Nerve Myelinated Axons Research Articles

2,5-Hexanedione alters elemental composition and water content of rat peripheral nerve myelinated axons.

Effects of 2,5-hexanedione on elemental concentrations and water content of peripheral nerve myelinated axons were determined using electron probe x-ray microanalysis. Axons (small, medium, and large) were analyzed in unfixed cryosections from rat tibial and proximal sciatic nerve samples. Animals were intoxicated with 2,5-hexanedione by two dosing paradigms: intraperitoneal or oral. Regardless of the route of exposure, internodal axoplasm of small and medium axons from both nerve regions exhibited selective, progressive reductions in dry weight K concentrations and water content. When calculated on a wet weight basis, K levels were comparable to or slightly above control values in tibial nerve, whereas in sciatic nerve, small transient decreases in wet weight K were evident. These changes in K and water correlated with the development of axonal atrophy. The wet and dry weight internodal elemental changes reported here do not suggest a metabolic or axolemmal defect, but rather imply a homeostatic response possibly related to the process of axonal atrophy. Giant axonal swellings were primarily associated with oral 2,5-hexanedione intoxication, and corresponding analyses revealed few changes in element or water content compared with control. The absence of significant alterations in these swellings is consistent with mechanical expansion of the axon probably as a function of accumulating neurofilaments.

Ultrastrutitural Pathology of an Inherited Lower Motor Neuron Disease of Pigs

The ultrastructural features of a recently described inherited lower motor neuron disease were studied in 5 affected pigs. Clinical signs comprised progressive ataxia and paresis of variable severity. Affected pigs, 6, 7, 15, 15, and 19 weeks of age, and 2 unrelated healthy pigs, 9 and 15 weeks of age, were anesthetized and their tissues were fixed by whole body perfusion with mixed aldehydes. From 1 or more affected pigs, samples of cervical and lumbar spinal ventral horn, lateral and ventral spinal columns, dorsal and ventral lumbar spinal nerve roots, 2 peripheral nerves (Nn. phrenicus and fibularis communis), and 2 skeletal muscles (Mm. diaphragma and tibialis cranialis) were examined ultrastructurally. There was widespread degeneration of myelinated axons in peripheral nerves and in lateral and ventral columns of lumbar and cervical segments of spinal cord. Axonal degeneration was present in ventral spinal nerve roots and was absent in dorsal spinal nerve roots sampled at the same lumbar levels. Unmyelinated axons in peripheral nerves and spinal nerve roots were unaffected. In 4 of 5 affected pigs, there were atrophic alpha motor neurons in cervical spinal cord that contained dense, round osmiophilic perikaryal inclusions up to 4 microns in diameter and round swollen mitochondria. Axonal regeneration was present in N. phrenicus of the 19-week-old affected pig that had clinical signs of longest duration (10 weeks). There was no morphologic evidence of axonal degeneration or spinal neuronal atrophy in either control pig. The ultrastructural features of this motor neuron disease distinguish it from other reported progressive spinal neuropathies of pigs.

The therapeutic effects of 4-methylcatechol, a stimulator of endogenous nerve growth factor synthesis, on experimental diabetic neuropathy in rats

We investigated therapeutic effects of 4-methylcatechol (4-MC), a non-amine catechol compound, on streptozotocin (STZ)-induced diabetic neuropathy in rats. 4-MC is one of the potent stimulators of endogenous nerve growth factor (NGF) synthesis both in vitro and in vivo. Diabetic rats showed a statistically significant reduction in motor nerve conduction velocity (MNCV), mean myelinated axon diameter, and NGF content in the sciatic nerve during the experimental period of 8 weeks. The 4-MC treatment started 4 weeks after the STZ injection resulted in significantly greater NGF content, faster MNCV, and larger mean myelinated nerve fiber diameter and axon diameter than in untreated diabetic rats. These findings suggest that a decreased NGF level in the diabetic sciatic nerves may be involved in the pathogenesis of diabetic neuropathy and that 4-MC treatment could be useful for diabetic neuropathy.

