The reduced activity of the n-6 fatty acid biosynthetic pathway in the diabetic nerve could decrease the availability of AA for prostanoid formation and this could have deleterious consequences on the nerve vasculature, with resultant adverse effects on nerve function. The depletion of AA could be exacerbated by a heightened level of reactive oxygen species (ROS), which react readily with the double bonds of polyunsaturated fatty acids. A number of investigators have examined the effect of supplementing the diet of the diabetic animals with essential fatty acids, a treatment that might ameliorate the loss of AA. One approach has been to feed large amounts of LA and this has yielded variable results. In several studies, feeding a diet rich in corn oil or sunflower oil, which have a high content of LA but no GLA, failed to improve reduced nerve conduction velocity and nerve blood flow. In contrast, in one investigation corn oil administration was effective in preventing decreased nerve conduction velocity (Kuruvilla et al. 1998). In this study, the administration of LA elevated the proportion of ACMS in the nerve from normal animals, but it did not correct the fall in ACMS in diabetic nerve. Inclusion of LA in the diet was found to largely prevent diabetic cataract formation in rats, despite the persistence of high sorbitol levels in the lens (Hutton et al. 1976). Beneficial effects on diabetic complications in patients fed an increased proportion of calories in the diet as LA has been reported (Houtsmuller et al. 1982).
The presumption in these studies has been that the presence of massive amounts of LA tends to promote the diminished activity of the A6 desaturase and hence the overall activity of the n-6 pathway. It remains possible, however, that enhanced availability of LA might exert a beneficial action by formation of other LA metabolites with incompletely understood biological effects. Thus, 13-05) hydroxy-octadecadienoic acid, which is synthesized from LA by 15-lipoxygenase, has been reported to enhance prostacyclin production in endothelial cells by stimulating the liberation of AA from phospholipids (Setty et al. 1987). Interestingly, there is evidence that 15-lipoxygenase pathway activity is elevated in diabetic retina and in endothelial cells cultured in elevated glucose (Brown et al. 1988; Tesfamariam et al. 1995; Ottlecz et al. 1997). Another oxidized product of LA, 9-hydroxyoctadidecanoic acid, has recently been found in increased amounts in diabetic erythrocyte membranes, perhaps as a consequence of oxidative stress-mediated peroxidation (Inouye et al. 1999).
An alternative approach to compensating for diminished n-6 pathway activity in the diabetic nerve by feeding large amounts of LA in the diet would be to eliminate the need for one of more of the steps by supplying a pathway intermediate. During the past decade, much attention has been paid to the effects of feeding diets enriched in GLA, a maneuver that should bypass the A6 desaturase step. For this purpose, most investigators have utilized evening primrose oil, a naturally occurring oil that contains about 70% LA and 10% GLA. Others have fed either GLA itself or triacylglycerols enriched in this fatty acid. Administration of GLA has been shown to improve diabetic nerve function in both animals and humans, as judged by correction of the nerve conduction velocity deficit, reduced blood flow, and attentuation of resistance to ischemic conduction failure, but not the buildup of polyol pathway metabolites (Julu et al. 1988; Tomlinson et al. 1989; Dines et al. 1993, Cameron and Cotter 1994, Dines et al. 1995, Kuruvilla et al. 1998). However, GLA treatment failed to prevent the depletion of AA in the diabetic nerve (Kuruvilla et al. 1998). GLA administration also amplifies the reduction in nerve Na,K-ATPase activity characteristic of diabetic animals (Lockett and Tomlinson 1992), a finding that tends to dissociate this change from a causative role in decreased nerve conduction velocity. A longer-term effect of GLA supplementation is to promote endoneurial capillary density (Cameron et al. 1991). Dietary AA also has therapeutic effects in that both nerve conduction velocity and blood flow improve when diabetic animals are fed AA-rich oils (Cotter et al. 1997).
The underlying mechanism for the beneficial action of GLA in the diabetic nerve is not fully established. An attractive possibility is that the fatty acid brings about an increase in the synthesis of vasodilatory prostanoids and thus tends to restore the perturbed balance in the synthesis of prostacyclin and thromboxane A2, eicosanoids that have antagonistic actions on nerve vasculature. A reduction in the availability of arachidonoyl moieties may contribute to the decreased formation of prostacyclin, which occurs in diabetic nerve, but diminished activity of cyclo-oxygenase must also be taken into account (Ward et al. 1989; Stevens et al. 1993). In this regard, the level of constitutive cyclo-oxygenase (COX-1) mRNA is considerably reduced in the diabetic nerve (Fang et al. 1997). Whether an increase in thromboxane A2 formation occurs in the nerve from diabetic animals is not known, although this is the case in non-neural tissues (Karpen et al. 1982; Peredo et al. 1994). Interestingly, prolonged dietary administration of GLA to human subjects is able to increase production of prostacyclin and decrease generation of thromboxane A2 in plasma.
Perhaps the strongest evidence that GLA acts via stimulation of prostanoid synthesis is that flurbiprofen, a cyclo-oxygenase inhibitor, blocks improvement in nerve conduction velocity and blood flow elicited by administration of evening primrose oil (Cameron et al. 1993). Greater availability of endogenous GLA might also be expected to enhance the formation of PGE1. This prostanoid, in addition to its vasodilatory action, tends to fluidize membranes and has been proposed to modulate nerve conduction (Horrobin et al. 1977; Horrobin 1988). It is noteworthy that several PGE1 analogs have been shown to ameliorate decreased conduction velocity and blood flow and to increase Na+,K+-ATPase activity in nerves of experimentally diabetic animals (Yasuda et al. 1999). In opposition to the idea that PGE1 is primarily involved in the therapeutic action of GLA are the results of experiments in which rats were fed a mixture of fish oil, which is rich in the n-3 fatty acid, eicosapentaenoic acid, together with either evening primrose oil or GLA. Because conversion of DHGLA, the immediate metabolic product of GLA, to AA is inhibited by eicosapentaenoic acid (Lands 1992), the predicted outcome would be enhanced formation of PGE1 at the expense of prostacyclin synthesis. The results showed that the mixture was not as efficacious in correcting reduced conduction velocity as is GLA alone, thus arguing against a major role for PGE1 (Cameron and Cotter 1994). Recent evidence suggests that vascular effects of GLA may also be mediated by endothelium-derived hyperpolarizing factor, which also exerts a vasodilatory action (Cotter et al. 2000).
Finally, dietary polyunsaturated fatty acids and some of their eicosanoid metabolites have recently been recognized as regulators of gene transcription, largely through their ability to serve as ligands for peroxisome proliferator-activated receptors (PPARs) (Kerston et al. 2000). These members of the steroid nuclear receptor family bind to a specific response element in the promoter of a target gene as a heterodimer with the 9-cis-retinoic acid receptor and bring about gene activation. The genes affected by PPARs encode proteins involved in lipid transport and metabolism. Polyunsaturated fatty acids inhibit lipogenic gene expression and activate expression of genes associated with fatty acid oxidation. Although PPARs have been primarily studied in non-neural tissues, PPAR mRNAs occur in brain, especially during development, as well as in primary neural cell cultures, and have been detected in sciatic nerve (Granneman et al. 1998; Cullingford et al. 1999). There is experimental evidence that A6 desaturation of LA is an essential step for the inhibition of the fatty acid synthase gene expression by polyunsaturated fatty acids (Nakamura et al. 2000). Thus, it may be speculated that perturbations in the n-6 fatty acid biosynthetic pathway that occur in diabetic complications could have profound effects on lipid metabolism.
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