Changes In Myelinated Fibers Research Articles

Changes in myelinated fibers in the hippocampus of streptozotocin-induced diabetic rats: a stereological investigation.

Diabetes causes cognitive impairment, and the hippocampus is important for long-term and permanent memory function. However, the mechanism of their interaction is still unclear. In this study, rat models of diabetes mellitus were generated by a single injection of streptozotocin (STZ). This study aims to explore the changes in myelinated fibers in the hippocampus of type 1 diabetic rats. The unbiased stereological methods and transmission electron microscopy were used to obtain the total volume of the hippocampus, the total volume of the myelin sheath, the total length of the myelinated nerve fibers, the distribution of the length with different diameters of the myelinated fibers, and the distribution of the length with different thickness of the myelin sheath. Stereological analysis revealed that, compared to that of the control group, the total myelinated fibers volumes and the total myelinated fibers length were decreased slightly, while the total volume and the thickness of myelin sheaths were significantly decreased in the diabetic group. Finally, when compared with the control group, the total length of myelinated fibers in the diabetes group was significantly reduced, with diameters ranging from 0.7 to 1.1 μm and thicknesses of myelin sheaths from 0.15 to 0.17 μm. This study provides the first experimental evidence by stereological means to demonstrate that myelinated nerve fibers may be the key factor in cognitive dysfunction in diabetes.

Zero Gravity is a Factor that Induces Negative Changes in Myelinated Fibers of the Spinal Tracts

The development of hypogravitational motor syndrome is an essential negative consequence of weightlessness for humans; an important role in the pathogenesis of this syndrome is played by changes in axons of the spinal tracts. Myelinated fibers and transcriptome of the spinal cord were studied in mice exposed to hypogravity during a 30-day flight on a biosatellite. Morphometric analysis of myelinated fibers of the spinal tracts showed a decrease in the thickness of the myelin sheath. Analysis of spinal cord transcriptome revealed a decrease in the expression of genes involved in the myelination of nerve fibers. These results suggest that the processes of nerve fiber myelination are involved in the development of the hypogravitational motor syndrome under weightless conditions; the 7-day readaptation period was found to be insufficient for reversion of the negative changes in the myelinated fibers of the spinal cord.

Stress-induced myelin damage in the hippocampal formation in a rat model of depression

BackgroundAccording to previous studies, myelin damage may be involved in the occurrence of depression. However, to date, no study has quantitatively investigated the changes in myelinated fibers and myelin sheaths in the hippocampal formation (HF) and hippocampal subfields in the context of depression. Methods: Male Sprague-Dawley (SD) rats (aged 4–5 weeks) were evenly divided into the control group and chronic unpredictable stress (CUS) group. Behavioral tests were performed, and then changes in myelinated fibers and myelin ultrastructure in hippocampal subfields in depression model rats were investigated using modern stereological methods and transmission electron microscopy techniques. Results: After a four-week CUS protocol, CUS rats showed depressive-like and anxiety-like behaviors. The total length and total volume of myelinated fibers were reduced in the CA1 region and DG in the CUS group compared with the control group. The total volumes of myelin sheaths and axons in the CA1 region but not in the DG were significantly lower in the CUS group than in the control group. The decrease in the total length of myelinated nerve fibers in the CA1 region in CUS rats was mainly due to a decrease in the length of myelinated fibers with a myelin sheath thickness of 0.15 μm–0.20 μm. Limitations: The exact relationship between the degeneration of myelin sheaths and depression-like, anxiety-like behaviors needs to be further investigated. Conclusions: CUS induces depression- and anxiety-like behaviors, and the demyelination in the CA1 region induced by 4 weeks of CUS might be an important structural basis for these behaviors.

