 65 mg/kg, Sigma) freshly dissolved in citrate sodium buffer (10 mmol/L, pH 5.5). Control (C) rats received an injection of buffer solution only. All D rats were maintained without insulin. Diabetes was checked 3 d after the STZ induction and on the last day of the study by the presence of hyperglycemia (>25 mmol/L) in blood samples collected from the tip of the tail (Reflolux; Boehringer Mannheim). The rats consumed a standard nonpurified rodent diet [A04, UAR, with the following composition (per kg): carbohydrates, 704 g, including starch, 380 g; proteins, 193 g; lipids, 30 g; and a vitamin and mineral mix as previously described] (17) and water ad libitum. Forced feeding for supplements was started on the day of STZ or buffer administration. The rats were intubated with a flexible stomach cannule and 2 groups, the C and D groups, were given water. The C group supplemented with DHA (CDHA) and D group supplemented with DHA (DDHA) were given DHA-enriched PL at a daily dose of 0.4 g · kg–1 · d–1, corresponding to 30 mg DHA · kg–1 · d–1 (15). The C group supplemented with GLA-LA (CGLA) and D group supplemented with GLA-LA (DGLA) were given corn oil enriched with GLA-LA at a daily dose of 30 mg/kg. The fatty acid compositions of the supplements are given in Table 1. All the supplements were administered daily at 0900 for 8 wk.


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  		TABLE 1 Fatty acid compositions of the diet and supplement intakes

 
    Plasma glucose and insulin concentrations. On the day of death, we took blood samples to determine plasma glucose and insulin concentrations. Blood plasma glucose was measured spectrophotometrically at a wavelength of 505 nm using standard assay kit (GOD-PAP, Sigma Chemical). Plasma insulin was determined using a rat/mouse insulin ELISA kit (EZRMI-13K, Linco Research).

    NCV measurement. The rats were anesthetized intraperitoneally using pentobarbital (50–100 mg/kg). After anesthesia, rat backs were shaved and motor NCV was recorded as previously described (14) in a temperature-controlled environment from the left sciatic tibial nerve by a modified noninvasive method adapted from Stevens et al. (18). Briefly, the rectal temperature was maintained at 37°C and the left sciatic nerve was stimulated proximally at the sciatic notch and distally at the knee via bipolar electrodes by a Neuromatic 2000C (Disa). The muscle action potential was recorded from the ankle by unipolar pin electrodes. NCV was calculated as the ratio of the distance in mm between the 2 sites of stimulation divided by the difference between proximal and distal latencies measured in ms, giving a value for NCV in m/s.

    NBF measurement. After NCV recording, NBF was assessed according to Yasuda et al. (19) using a laser Doppler flowmeter (Periflux, model 4001 Master, Perimed) as previously described (20). Briefly, the left sciatic nerve was exposed without bleeding and the probe was lowered at a right angle relative to the surface of perineurium 1 cm below the sciatic notch. NBF was then recorded continuously for at least 10 min and the values were averaged to 1 value.

    Tissue preparation. After physiological measurements, sciatic nerves from the spin to the peroneal bifurcation were dissected, rinsed in ice-cold saline solution, and frozen in liquid nitrogen after removal of adherent tissue. Samples were kept at –80°C until use. On the day of the homogenate preparation, sciatic nerve segments were measured, weighed, and rinsed in ice-cold saline solution. Sciatic nerves were cut into small pieces and then homogenized at 4°C in 2 mL of ice-cold saline (11 mmol/L Tris buffer, pH 7.4) with a motorized Potter homogenizer (model 94348, Heildoph) using 3 15-s bursts. The resulting homogenate was passed through a cellulose filter (600F4252, Fioroni) to remove impurities and divided into aliquots for fatty acid composition determination.