Acrylamide Disrupts Elemental Composition and Water Content of Rat Tibial Nerve: III. Recovery

We have previously demonstrated that subacute and subchronic acrylamide (ACR) intoxication are associated with a loss of subcellular elemental regulation in myelinated axons and Schwann cells of rat tibial nerve (LoPachin et al., Toxicol. Appl. Pharmacol.115, 21-34, 1992; LoPachin et al., Toxicol. Appl. Pharmacol.115, 35-43, 1992). In the present study, rats were allowed to recover partially from subchronic oral ACR intoxication (2.8 mM in drinking water for approximately 30 days). Elemental composition and water content of tibial nerve myelinated axons and Schwann cells were measured by electron probe X-ray microanalysis. Results show that K and Cl concentrations in larger tibial nerve axons were shifted toward normal values or above. For the most part, small axons also exhibited elemental changes that reflected recovery from ACR intoxication. Mitochondria displayed elemental changes that were similar to corresponding axoplasm. Schwann cells in tibial nerve of recovering animals had altered Na, P, Cl, K, and Mg concentrations that were similar in magnitude and extent to those occurring during ACR intoxication. In contrast, myelin displayed few changes. These results suggest that the recovery process following ACR intoxication is associated with characteristic changes in subaxonal elemental composition that might be related to repair mechanisms. That recovery-related elemental changes differ from those associated with intoxication provides additional support for the hypothesis (LoPachin et al., Toxicol. Appl. Pharmacol.115, 21-34, 1992) that perturbation of elemental regulation is a specific component of ACR neurotoxicity. The observation of persistent Schwann cell disruption during recovery might reflect either long-term secondary consequences or delayed recovery from direct injury. Further studies are necessary to resolve this issue.

Effects of acrylamide on subcellular distribution of elements in rat sciatic nerve myelinated axons and Schwann cells

Electron probe X-ray microanalysis was used to determine whether experimental acrylamide (ACR) neuropathy involves deregulation of subcellular elements (Na, P, S, Cl, K, Ca and Mg) and water in Schwann cells and small, medium and large diameter myelinated axons of rat sciatic nerve. Results show that in proximal but not distal sciatic nerve, ACR treatment (2.8 mM in drinking water) was associated with an early (15 days of exposure), moderate increase in mean axoplasmic K concentrations (mmol/kg) of medium and small diameter fibers. However, all axons in proximal and distal nerve regions displayed small increases in dry and wet weight contents of axoplasmic Na and P. As ACR treatment progressed (up to 60 days of exposure), Na and P changes persisted whereas proximal axonal K levels returned to control values or below. Alterations in mitochondrial elemental content paralleled those occurring in axoplasm. Schwann cells in distal sciatic nerve exhibited a progressive loss of K, Mg and P and an increase in Na, Cl and Ca. Proximal glia displayed less extensive elemental modifications. Elemental changes observed in axons are not typical of those associated with cell injury and might reflect compensatory or secondary responses. In contrast, distal Schwann cell alterations are consistent with injury, but whether these changes represent primary or secondary mechanisms remains to be determined.

Ganglioside Treatment Modifies Abnormal Elemental Composition in Peripheral Nerve Myelinated Axons of Experimentally Diabetic Rats

Effects of ganglioside administration on elemental composition of peripheral nerve myelinated axons and Schwann cells were determined in streptozotocin-induced diabetic rats and nondiabetic controls. Diabetic rats (50 days after administration of streptozocin) exhibited a loss of axoplasmic K and Cl concentrations in sciatic nerve relative to control, whereas intraaxonal levels of these elements increased in tibial nerve. These regional changes in diabetic rat constitute a reversal of the decreasing proximodistal gradients for K and Cl concentrations that characterize normal peripheral nerve. Treatment of diabetic rats with a ganglioside mixture for 30 days (initiated 20 days after the administration of streptozocin) returned proximal sciatic nerve axoplasmic K and Cl concentrations to control levels, whereas in tibial axons, concentrations of these elements increased further relative to diabetic levels. Also in the ganglioside/diabetic group, mean axoplasmic Na concentrations were reduced and Ca levels were elevated. Mixed ganglioside treatment of nondiabetic rats significantly increased axoplasmic dry weight concentrations of K and Cl in proximal sciatic and tibial axons. Schwann cells did not exhibit consistent alterations in elemental content regardless of treatment group. Changes in elemental composition evoked by ganglioside treatment of diabetic rats might reflect the ability of these substances to stimulate Na+,K(+)-ATPase activity and might be related to the mechanism by which gangliosides improve functional deficits in experimental diabetic neuropathy.