Morphological changes in myelinated fibers of the spinal cord and the sciatic nerve in mice after modeling of the hypogravity and the approach of their correction by preventive gene therapy

Earlier, in mice after a 30-day space flight on the Bion-M1 biosatellite, we found signs of a negative effect of weightlessness on the structure of myelinated fibers of the spinal cord tracts; these findings indicate their involvement in the pathogenesis of hypogravitational motor syndrome (HMS). In the present study, under conditions of hypogravity modeling by the hindlimb unloading, we obtained data on destructive changes in the myelinated fibers of the motor posterior corticospinal tract (tractus corticospinalis posterior), sensitive anterior spinocerebellar tract (tractus spino-cerebellaris anterior), and the gracile fascicle (fasciculus gracilis), as well as in the tibial fascicle (fasciculus tibialis) of the sciatic nerve of mice 30 days after unloading. The obtained data confirm our hypothesis on the role of disturbance in the processes of myelination of nerve fibers during the development of HMS, both during space flight and under conditions of simulating hypogravity on Earth. Morphometric analysis after a 7-day period of readaptation did not reveal signs of restoration of pathological changes in myelinated fibers that arose after 30 days of hanging. However, preventive gene therapy (administration of a gene construct providing the synthesis of recombinant vascular endothelial growth factor, glial cell line-derived neurotrophic factor, and neural cell adhesion molecule, prior to hindlimb unloading) has been shown to be effective in the preservation of myelinated fibers in projection anterior spininocerebellar tract, compared with control animals that did not receive gene therapy. The research carried out at this stage gives ground to make a preliminary conclusion about the advisability of developing methods of preventive gene therapy to prevent the development of GDS during long-term space flights.

Long-Term Running Exercise Delays Age-Related Changes in White Matter in Rats.

Running exercise, one of the strategies to protect brain function, has positive effects on neurons and synapses in the cortex and hippocampus. However, white matter, as an important structure of the brain, is often overlooked, and the effects of long-term running exercise on white matter are unknown. Here, 14-month-old male Sprague–Dawley (SD) rats were divided into a middle-aged control group (18-month-old control group), an old control group (28-month-old control group), and a long-term runner group (28-month-old runner group). The rats in the runner group underwent a 14-month running exercise regime. Spatial learning ability was tested using the Morris water maze, and white matter volume, myelinated fiber parameters, total mature oligodendrocyte number, and white matter capillary parameters were investigated using stereological methods. The levels of growth factors related to nerve growth and vascular growth in peripheral blood and the level of neurite outgrowth inhibitor-A (Nogo-A) in white matter were measured using an enzyme-linked immunosorbent assay (ELISA). The present results indicated that long-term running exercise effectively delayed the age-related decline in spatial learning ability and the atrophy of white matter by protecting against age-related changes in myelinated fibers and oligodendrocytes in the white matter. Moreover, long-term running exercise prevented age-related changes in capillaries within white matter, which might be related to the protective effects of long-term exercise on aged white matter.

Stereological study on the numerical plasticity of myelinated fibers and oligodendrocytes in the rat spinal cord with painful diabetic neuropathy

Painful diabetic neuropathy may associate with nerve morphological plasticity in both peripheral and central nervous system. The aim of this study was to determine numerical changes of myelinated fibers in the spinothalamic tract region and oligodendrocytes in the spinal dorsal horn of rats with painful diabetic neuropathy and the effects of metformin on the above changes. Male Sprague–Dawley rats were randomly allocated into the control group (n = 7), the painful diabetic neuropathy group (n = 6) and the painful diabetic neuropathy treated with metformin group (the PDN + M group, n = 7), respectively. Twenty-eight days after medication, numbers of myelinated fibers in the spinothalamic tract and oligodendrocytes in the spinal dorsal horn were estimated by the optical disector (a stereological technique). Compared to the control group, number of myelinated fibers in the spinothalamic tract increased significantly in the painful diabetic neuropathy and PDN + M group, compared to the painful diabetic neuropathy group, number of myelinated fibers decreased in the PDN + M group (P < 0.05). As the oligodendrocyte in the spinal dorsal horn was considered, its number increased significantly in the painful diabetic neuropathy group compared to the control and the PDN + M group (P < 0.05), there was no significant difference between the control and the PDN + M group (P > 0.05). Our results indicate that painful diabetic neuropathy is associated with a serial of morphometric plasticity in the rat spinal cord including the numerical increase of the myelinated fibers in the spinothalamic tract and the oligodendrocytes in the spinal dorsal horn. The analgesic effect of metformin against painful diabetic neuropathy might be related to its adverse effects on the above morphometric plasticity.

