Nerve injury, axonal degeneration and neural regeneration: basic insights

Axotomy or crush of a peripheral nerve leads to degeneration of the distal nerve stump referred to as Wallerian degeneration (WD). During WD a microenvironment is created that allows successful regrowth of nerve fibres from the proximal nerve segment. Schwann cells respond to loss of axons by extrusion of their myelin sheaths, downregulation of myelin genes, dedifferentiation and proliferation. They finally aline in tubes (Büngner bands) and express surface molecules that guide regenerating fibres. Hematogenous macrophages are rapidly recruited to the distal stump and remove the vast majority of myelin debris. Molecular changes in the distal stump include upregulation of neurotrophins, neural cell adhesion molecules, cytokines and other soluble factors and their corresponding receptors. Axonal injury not only induces muscle weakness and loss of sensation but also leads to adaptive responses and neuropathic pain. Regrowth of nerve fibres occurs with high specificity with formerly motor fibres preferentially reinnervating muscle. This involves recognition molecules of the L2/HNK-1 family. Nerve regeneration occurs at a rate of 3-4 mm/day after crush and 2-3 mm/day after sectioning a nerve. Nerve regeneration can be fostered pharmacologically. Upon reestablishment of axonal contact Schwann cells remyelinate nerve sprouts and downregulate surface molecules characteristic for precursor/premyelinating or nonmyelinating Schwann cells. At present it is unclear whether axonal regeneration after nerve injury is impeded in neuropathies.     

Nerve fiber regeneration in preformed tissue spaces

Described in this paper is a new artificial chamber model to enable in vivo investigation of nerve fiber regeneration. Transection of the sciatic nerve of a rat was followed by analysis of axonal regeneration and revascularisation in the tissue chamber. Vascularisation of the endoneurium via the newly formed epineurium and perineurium was almost physiological in the cavity formed. The latter was found to be suitable for application of drugs and neurotrophic substances.     

Influence of fiber,xylitol and fructose in enteral formulas on glucose and lipid metabolism in normal subjects

Summary To verify the benofit of nonglucose carbohydrates and fiber in enteral formula diets we studied the postprandial metabolism of eight healthy subjects after the intake of two helpings (25 g carbohydrates each) of five commonly used enteral formulas over 4 h. There were no significant differences in postprandial concentrations of blood glucose among the formulas. The area under the curve of postprandial insulin values, however, was significantly smaller after consumption of the fructose-containing formula (1948±285 U min ml^–1, P<0.05) than after fiber-free (3222 ±678 U min ml^–1) or two fiber-containing products (2664±326 U min ml^–1, P<0.05; and 3040±708 U min ml^–1, P<0.05). The insulin area of the xylitol-containing formula (2307±364 U min ml^–1) was significantly smaller compared to the fiber-free product (P<0.05). In addition, we found the postprandial increase in triglycerides to be significantly higher after the xylitol-containing formula (from 0.93±0.14 to 1.25±0.22 mmol/1) than after the fiber-free product (from 0.82±0.13 to 0.97±0.16 mmol/1, P<0.05) or the two fiber-containing products (from 0.88±0.16 to 0.96±0.18 mmol/1, P<0.05; and from 0.80±0.08 to 0.95±0.10 mmol/l, P<0.05). We conclude that a patient with type 11 diabetes may benefit from replacing glucose and glucose-equivalent carbohydrates with fructose or xylitol.Abbreviation IAB area under curve of current insulin values minus baseline insulin values     

Epidermal nerve fiber quantification in the assessment of diabetic neuropathy

Assessment of cutaneous innervation in skin biopsies is emerging as a valuable means of both diagnosing and staging diabetic neuropathy. Immunolabeling, using antibodies to neuronal proteins such as protein gene product 9.5, allows for the visualization and quantification of intraepidermal nerve fibers. Multiple studies have shown reductions in intraepidermal nerve fiber density in skin biopsies from patients with both type 1 and type 2 diabetes. More recent studies have focused on correlating these changes with other measures of diabetic neuropathy. A loss of epidermal innervation similar to that observed in diabetic patients has been observed in rodent models of both type 1 and type 2 diabetes and several therapeutics have been reported to prevent reductions in intraepidermal nerve fiber density in these models. This review discusses the current literature describing diabetes-induced changes in cutaneous innervation in both human and animal models of diabetic neuropathy.     