    Sciatic nerve fatty acid composition. Lipids were extracted from sciatic nerve homogenates with methanol and chloroform according to the method of Bligh and Dyer (21) that we modified using a sonicator. Fatty acid composition was determined after methylation with BF3-methanol (Sigma) according to Ohta et al. (22). The fatty acid methyl esters were analyzed by GC on a Perkin Elmer Autosystem XL using a fused silica capillary column (25 m x 0.22-mm i.d.), BPX 70, 0.25µm (SGE) equipped with a flame ionization detector and the Turbochrom software. Hydrogen was used as the carrier gas. The temperature program ranged from 160°C to 205°C with a temperature rise of 1°C/min. Fatty acids were identified by their retention times on the column with respect to appropriate standards.

    Statistical analysis. Results are presented as means ± SEM. A Kolmogorov-Smirnov test for normality and a Bartlett test for homogeneous variance were performed for each group. We analyzed all the data using a nonparametric Kruskal-Wallis test and differences between groups were identified using the Mann-Whitney U test. P-values of <0.05 were considered significant. Regressions were considered significant for P-values of <0.05; r and P were calculated with values from all rats in each group. All analyses were done using the STATVIEW software (Abacus Concepts) on a Macintosh PowerBook (Apple Computer).


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Metabolic characteristics. In D rats, the plasma glucose concentrations were ~350% greater than those of C rats (P < 0.0001, Table 2). In C rats, the DHA-enriched PL supplementation did not affect body weight, whereas the GLA-LA supplementation decreased body weight (P < 0.0001). As expected, body weight gain and plasma insulin were much lower in D groups than in C groups (P < 0.0001) and food intake was greater in all groups of D rats due to the diabetes-induced hyperphagia (P = 0.001).


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  		TABLE 2 Body weight, food intake, and plasma glucose and insulin concentrations after 8 wk in unsupplemented and GLA-LA-or DHA-supplemented C and D rats1

 
    NCV measurement. After 8 wk, sciatic NCV was 30% less in group D than in group C (P < 0.0001, Fig. 1). This deficit was completely prevented by supplementation with 30 mg/kg of GLA-LA; the DGLA group did not differ from the C group. DHA supplementation partially normalized NCV; the velocity in the DDHA group was greater than in group D but still less than in group C (P = 0.001). Moreover, GLA-LA supplementation produced an increase in C rats' NCV. Indeed, the NCV value for the CGLA group was greater than C and CDHA group values (P < 0.01).


Figure 1
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  		Figure 1  NCV in C and D Sprague-Dawley rats that were unsupplemented or supplemented with DHA or GLA-LA for 8 wk. Values are means ± SEM, n = 11. Means without a common letter differ, P < 0.05.

 
    NBF measurement. As observed with NCV, sciatic NBF was decreased ~50% in group D when compared with group C after 8 wk (P < 0.0001, Fig. 2). This decrease was completely prevented by supplementation with 30 mg/kg of GLA-LA; the DGLA group did not differ from the C group (P < 0.0001). The supplementation with DHA had no effect on NBF. Contrary to the NCV, the supplementations did not have any beneficial effect on NBF in C rats.


Figure 2
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  		Figure 2  NBF in C and D Sprague-Dawley rats that were unsupplemented or supplemented with DHA or GLA-LA for 8 wk. Values are means ± SEM, n = 11. Means without a common letter differ, P < 0.05.

 
    Fatty acid composition of sciatic nerve. Diabetes induced a decrease of the DHA:AA ratio in the D group (P < 0.003, Table 3). The supplementations with DHA or GLA-LA prevented this decrease in DDHA and DGLA groups. The different groups presented small variations in their SFA and monosaturated fatty acid (MUFA) compositions. A decrease in PUFA levels was observed in the CDHA and DDHA groups when compared with C, D, CGLA, and DGLA groups (P < 0.005), whereas (n-6) fatty acid levels were decreased in only the CDHA group when compared with C and CGLA groups (P < 0.001). The supplementation with GLA-LA increased the (n-3) fatty acid levels in CGLA and DGLA groups when compared with C, CDHA, and DDHA groups. Regarding the (n-6):(n-3) ratio, there were no significant differences between all groups.