Nodes of Ranvier in skin biopsies of patients with diabetes mellitus.

Paranodal demyelination has been discussed as a potential mechanism of nerve fiber damage in diabetic neuropathy (DNP). Studies on human tissue are limited, as nerve biopsies are invasive and only rarely performed in patients with confirmed DNP. Skin biopsy has recently been suggested as a tool to analyze paranodal and nodal changes of myelinated fibers. We analyzed the myelinated fibers of skin biopsies of 35 patients with DNP, 17 patients with diabetes mellitus (DM) without neuropathy, and 30 normal controls. Immunofluorescence of skin sections with antibodies against Caspr, neurofascin, sodium channels, and myelin basic protein was performed to assess paranodal/nodal architecture, segmental demyelination, and myelinated nerve fibers. Staining with antibodies against protein gene product 9.5 was used to quantify unmyelinated nerve fibers. There was an increase of elongated Ranvier nodes and a dispersion of neurofascin at the distal leg in patients with DM with and without neuropathy and at the finger in patients with DNP. An increased dispersion of Caspr was only found in biopsies of the finger in patients with DNP. Skin biopsy may be an appropriate tool to analyze nodes of Ranvier in patients with DM. Structural nodal changes are detectable in DNP and even in diabetic patients without neuropathy.

Stereological quantification of age-related changes in myelinated fibers of rat white matter.

We investigated changes in myelin sheaths in the myelinated fibers of subcortical white matter in young (6-8 months old), middle-aged (18 months old), and elderly (27-28 months old) female Long-Evans rats using transmission electron microscopy and unbiased stereological techniques. We observed three age-related changes in myelin sheaths in the white matter of elderly rats: local splitting of the major dense line, myelin ballooning, and the formation of abundant myelin sheaths. Stereological analysis showed that the total length of myelinated fibers in white matter was 115±12 km (mean±SD) in young rats, 135±21 km in middle-aged rats, and 62±11 km in elderly rats. Myelinated fibers with diameters less than 1.0 μm and myelin sheath thicknesses less than 0.1 μm were significantly shorter in middle-aged and elderly rats compared with young rats. Age-related changes in myelin sheaths were evident in aged white matter. The loss of myelinated fibers with both small diameters and thin myelin sheaths is a potentially important change in aged white matter. Our results suggest that the myelin sheath changes in aged white matter may have important implications for age-related cognitive impairments.

Ultrastructural abnormalities and loss of myelinated fibers in the corpus callosum of demyelinated mice induced by cuprizone.

It is now accepted that white matter abnormalities play an important role in demyelinating diseases and a wide range of psychiatric disorders. Experimental demyelination (especially induced by cuprizone) has been investigated extensively. However, details regarding demyelination and ultrastructural changes of myelinated fibers have not been previously reported. Therefore, we determined the extent of demyelination using quantitative stereology. Mice exposed to cuprizone in the current study showed abnormal anxiety-like behavior without impaired spatial learning or memory. The myelinated fibers in whole corpus callosum of mice exposed to cuprizone showed extensive myelin deficiencies and occasional axonal injuries. The total length of the myelinated fibers in whole corpus callosum of mice exposed to cuprizone was significantly decreased by 45% compared with control mice. The loss of myelinated fibers was mainly due to the marked loss of the fibers with a diameter of 0.4 to 0.8 μm. The g-ratio of the myelinated fibers in the corpus callosum of mice exposed to cuprizone (0.69 ± 0.02) was significantly decreased compared with control mice (0.76 ± 0.02). These results might help us to further understand the role of white matter abnormalities in demyelinating diseases or a wide range of psychiatric disorders. © 2016 Wiley Periodicals, Inc.