Substrate depletion upregulates uptake of myo-inositol, glucose and adenosine in Leishmania

Leishmania flagellates undergo a digenetic life cycle in the gut of the sandfly insect vector and in macrophage phagolysosomes of the mammalian host. This involves vast changes of the environment to which the parasite has to adapt, including temperature, pH and concentration of nutrients between different types of meals of the insect vector or within the enclosed intracellular environment of the phagolysosome. The regulation of transporters for important organic substrates in Leishmania donovani, Leishmania mexicana and Leishmania enriettii has been investigated. A pronounced upregulation of inositol (25-fold), adenosine (11-fold) or glucose (5-fold) uptake activities was found when cells were depleted of the respective substrates during culture. Inositol-depleted cells showed a half-maximal uptake rate at nanomolar inositol concentration. Depletion of inositol only affected inositol uptake but did not affect uptake of glucose analog or proline in control experiments, indicating the specificity of the mechanism(s) underlying transport regulation. Adenosine-depleted cells showed an approximately 10-fold increase in both adenosine and uridine uptake, both mediated by the L. donovani nucleoside transporter 1 (LdNT1), but no change in guanosine uptake, which is mediated by the L. donovani nucleoside transporter 2 (LdNT2). These results suggest that extracellular adenosine concentration specifically regulates LdNT1 transport activity and does not affect LdNT2. The data imply that upregulation of transport activities by substrate depletion is a general phenomenon in protozoan flagellates, which is in remarkable contrast to bacteria where upregulation typically follows an increase of extracellular organic substrate. Hence, the parasites can maximize the uptake of important nutrients from the host even under limiting conditions, whereas bacteria often have dormant stages (spores) to overcome unfavorable environmental conditions or are heterotrophic for organic substrates.     

Diabetic neuropathy and nerve regeneration

Diabetic neuropathy is the most common peripheral neuropathy in western countries. Although every effort has been made to clarify the pathogenic mechanism of diabetic neuropathy, thereby devising its ideal therapeutic drugs, neither convinced hypotheses nor unequivocally effective drugs have been established. In view of the pathologic basis for the treatment of diabetic neuropathy, it is important to enhance nerve regeneration as well as prevent nerve degeneration. Nerve regeneration or sprouting in diabetes may occur not only in the nerve trunk but also in the dermis and around dorsal root ganglion neurons, thereby being implicated in the generation of pain sensation. Thus, inadequate nerve regeneration unequivocally contributes to the pathophysiologic mechanism of diabetic neuropathy. In this context, the research on nerve regeneration in diabetes should be more accelerated. Indeed, nerve regenerative capacity has been shown to be decreased in diabetic patients as well as in diabetic animals. Disturbed nerve regeneration in diabetes has been ascribed at least in part to all or some of decreased levels of neurotrophic factors, decreased expression of their receptors, altered cellular signal pathways and/or abnormal expression of cell adhesion molecules, although the mechanisms of their changes remain almost unclear. In addition to their steady-state changes in diabetes, nerve injury induces injury-specific changes in individual neurotrophic factors, their receptors and their intracellular signal pathways, which are closely linked with altered neuronal function, varying from neuronal survival and neurite extension/nerve regeneration to apoptosis. Although it is essential to clarify those changes for understanding the mechanism of disturbed nerve regeneration in diabetes, very few data are now available. Rationally accepted replacement therapy with neurotrophic factors has not provided any success in treating diabetic neuropathy. Aside from adverse effects of those factors, more rigorous consideration for their delivery system may be needed for any possible success. Although conventional therapeutic drugs like aldose reductase (AR) inhibitors and vasodilators have been shown to enhance nerve regeneration, their efficacy should be strictly evaluated with respect to nerve regenerative capacity. For this purpose, especially clinically, skin biopsy, by which cutaneous nerve pathology including nerve regeneration can be morphometrically evaluated, might be a safe and useful examination.     

Nerve growth factor induces proliferation and enhances fiber regeneration in oligodendrocytes isolated from adult pig brain.

Mature oligodendrocytes (OL) isolated from adult pig brains start to regenerate their fibers after 4-5 days in vitro (DIV); after 14 DIV a network of OL fibers is formed. Growth factors, of which it was known that they play an important part during proliferation and differentiation of OL progenitor cells, were used to study their influence on the regeneration of mature OL. For this purpose, OL were treated at 6 DIV with different concentrations of various growth factors. At 24 h intervals the [3H]thymidine incorporation was measured and at 8 DIV the OL fiber production evaluated. None of these factors did influence the regenerative process to any significant extent except nerve growth factor (NGF). For the first time it could be shown that NGF enhanced the OL fiber regeneration considerably and induced the proliferation of a subset of OL. These results may have important implications for the remyelinating process in demyelinating diseases such as multiple sclerosis.     

The hepatocellular uptake of glucose, galactose and fructose in conscious sheep.

