Osmotically-induced nerve taurine depletion and the compatible osmolyte hypothesis in experimental diabetic neuropathy in the rat

Abstract

Diabetic neuropathy results from progressive nerve fibre damage with blunted nerve regeneration and repair and may be complicated by nerve hyperexcitability resulting in pain. The naturally occurring amino acid taurine functions as an osmolyte, inhibitory neurotransmitter, and modulator of pain perception. It is also known to have neurotrophic actions. The compatible osmolyte hypothesis proposes that levels of intracellular organic osmolytes including taurine and myo-inositol, respond co-ordinately in response to changes in intracellular sorbitol or external osmolality to maintain the intracellular milieu. We hypothesize that glucose-induced sorbitol accumulation in diabetes mellitus will result in taurine depletion in peripheral nerve which may potentially impair nerve regeneration and precipitate neuronal hyperexcitability and pain. This study explored the relationships of taurine, myo-inositol and sorbitol in the rat nerve and their effects on nerve conduction velocity. Osmolyte levels and nerve conduction velocity were determined in sciatic nerve from non-diabetic and streptozotocin-induced diabetic rats, with or without dietary taurine or myo-inositol supplementation. Taurine levels decreased by 31% (p < 0.01) and myo-inositol decreased by 37% (p < 0.05) in diabetic nerve as sorbitol accumulated. Taurine supplementation of diabetic animals did not affect nerve conduction velocity but further reduced nerve myo-inositol levels. Prevention of sorbitol accumulation with the aldose reductase inhibitor sorbinil increased nerve taurine levels by 22% (p < 0.05) when compared with untreated diabetic animals. Thus, we have demonstrated an interdependence of organic osmolytes within the nerve. Abnormal accumulation of one osmolyte results in reciprocal depletion of others. Diabetic neuropathy may be an example of maladaptive osmoregulation, nerve damage and instability being aggravated by taurine depletion.

Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

“…A partial reciprocity between sorbitol and myoinositol levels was noted for nerve and lens, in accordance with a role as a compensatory osmolyte [20,53]. This may be reflected by changes in nerve water content.…”

“…These include the prevention of tissue sorbitol accumulation and sequelae consequent on the resultant osmotic imbalance such as reduced nerve myo-inositol [19,20], and deleterious effects on Na + -K + ATPase activity [21]. Aldose reductase requires NADPH as a co-factor, and depletion by elevated flux through the polyol pathway could alter the glutathione redox cycle, which would diminish protection against reactive oxygen species [22].…”

Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells

“…8). Studies in other tissues indicate that increased AR activity and resulting osmotic stress and/or NADPH deficiency are responsible for downregulation of antioxidative defense provided by both nonenzymatic antioxidants, i.e., GSH, ascorbate [55,[61][62][63], and taurine [73], and antioxidative defense enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione transferase) [45]. In addition, increased AR activity contributes to oxidative-nitrosative stress indirectly, via other pathways, such as nonenzymatic glycation and activation of PKC.…”

Dissection of Metabolic, Vascular, and Nerve Conduction Interrelationships in Experimental Diabetic Neuropathy by Cyclooxygenase Inhibition and Acetyl-l-Carnitine Administration

“…Measurement of sciatic nerve MI, taurine, sorbitol, and fructose content. Sciatic nerve MI, sorbitol, and fructose were determined by gasliquid chromatography of aldonitrile acetate derivatives as previously described (17). Nerve taurine was measured by reverse-phase high-performance liquid chromatography (43).…”

“…Activation of the AR pathway alters cellular redox couples, exacerbates oxidative stress (6,(12)(13)(14), and promotes intracellular sorbitol and fructose accumulation. Sorbitol accumulation in the diabetic nerve can lead to compensatory depletion of other nonionic organic osmolytes such as myo-inositol (MI) (6,15,16) and the ␤-amino acid taurine (17), with resultant effects on signal transduction pathways, Na,KATPase activity (16), and antioxidative capacity (18). Alternatively, a reduction in nerve blood flow (NBF) and the development of endoneurial hypoxia-attributed to oxidative stress (2,5,19,20) and to alterations in vasoactive agents, including endothelium-derived nitric oxide (NO) (21)(22)(23), endothelin-1 (24), and eicosanoids (23)-have been invoked as fundamental etiologic factors in EDN.…”