Structural reorganization of the sciatic, peroneal, and tibial nerves during osteosynthesis of lower leg fracture and after fracture consolidation (an experimental study)

The study purpose was to identify histological changes in the peripheral nerves and determine functional significance of subclinical neuropathy in experimental simulation of lower leg fractures. We simulated a tibial shaft fracture in 24 dogs under anesthesia and performed osteosynthesis using an Ilizarov apparatus. After 7, 14, 20, 35–37, and 50 days of fixation using the apparatus and 30, 60–90, and 120 days after removal of the apparatus, the dogs were euthanised. Electromyography was performed before fracture and within the main phases of the experiment. Samples of the sciatic, peroneal, and tibial nerves were studied histologically using computer morphometry of semithin araldite sections. After 37 days of fixation, the amplitude of M-responses of the tibialis anterior and gastrocnemius muscles decreased by 70% compared to the baseline value, increased after removal of the apparatus, but not restored. There were no sighs of nerve damage by bone fragments or wires. The fraction of degenerating myelinated fibers in the studied nerves was less than 13%. Reorganization of the Remak bundles led to a temporary increase in the number density of nerve fibers. Along with axonal atrophy, the peroneal nerve was characterized by demyelination-remyelination, and the tibial nerve was characterized by hypermyelination. The dynamics of numerical density of endoneurial blood vessels was also different. Despite minor sharp degenerative changes in myelinated fibers, persistent axonal atrophy, demyelination, and retrograde changes were not compensated for up to 120 days after removal of the apparatus. Correlations between the morphometric parameters of myelinated fibers and the M-response amplitude indicated a causal role of subclinical neurological changes in functional outcomes of fractures.

Diabetic Complications in a New Animal Model (TSOD mouse) of Spontaneous NIDDM with Obesity

The TSOD mouse has been established as an inbred strain with spontaneous development of diabetes mellitus as the first clinical signs of diabetes. Polydipsia and polyuria are observed at about 2 months old only in male mice, after which hyperglycemia and hyperinsulinemia are detected. Following these symptoms obesity gradually develops until about 12 months old. In histopathological examination of the pancreas, severe hypertrophy of pancreatic islets was observed due to proliferation and swelling of B cells. In the kidney, thickening of the basement membrane in glomeruli and an increase of the mesangial area were observed at 18 months old. Motor neuropathy in TSOD mice began to appear at 14 months old and most male mice at 17 months old showed weakness of front and hind paws caused by neuron degeneration in the peripheral nerve. In sensory neuropathy, the threshold in the tail pressure test decreased significantly at 12 months old. Light microscopic and electron microscopic examination of sciatic nerves showed a decrease in the density of nerve fibers by the endoneural fibrosis and loss of these fibers. Degenerative changes of myelinated fibers, separation of myelin sheaths with intralamellar edema and remyelination were frequently observed. In the severely affected nerve fibers, the lamellar structure was completely destroyed and macrophages migrated around the myelin sheath or invaded the intramyelin space. Considering these findings similar to non-insulin dependent diabetes mellitus (NIDDM) in humans, the TSOD mouse should be a useful model for the pathogenic study of diabetic complications, especially of peripheral neuropathy.

Schwann cell changes induced as early as one week after galactose intoxication

In galactose neuropathy, aldose reductase inhibitor (ARI)-preventable Schwann cell injury has been reported in studies in which galactose feeding continued over a period of months. Given the link between these morphologic changes and polyol pathway flux, polyol accumulation after just days of galactose feeding points to the possibility that structural changes occur much earlier than previously reported. The aim of this study was to examine rat sciatic nerve after 7 days of galactose feeding for evidence of myelinated fiber injury and establish whether it is related to polyol accumulation. Compared to control or ARI-treated galactose-fed rats, nerves from untreated galactose-fed rats had increased water (P < 0.05) ad dulcitol (P < 0.008) content and decreased amounts of myo-inositol (P < 0.01). Electron microscopy revealed reactive Schwann cell changes in myelinated fibers characterized by increased cytoplasmic volume, and the occurrence of lipid droplets pi granules of Reich and enlarged mitochondria. Dystrophic accumulation of intermediate filaments was also observed in the inner glial loop. Degenerative changes included periaxonal swelling, enlarged mitochondria without recognizable cristae, lysis of Schwann cell cytoplasm and demyelination. Reactive (P < 0.05) and degenerative (P < 0.01) changes as well as the number of redundant basal lamina profiles (P < 0.05) were significantly more frequent in untreated galactose-fed rats compared to controls. ARI treatment attenuated these changes. Consistent with the initial stages of onion-bulb formation, profiles with imbricate Schwann cells were also seen only in untreated galactose-fed rats. The findings suggest that short-term increases in polyol pathway activity can have deleterious effects Schwann cells of myelinated fibers.