Histopathologic changes in snoring and obstructive sleep apnea syndrome

The pathophysiologic events that lead to the loss of airway compensation in obstructive sleep apnea (OSA) are poorly understood. The development of airway instability may be secondary to changes in neurologic control, airway morphology, or both. To identify potential histopathologic features of pharyngeal tissues that may contribute to OSA, transverse sections of the distal soft palate and uvula were qualitatively compared using light and electron microscopy from 4 severe apneics (greater than 50 apnea/hour), 4 severe snorers (less than 20 apnea/hour), and 4 nonsnorers. Light microscopy of both apneics and snorers revealed mucous gland hypertrophy with ductal dilation and focal squamous metaplasia, disruption of muscle bundles by infiltrating mucous glands, focal atrophy of muscle fibers, and extensive edema of the lamina propria with vascular dilation. Severe snorers did not differ qualitatively from apneics in the characteristic changes found; however, some snorers had less extensive changes. No distinctive histopathologic findings could be associated with the development of apnea. Electron microscopy of severe apneics identified frequent focal degeneration of myelinated nerve fibers and axons. The finding of similar histopathologic changes in apneics and severe snorers supports previous speculation of a common etiology not directly related to apnea, such as vibratory trauma to pharyngeal tissues. Degenerative changes in peripheral nerves, identified on electron microscopy, however, may contribute to airway instability and the development of obstructive apnea by impairing pharyngeal reflexes.

Morphometric Analysis of Rat Trigeminal Ganglion Cells and Their Vibrissa Follicle Nerve Axons Following Multiple Low-Dose Exposure to the Carbamate Insecticide Aldicarb

Chronic carbamate exposure is reported to cause somatosensory dysfunction in humans. The limited experimental literature on neuropathic effects of repeated, low-level carbamate exposure is equivocal and does not address effects on well-defined somatosensory pathways. In this study, adult Sprague-Dawley rats were given 0.2 mg/kg/day of aldicarb, by oral gavage, for 90–114 days. The daily dose was below that capable of inducing clinical signs of cholinergic poisoning but inhibited acetylcholinesterase in spinal cord and blood. Aldicarb was evaluated for its ability to cause death or morphologic alteration of sensory neurons innervating C1 mystacial vibrissa follicles. Light and electron microscopy were used to examine the number of myelinated axons in C1 vibrissa follicle nerves and the respective areas of these axons and their myelin sheaths. Retrograde axonal transport was used with fluorescence microscopy to examine the number and diameter of the cell bodies of C1 vibrissa follicle nerve axons. No differences were observed between aldicarb-treated and control groups for any of these dependent variables. This study indicates that repeated exposure to aldicarb, at a dose below that causing sufficient acetylcholinesterase inhibition to elicit clinical signs, does not produce an anatomic correlate for somatosensory dysfunction in rats.

A mathematical study on effects of narrow gap width in myelinated nerve axons

A mathematical model of myelinated nerve axons is studied. The nodes of Ranvier are assumed to have a finite width δ. We discuss the propagation of the excited state and its failure by adopting δ and the length of the myelinated membrane as parameters, and show theoretically an advantage of suitably narrow width of the nodes of Ranvier for nerve propagation.

Stimulation of a myelinated nerve axon by electromagnetic induction

A model of electromagnetic stimulation predicts the transmembrane potential distribution along a myelinated nerve axon and the volume of stimulated tissue within a limb. Threshold stimulus strength is shown to be inversely proportional to the square of the axon diameter. It is inversely proportional to pulse duration for short pulses and independent of pulse duration for long ones. These results are also predicted by dimensional analysis. Two dimensionless numbers, Sem, the ratio of the induced transmembrane potential to the axon's threshold potential, and Tc/T, the ratio of the pulse duration to the membrane time constant, summarise the dependence of threshold stimulus strength on pulse duration and axon diameter.

Involvement of extraocular muscle in mitochondrial encephalomyopathy

We carried out a histological examination of the extraocular muscles (EOMs) in a case of myoclonus epilepsy associated with ragged-red fibers (MERRF) and two cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which did not manifest external ophthalmoplegia clinically. By light microscopy, many granular and vesicular fibers were seen associated with endomysial fibrosis. Electron microscopy revealed that the fibers showed prominent accumulation of abnormal mitochondria, extensive loss of myofibrils, proliferation of free sarcoplasmic reticulum and an increased amount of lipid vacuoles. These changes were more pronounced in MELAS than in MERRF. Hirano bodies were often seen in the subsarcolemmal area of muscle fibers and also in the intramuscular myelinated nerve fibers and axon terminals. These findings suggest the presence of mitochondrial myopathy of the EOMs in cases of MELAS and MERRF.