1. Surgical techniques for chronic catheterization of hepatic and portal veins in the sheep are described. These catheters remained usable for 2-6 months and did not alter hepatic morphology. 2. Hepatocellular uptake of monosaccharides was estimated from their ability to pass the boundaries of the sucrose space in a double indicator dilution procedure in conscious fed sheep. 3. A large proportion (81%) of D-glucose carried in the portal blood was found to enter an hepatic cellular compartment. 4. The radioactive label of D-glucose infused in the portal vein remained associated with D-glucose in hepatic venous blood samples during the experimental period. 5. A large proportion (74%) of an infused trace of D-galactose, a smaller proportion (33%) of D-fructose, and negligible amounts of L-glucose were taken up in a single passage through the liver. 6. Raised blood concentrations of sucrose or of methyl-alpha-D-glucoside (Me-alpha-DG) significantly diminished the proportional uptake of D-glucose. Raised blood concentrations of glucose, galactose or Me-alpha-DG diminished the proportional uptake of D-galactose. Raised blood concentrations of fructose diminished the proportional uptake of fructose. 7. Neither total hepatic blood flow changes nor competitive effects within the cell could account for these findings. 8. It is concluded that these monosaccharides enter the liver cell by facilitated diffusion, and share at least some of the membrane elements that mediate this process. It seems likely that only a proportion of the glucose-transporting apparatus is accessible to galactose.     

Role of microglia in neuronal degeneration and regeneration

Microglial cells, the resident macrophage population of the central nervous system (CNS), actively scan tissue under both normal and pathologic contexts. Their resulting engagement can become either neuroprotective or neurotoxic, leading to amelioration or aggravation of disease progression. In this review, we focus on the molecular signaling molecules involved in microglial responses and discuss observations demonstrating the diverse effects of microglia in animal models of CNS diseases.     

Histogenesis, degeneration, regeneration and adaptation, aging and compensation in the skeletal muscles

The concept of multicellular histogenesis of skeletal muscle fibre is the basis for understanding embryonal genesis of the voluntary muscles as well as muscle fibre regeneration. Formation and maintenance of the neuromuscular units are preconditions for function. Embryonic development and histogenesis regeneration are described. Changes resulting from metabolic defects, trauma, neurogenic and muscular disease are contrasted. Changes in nerves and synaptic junctions due to degeneration and regeneration are illustrated. Alteration in fibre type composition and muscle fibre diameter are regarded as the principle form of muscle adaptation to a changed loads. A central nervous system mechanism influencing fibre type and a peripheral humoral mechanism influencing the magnitude of peripheral motor units are postulated. The role of intramuscular sprouting is underlined. The structurally recognizable correlates of aging, such as decreased fibre diameter, increasing fibre type grouping and reduction of the total number of muscles fibres should be viewed as physiological phenomena. Sensomotor regulation of compensatory mechanism of muscular activity including fibre type grouping, compensatory hypertrophy, target fibres and ring fibres results in distinctive patterns under etiologically distinct pathological conditions.     

Carbohydrate taste preferences in rats: glucose, sucrose, maltose, fructose and polycose compared

The taste preferences of adult female rats for solutions of five different carbohydrates were evaluated using brief (3-min) two-bottle preference tests. At the lowest concentration tested (0.03 molar) the order of preference was Polycose greater than maltose greater than sucrose greater than glucose = fructose. Whereas at the highest concentrations tested (0.5 or 1.0 molar) the preference order was sucrose greater than maltose greater than or equal to Polycose greater than glucose greater than fructose. Thus, at low concentrations starch-derived polysaccharides (Polycose) are more palatable to rats than are sugars. These findings are consistent with the hypothesis that rats have separate taste receptors for sugars and for starch-derived polysaccharides. The fact that maltose is the most preferred sugar at low concentrations is attributed to its stimulation of "polysaccharide" taste receptors.     

Nerve conduction velocity distribution in normal subjects and in diabetic patients without clinical neuropathy. I. Motor nerve.

A computer-assisted collision method to evaluate motor conduction velocity distribution of the ulnar and external peroneal nerves in normal subjects and in insulin-dependent and non-insulin-dependent diabetics without clinical signs of neuropathy is described. Distribution curves were sigmoidally (bimodally) shaped in normal and in insulin- and non-insulin-dependent subjects. In insulin-dependent patients, motor conduction velocity of the peroneal nerves was globally impaired, whereas of the ulnar nerves it was normal. In non-insulin-dependent patients, slower conduction velocity was involved in both nerves.     

Small fiber neuropathy in Fabry disease

Previous studies have explicitly shown that small nerve fibers are affected in Fabry disease which is assumed to cause the severe neuropathic pain that patients may have from childhood on. Neuropathic pain and small fiber neuropathy characteristics have therefore been considered as appropriate study endpoints in studies on the efficacy of enzyme replacement therapy. However, the relationship between small fiber neuropathy characteristics and pain, as well as the course of small fiber neuropathy in Fabry disease is still uncertain. In this article a comprehensive overview of the existing literature on small nerve fiber function and structure and the relationship with pain, age and disease severity is presented supplemented with data from the Dutch Fabry cohort, with the aim to identify consensus as well as controversies and to propose a hypothesis on the evolution of neuropathy in Fabry disease.