Effects of cilostazol on development of experimental diabetic neuropathy: functional and structural studies, and Na +-K +-ATPase acidity in peripheral nerve in rats with streptozotocin-induced diabetes

We studied the ability of cilostazol (CL), an antithrombotic and vasodilating agent, to prevent functional, structural and biochemical abnormalities including delayed motor nerve conduction velocity (MNCV), morphological changes in myelinated fibers, and decreased Na +-K +-ATPase activity in the peripheral nerves of rats with streptozotocin (STZ)-induced diabetes. Cilostazol treatment (30 mg/kg/day p.o.) for 10 weeks significantly prevented the delay in MNCV in the tail nerve, and morphometric analysis of the sural nerves revealed that this dose of cilostazol had a significant effect on reduction of average size of myelinated fibers. In untreated diabetic rats, cyclic AMP content and Na +-K +-ATPase activity of peripheral nerve were each significantly less than in normal control rats. Cilostazol (30 mg/kg/day) prevented reduction of Na +-K +-ATPase activity. Decrease in cyclic AMP content was completely prevented with both doses of cilostazol (30 and 10 mg/kg/day). These findings suggest that cilostazol may have beneficial effects in the treatment of diabetic neuropathy, possibly via improvement of nerve Na +-K +-ATPase activity and cyclic AMP content. Cilostazol may thus be a potent drug for the clinical treatment of diabetic neuropathy.

Quantitative analysis of myelinated nerve fibers of peripheral nerve in streptozotocin-induced diabetes mellitus.

The purpose of this study was to examine morphometric changes of myelinated fibers in early stages of experimental diabetes mellitus. Adult male Wistar rats aged 17 wk were used in this study. Diabetes mellitus was induced by streptozotocin. Samples of common peroneal nerve from diabetic rats (4 and 8 wk after induction of diabetes mellitus) and age-matched control animals were removed and processed. The semithin cross sections were stained with toluidine blue and used for myelinated fiber computer-aided morphometric analysis. There were no significant changes in diabetic animals after 4 wk duration of the disease. There was significant reduction in myelinated nerve fiber caliber in diabetic rats 8 wk after induction of diabetes as compared to age-matched controls. There was no significant reduction of axonal area in this group of diabetic rats, so diminution of fiber area was caused predominantly by reduction of myelin sheath area. The study demonstrates that the induction of diabetes mellitus in rat by streptozotocin is accompanied by early changes of the morphometric indices of myelinated nerve fibers of peripheral nerve.

Primary segmental demyelination in the sural nerve in Cockayne's syndrome.

In a typical case of Cockayne's syndrome, morphometric histopathologic findings of the sural nerve were described and compared with data on two controls. The main pathologic changes of myelinated fibers were segmental demyelination and remyelination with onion bulb formation and a moderate decrease of myelinated fibers. There was no evidence of axonal atrophy in relation to myelin spiral length. In addition, no evidence of the clustered occurrence of demyelinated and remyelinated internodes was obtained on the statistical evaluation of the distribution of such internodes. Although the presence or absence of hypomyelination of a mild degree and maldevelopment of axons to be myelinated has not been clarified, our morphometric data do suggest the presence of primary segmental demyelination of the biopsied sural nerve.

Schwann cell changes and demyelination in chronic galactose neuropathy.