Glial hyaluronate-binding protein (GHAP) optic nerve and retina

The distribution of glial fibrillary acidic protein (GFAP) and of glial hyaluronate-binding protein (GHAP) was studied by indirect immunofluorescence with monoclonal and polyclonal antibodies in dog, rat and rabbit optic nerve. In dog and rabbit myelination extends into the optic nerve head inside the eye, while in the rat myelination of the optic nerve ceases abruptly at its entry into the eye. Outside the eye the distribution of the two proteins was similar. Both antigens formed a delicate mesh surrounding myelinated optic nerve axons. In all 3 species GFAP immunoreactivity continued uninterrupted into the optic nerve head inside the eye. Conversely, in both dog and rat, GHAP immunoreactivity ceased abruptly in the region of the lamina cribrosa, a sieve-like structure continuous with the sclera through which bundles of optic nerve axons pass. No staining was observed in the myelinated optic nerve head of the dog nor in the non-myelinated optic nerve head of the rat. In the rabbit lacking a lamina cribrosa, GHAP immunoreactivity did not cease abruptly at the optic nerve entry into the eye, but the staining intensity was reduced in the optic nerve head.

Propagation of excited state and its failure in a simple model of myelinated nerve axons

The present paper deals with a mathematical model of a myelinated nerve axon, where nodes of Ranvier are assumed to have a finite longitudinal length. The myelinated axon contains an electrically passive part wrapped in a lipoprotein sheath. After showing the unique existence of solution and a comparison theorem, we study the propagation of excited state and its failure in the case where the passive part consists of a single segment, by adopting a coupling coefficientd as a parameter,d=1/(RL 2) with the resistanceR per unit length of axoplasm and the lengthL of segment. It is shown that there existsd *>0 such that the propagation succeeds ifd>d *, but fails ifd<d *. Regions of attraction of stable steady states are also given, and some of these results are applied to general cases.

Effects of halothane and enflurane on firing threshold of frog myelinated axons.

1. Firing thresholds and conduction latencies of single myelinated axons in frog sciatic nerves were monitored during impulse activity in vitro. Resting threshold and the activity dependence of threshold were studied as a function of the concentration of two inhalational anaesthetic agents, halothane and enflurane. 2. At concentrations comparable to those obtained during general anaesthesia both agents produced biphasic effects on the resting threshold. A step increase in the partial pressure of anaesthetic was followed first by a transient lowering of threshold, then by a slow rise to a steady-state level above the original baseline. Step decreases in anaesthetic were followed by transient rises before threshold dropped. Transients lasted 20-30 min. During these threshold transients, the average latency of impulse conduction changed monotonically. The prolongation of latency following an increase in anaesthetic was progressive, reaching steady state concurrently with threshold (20 min to greater than 1 h). 3. The anaesthetics reduced the long-lasting increased threshold ('depression') which normally follows repetitive impulse activity in axon membrane. 4. These actions of halothane at concentrations of 0.25-2.7% (0.14-1.54 mM) and enflurane at concentrations of 0.62-3.08% (0.35-1.73 mM) on resting threshold and on the activity-dependent increase in threshold increased monotonically with anaesthetic concentration. 5. The effects on excitability at steady state are consistent with block of voltage-dependent Na+ and K+ channels by these inhalational agents. Reduced depression may occur because the anaesthetics reduce the net ion transfer per impulse, slowing the substrate-driven Na+-K+-ATPase and thereby reducing electrogenic hyper-polarization. 6. The finding that general anaesthetics inhibit depression at clinically relevant concentrations supports the possibility that general anaesthesia is produced by inhibition of processes that modulate excitability of nerve membrane. We suggest that general anaesthetics produce unconsciousness and amnesia because they disrupt activity-dependent processes, which may thus remove temporal 'context' essential for interpreting nerve impulse patterns.