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  		TABLE 3 Fatty acid composition of sciatic nerve from C and D Sprague-Dawley rats fed with DHA or GLA-LA supplementation1

 
    Relation between NCV and other parameters. NCV was strongly correlated with NBF (r = 0.61, P < 0.0001). Regarding sciatic nerve fatty acid composition, there were correlations with only DHA (r = 0.26, P = 0.0063) and the DHA:AA ratio (r = 0.34, P = 0.0003).


   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
This study demonstrates a neuroprotective effect of a low dose of GLA-LA (30 mg · kg–1 · d–1) in rat diabetic neuropathy. Indeed, we found a beneficial effect of GLA-LA on 2 altered physiological markers of diabetic neuropathy, NCV and NBF. Furthermore, we showed that DHA-enriched PL (30 mg · kg–1 · d–1) partially prevented the deficit in sciatic NCV in D rats.

In experimental diabetic neuropathy, dramatic decreases in NCV and NBF have been widely reported (2,14,23,24). The impairment of (n-6) and (n-3) essential fatty acid metabolism is important for explaining these defects in nerve physiology. Diabetes impairs essential fatty acid metabolism by decreasing activities of desaturases, and as a result, AA and DHA levels are reduced in membrane PL of several tissues, including RBC and sciatic nerve, in patients with type 1 diabetes and in D rats (25–27). Membrane fatty acid composition seems to be important, because a positive correlation has already been shown between DHA level in sciatic nerve membranes and NCV in rats (16). Modifications in membrane fatty acid compositions induce changes in membrane properties, which modify the activity of transmembrane enzymes, such as the Na/K-ATPase, involved in the propagation of nerve impulses. In a previous study, our group showed a positive correlation between the Na/K-ATPase activity in sciatic nerve and NCV (20). Therefore, alterations in membrane fatty acid compositions can affect the functionality of some tissues in diabetes and explain in part the development of degenerative complications.

We found a significant impairment in the NCV in the D group after 8 wk of diabetes, in agreement with the literature (3). In this study, a daily dose of 30 mg/kg of DHA partially prevented the deficit in NCV induced by diabetes. In another study (16), we showed that a daily dose of 60 mg/kg of DHA totally prevented this deficit. The dose we used here was not sufficient to totally prevent the deficit in NCV. Hounsom et al. (13) previously showed that a daily dose of ~100 mg/kg of GLA-LA totally prevented the decrease of NCV in D rats. We showed that the deficit in sciatic NCV was completely prevented by a smaller supplementation with 30 mg · kg–1 · d–1 of GLA-LA. Our results demonstrate that at the dose used (30 mg/kg), GLA-LA is more effective than DHA in preventing the NCV deficit in D rats. However, the dose of 30 mg · kg–1 · d–1 of DHA used in this study was as effective as the dose of 150 mg · kg–1 · d–1 of combined DHA and eicosapentaenoic acid used by Gerbi et al. (28,29) on the NCV deficit induced by diabetes. One could hypothesize that the better efficiency of the GLA-LA compared with DHA observed in this study can result from the presence of LA, an antioxidant that can enhance the effect of GLA. Indeed, small doses of GLA alone only partially restore the NCV deficit (30,31). Surprisingly, in the CGLA, the NCV is significantly higher than in the C group without supplementation. One could suppose that this phenomenon is due to a neuroprotective effect of the GLA-LA slowing the effects of age, attributable to its antioxidant value (32).