Dystrophic changes of Schwann cells and demyelination occurred in rats with chronic nerve edema induced by feeding a galactose-rich diet for two years. The mechanism for edema is the sorbitol pathway which generates osmotically active polyols from galactose or glucose. The blood-nerve barrier impedes diffusion of macromolecules from peripheral nerves, and endoneurial fluid pressure (EFP) becomes elevated. After 24-26 months of feeding with 40% galactose diet, myelinated nerve fibers showed segmental demyelination with bubbly disintegration of myelin sheaths, axonal degeneration, and remyelination. These pathologic changes were significantly more common than similar abnormalities in age-matched controls. Massive glycogen accumulation in Schwann cells, a unique morphologic finding, appeared only in experimental rats. Since edema and increased EFP are the earliest pathologic changes and are present for months before demonstrable nerve fiber injury, we suggest that they are responsible for the changes of myelinated fibers in chronic galactose neuropathy.

Electron microscopic studies on the cerebral lesions of rats in experimental chronic disulfiram poisoning.

Following chronic administration of disulfiram to rats, changes of the brain were examined electron-microscopically. Pathological findings were observed in the nerve cells of the cerebral cortex and hypothalamus at later stage and synaptic changes in the hypothalamus from initial stage. On the other hand, changes of myelinated fibers, neuroglias and capillaries were very slight. It was considered that neurons were affected more predominantly than other neuronal elements by the cytotoxic action of the drug, and that the synaptic changes of the hypothalamus might reveal chronic disturbance of noradrenergic transmission by inhibition of dopamine-beta-hydroxylase. These ultrastructural findings might relate to the pathogenic mechanism of the disulfiram psychosis.

Effects of energy deprivation on Wallerian degeneration in isolated segments of rat peripheral nerve

An acceleration in the progression of Wallerian degeneration was demonstrated in isolated segments of rat peripheral nerve following incubation under energy-deprivational conditions. The additions of1m M cyanide, azide or dinitrophenol to Ringer's incubational solutions brought about granular disintegrative axoplasmic changes, varicosity formation and linear fragmentation of the myelinated nerve fibers within 2–4 h of incubation at 37°C. Incubations in Ringer's solutions without glucose or with the addition of1m M iodoacetate led to identical Wallerian-like degenerative changes of myelinated fibers during the 8–12 h incubational interval. In contrast, the myelinated nerve fibers remained well-preserved following 16 h of incubation in glucose-enriched Ringer's solutions. The progressions of degenerative changes under energy-deprivational conditions were calcium-dependent as evidenced by their failure to occur in calcium-free media. Accordingly, it is believed that an influx of calcium ions into axoplasm is a critical event in bringing about accelerated as well as the natural degradative changes within isolated nerve fibers. It would follow that the maintenance of axolemmal integrity, especially the calcium-excluding mechanism(s), is an active process which utilizes energy and is vulnerable to energy-deprivational conditions.

Experimental organic mercury poisoning--pathological changes in peripheral nerves.

Organic mercury firstly affects peripheral nerves all over the nervous system. In peripheral nerves, pathological changes are selectively observed in sensory nerve fibres and are as follows: Swelling and degeneration of Schwann cells, noticeable changes in both myelin sheaths and axons. Proliferating cells such as Schwann cells and macrophages may be acting the role of removal and digestion of degenerated myelin and axon. The pathological changes in myelinated fibres tend to begin at the nodes of Ranvier. With the quantity of organic mercury which was administered, only peripheral nerves were injured. From this point of view, we speculate that, of the neurological signs, only sensory disturbance might be found in some of the patients poisoned by organic mercury.

The pathology of trigeminal neuralgia. Electron microscopic studies.

LIGHT microscopy of the trigeminal ganglion and posterior root obtained at operation from patients with trigeminal neuralgia has yielded controversial and uncertain results in the past; a review of the literature indicates that the opinions ranged from statements that there were no pathologic changes to those that claimed that there were degenerative changes in myelinated fibers, loss of ganglion cells, pronounced hypertrophy of interstitial tissue, or arteriosclerotic changes. 1-9 The electron microscopic characteristics of the trigeminal ganglion and associated root have been well described; 10-13 until the recent report by Beaver and associates, 14 no investigation of the ultrastructure of the trigeminal nerve in tic douloureux was available. We fully confirm their finding of pathologic changes in myelinated fibers and note some additional changes. Material and Methods Patients.— Specimens of the ganglion and posterior root were obtained at operation from 13 patients who had trigeminal neuralgia. Of these, six fulfilled