Myelinated axons in peripheral nerves of adult beagle dogs: morphometric and electrophysiological measurements

The myelinated fibre composition and conduction velocities were measured for the ulnar, saphenous and caudal cutaneous sural nerves of 10 healthy beagle dogs. A systematic random sampling technique was used to estimate the fibre diameter frequency distributions and densities. Conduction velocities were measured from evoked compound nerve action potentials. All nerves showed bimodal diameter frequency distributions with modes being approximately the same for each nerve (2 to 4 microns and 8 to 10 microns or 10 to 12 microns). The variation in the average densities and in the shapes of histograms of the different nerves was slight; however, there was a wide variation for the same nerve in different individuals. The conduction velocities for the fastest conducting axons in the nerves ranged from 63 to 79 m s-1. These normal quantitative processes affecting peripheral nerves in the dog.

Identifying motor and sensory myelinated axons in rabbit peripheral nerves by histochemical staining for carbonic anhydrase and cholinesterase activities

Carbonic anhydrase (CA) and cholinesterase (CE) histochemical staining of rabbit spinal nerve roots and dorsal root ganglia demonstrated that among the reactive myelinated axons, with minor exceptions, sensory axons were CA positive and CE negative whereas motor axons were CA negative and CE positive. The high specificity was achieved by adjusting reaction conditions to stain subpopulations of myelinated axons selectively while leaving 50% or so unstained. Fixation with glutaraldehyde appeared necessary for achieving selectivity. Following sciatic nerve transection, the reciprocal staining pattern persisted in damaged axons and their regenerating processes which formed neuromas within the proximal nerve stump. Within the neuromas, CA-stained sensory processes were elaborated earlier and in greater numbers than CE-stained regenerating motor processes. The present results indicate that histochemical axon typing can be exploited to reveal heterogeneous responses of motor and sensory axons to injury.

Existence of Global Solutions to a Model of a Myelinated Nerve Axon

The main result is a proof of the existence of solutions which are global in time for a.differential equation arising in the theory of myelinated nerves. The equation differs from the usual reaction-diffusion equations occurring in nerve models in that the second derivative operator in the spatial direction is replaced at a sequence of discrete nodes by an operator defined as the jump in the first derivative in the spatial direction across the node. The nonlinear dynamics are assumed to be concentrated at the nodes. Local existence of solutions is obtained via semigroup theory; global bounds and hence global existence via energy or Lyapunov methods.

Numerical solution of a nonlinear advance-delay-differential equation from nerve conduction theory.

A functional differential equation which is nonlinear and involves forward and backward deviating arguments is solved numerically. The equation models conduction in a myelinated nerve axon in which the myelin completely insulates the membrane, so that the potential change jumps from node to node. The equation is of first order with boundary values given at t = +/- infinity. The problem is approximated via a difference scheme which solves the problem on a finite interval by utilizing an asymptotic representation at the endpoints, cubic interpolation and iterative techniques to approximate the delays, and a continuation method to start the procedure. The procedure is tested on a class of problems which are solvable analytically to access the scheme's accuracy and stability, then applied to the problem that models propagation in a myelinated axon. The solution's dependence on various model parameters of physical interest is studied. This is the first numerical study of myelinated nerve conduction in which the advance and delay terms are treated explicitly.

Temperature-induced changes in fatty acid composition of myelinated and non-myelinated axon phospholipids

1. 1. The olfactory (non-myelinated) and trigeminal (myelinated) nerve axons of garfish show changes in phospholipid fatty acid composition when these fish are acclimated to temperatures ranging from 11 to 35°C. 2. 2. Myelinated and non-myelinated nerve axons show similar changes in the percent saturated, percent 16-carbon, percent 18-carbon, and percent 20-carbon-and-greater unsaturated fatty acids. 3. 3. The observed changes in phospholipid fatty acid composition fit a linear regression model suggesting a gradual change in axonal phospholipid fatty acid composition with temperature. 4. 4. The temperature-induced changes in garfish nerve phospholipid fatty acid composition are consistent with the general observation of increased saturated fatty acid residues in plasma membrane phospholipids of organisms acclimated to higher environmental temperatures. 5. 5. The garfish data are similar to data previously obtained for goldfish tissues and Tetrahymena.

A model of a myelinated nerve axon: threshold behaviour and propagation.

A model of a myelinated nerve axon is developed on the basis of FitzHugh-Nagumo dynamics under the assumption that the nodes of Ranvier are of small but finite width. It is shown that a periodic excited state may not exist if the width of the nodes is too small and the leakage across the myelin sheath is too great. The propagation of a super threshold pulse is prevented in the absence of nodes. Global stability of the resting equilibrium state is investigated as well as the propagation of "wave front", type solutions.