As expected, we also found a significant impairment in the NBF for the D group after 8 wk of diabetes. We showed that a dose of 30 mg · kg–1 · d–1 of DHA had no effect on this decrease, contrary to a previous study where a dose of 60 mg · kg–1 · d–1 totally prevented this decrease (16). So, this dose-dependent effect could be explained by a minimal requirement of DHA for the improvement of both NCV and NBF. Increasing amounts of DHA in RBC membrane PL improved the RBC deformability and could have positive repercussions on NBF (33). Contrary to DHA, a dose of 30 mg · kg–1 · d–1 of GLA-LA totally prevented the alteration of NBF in D rats. Many studies have already shown the effectiveness of GLA (3,31), LA (31,34), or GLA and LA (31) in combination to ameliorate blood flow in D rats. But to our knowledge, this is the first time the effectiveness of the conjugate GLA-LA compound for improving NBF was demonstrated, because the effect of GLA-LA on NBF was not investigated in the study of Hounsom et al. (13). As discussed with DHA, changes in RBC deformability could be a possible mechanism to explain these effects. Indeed, oral supplementation with GLA improved the poor deformability of RBC in hemodialysis patients, partly by inducing changes in the composition of fatty acids in plasma and RBC membranes (35). The positive effects of our supplementations on NBF could also be explained by a normalization of the diabetes-induced imbalance in eicosanoid synthesis.

The activation of PPAR by GLA-LA and DHA can be a possible common mechanism explaining their beneficial effects in D rats. Indeed, it has been demonstrated that PUFA, and in particular GLA and DHA, are natural ligands for PPAR and regulate the expression of many genes involved in different pathways (36–39). However, it seems that the effects cannot be mediated by an improvement in the symptoms of diabetes, because there is no change in the hyperglycemic and hypoinsulinemic state of D rats. But a PPAR-mediated increase in vascular tone could be responsible for the improvement of NBF, for example (37,39). Further studies are required to determine which PPAR isoforms and metabolic pathways may be involved in these effects.

We also showed, in the D group without supplementation, a diabetes-induced decrease of the sciatic nerve DHA:AA ratio that is prevented by the supplementations with DHA and GLA-LA. Our study confirms the fact that changes observed in fatty acid composition are always minor in nervous tissues (i.e. nerves and also the brain), likely as a result of the weak turnover of their constitutive fatty acids, due to the importance of specific fatty acid composition for the functionality of their membranes.

In conclusion, our study confirms that the desaturation deficit induced by diabetes may be bypassed by treatment with GLA-LA or DHA. Nevertheless, higher doses of DHA must be required to obtain an optimal and global neuroprotective effect in D rats. The better efficiency of the GLA-LA compared with DHA observed in this study is probably due to the presence of the antioxidant LA. Supplementations with PUFA seem to be an efficient, harmless, and affordable way to treat diabetic neuropathy.


   ACKNOWLEDGMENTS
 
Critical reading of the manuscript by Pr. Jean Lebacq is gratefully acknowledged. The authors thank David F. Horrobin for his indefectible support. GLA-LA conjugate was a gift from Scotia Pharmaceuticals (UK) and DHA-enriched egg PL were a gift from LMA Biotechnologie (Marseille, France). Presented in part at the 3rd Lipidomics Meeting, Marseille, France, May 10–12, 2006. Pitel S, Raccah D, Gerbi A, Pieroni G, Vague P, and Coste TC. Comparative neuroprotective effects of (n-6) and (n-3) fatty acids in experimental diabetic neuropathy.


   FOOTNOTES
 
1 Supported by Scotia Pharmaceuticals. Back

4 Abbreviations used: AA, arachidonic acid; C, control group; CDHA, control group supplemented with DHA; CGLA, control group supplemented with GLA-LA; D, diabetic group; DDHA, diabetic group supplemented with DHA; DGLA, diabetic group supplemented with GLA-LA; DHA, docosahexaenoic acid; GLA, {gamma}-linolenic acid; GLA-LA, {gamma}-linolenic acid-lipoic acid; LA, lipoic acid; MUFA, monounsaturated fatty acid; NBF, nerve blood flow; NCV, nerve conduction velocity; PL, phospholipid; STZ, streptozotocin. Back

Manuscript received 13 July 2006. Initial review completed 23 August 2006. Revision accepted 10 November 2006.


   LITERATURE CITED
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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