Promoting myelin repair and return of function in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Conduction block in demyelinated axons underlies early neurological symptoms, but axonal transection and neuronal loss are believed to be responsible for more permanent chronic deficits. Several therapies are approved for treatment of relapsing-remitting MS, all of which are immunoregulatory and clinically proven to reduce the rate of lesion formation and exacerbation. However, existing approaches are only partially effective in preventing the onset of disability in MS patients, and novel treatments to protect myelin-producing oligodendrocytes and enhance myelin repair may improve long-term outcomes. Studies in vivo in genetically modified mice have assisted in the characterization of mechanisms underlying the generation of neuropathology in MS patients, and have identified potential avenues for oligodendrocyte protection and myelin repair. However, no treatments are yet approved that target these areas directly, and in addition, the relationship between demyelination and axonal transection in the lesions of the disease remains unclear. Here, we review translational research targeting oligodendrocyte protection and myelin repair in models of autoimmune demyelination, and their potential relevance as therapies in MS.     

Detection of sodium channel distribution in rat sciatic nerve following lysophosphatidylcholine-induced demyelination

Summary In vivo application of lysophosphatidylcholine (LPC) to rat sciatic nerve induces impaired hind leg movement within 2 days which is recovered by 6 days. Segmental demyelination was seen at 2 days after LPC application, and remyelination had barely started in a few axons by 6 days. Using sodium channel-specific monoclonal antibodies and immunofluorescence microscopy, we observed altered distribution of sodium channels in demyelinated axons. Bright fluorescent labeling was found along the segmentally demyelinated axolemma at 6 days in contrast to the dim staining of the demyelinated nerve found at 2 days. In addition, radioimmunoassays detected an elevated number of antibody binding sites on sciatic nerve trunk from the sixth day. Our data provide the immunocytochemical evidence for the assumption that recruitment of sodium channels into demyelinated axolemma contributes to the recovery of function following axon demyelination by LPC.     

Conduction along myelinated and demyelinated nerve fibres during the recovery cycle: Model investigations

The membrane excitability changes as well as the underlying mechanisms of these changes in a normal and in a systematically paranodally demyelinated nerve fibre have been investigated by paired stimulation during the first 30 ms of the recovery cycle. The ionic current kinetics determining the observed changes in the action potential parameters are presented also. The simulation of the conduction in the normal fibre is based on the Frankenhaeuser and Huxley (1964) and Goldman and Albus (1968) equations, while in the case of a demyelinated fibre according to the same equations modified by Stephanova (1988a). It has been shown for the demyelinated membrane that increased demyelination increases both the threshold current for the second potential as well as the absolute refractory period. With increasing interpulse interval, the subnormality of the membrane excitability is followed by supernormality in the case of the demyelinated membrane. For the recovery cycle of 30 ms under consideration no supernormality of the normal membrane excitability is obtained. With interpulse interval from 8.8 to 10.9 ms, the highest degree of demyelination (l=30 m) is accompanied by a refractory period of transmission. The membrane properties of the normal and demyelinated fibres recover 20 ms after the first pulse. For short interpulse intervals, the amplitude of the second action potential is decreased, and a slower propagation velocity is obtained. The most sensitive phenomenon is the excitability of the demyelinated membrane, which remains unrecovered 30 ms after the first pulses has been applied.     

Action potentials and ionic currents through paranodally demyelinated human motor nerve fibres: computer simulations

 The relationship between the changes in the passive paranodal properties of the myelinated human motor nerve fibres and the conduction abnormalities obtained is examined on the basis of a double-cable model. Simulated systematic demyelination (all paranodal regions uniformly affected) and focal demyelination (paranodal regions at each end of a single internode affected) of the fibres are defined as a reduction of the paranodal seal resistance. By increasing the degree of demyelination, the kinetics of the action potentials and ionic currents in different segments of the fibres are explored. The altered paranodal seal resistance is found to be a factor impeding the invasion of the demyelinated regions by an action potential. We established that the conduction along the most severely demyelinated fibres (i.e. in the case of systematically demyelinated fibres) is more affected than along the focally demyelinated fibres. Received: 8 July 1996/Accepted in revised form: 13 December 1996     

Conduction along myelinated and demyelinated nerve fibres with a reorganized axonal membrane during the recovery cycle: model investigations

The changes in the excitability of the reorganized axonal membrane in myelinated and demyelinated nerve fibres as well as the causes conditioning such changes have been investigated by paired stimulation during the first 30 ms of the recovery cycle. The variations of the action potential parameters (amplitude and velocity) are traced also. The simulation of the conduction along the normal fiber is based on the Frankenhaeuser and Huxley (1964) and Goldman and Albus (1968) equations, while the demyelination is considered to be an elongation of the nodes of Ranvier. The axonal membrane reorganization is achieved by means of potassium channel blocking and increase of the sodium-channel permeability. It is shown that potassium channels block decreases membrane excitability for the myelinated and demyelinated fibres in the cases of initial and paired stimulation. With increasing sodium-channel permeability on the background of the blocked potassium channels, the membrane excitability is increased. For the fibres with a reorganized membrane, a supernormality of the membrane excitability is obtained, the latter remaining unrecovered during the 30 ms cycle under investigation. The supernormality of the excitability grows from the demyelinated fibre without reorganized membrane to the demyelinated fibre with reorganized one. For short interstimulus intervals, the second action potential propagates along the fibres with a reduced velocity and a decreased amplitude. No supernormality of the potential parameters (amplitude, velocity) is observed during the cycle up to 30 ms. The membrane properties of the myelinated and demyelinated fibres with blocked potassium channels recover in the interval from 15 to 20 ms depending on whether the sodium channels' increase of the permeability is added on the background of the blocked potassium channel or not. In the recovery cycle, the axonal membrane reorganization leads to an improvement of the conduction along most severely demyelinated fibres.     

Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation

Demyelination is the hallmark of numerous neurodegenerative conditions, including multiple sclerosis. Oligodendrocyte progenitors (OPCs), which normally mature into myelin-forming oligodendrocytes, are typically present around demyelinated lesions but do not remyelinate affected axons. Here, we find that the glycosaminoglycan hyaluronan accumulates in demyelinated lesions from individuals with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. A high molecular weight (HMW) form of hyaluronan synthesized by astrocytes accumulates in chronic demyelinated lesions. This form of hyaluronan inhibits remyelination after lysolecithin-induced white matter demyelination. OPCs accrue and do not mature into myelin-forming cells in demyelinating lesions where HMW hyaluronan is present. Furthermore, the addition of HMW hyaluronan to OPC cultures reversibly inhibits progenitor-cell maturation, whereas degrading hyaluronan in astrocyte-OPC cocultures promotes oligodendrocyte maturation. HMW hyaluronan may therefore contribute substantially to remyelination failure by preventing the maturation of OPCs that are recruited to demyelinating lesions.     

Membrane property abnormalities in simulated cases of mild systematic and severe focal demyelinating neuropathies

The investigation of multiple nerve membrane properties by mathematical models has become a new tool to study peripheral neuropathies. In demyelinating neuropathies, the membrane properties such as potentials (intracellular, extracellular, electrotonic) and indices of axonal excitability (strength-duration time constants, rheobases and recovery cycles) can now be measured at the peripheral nerves. This study provides numerical simulations of the membrane properties of human motor nerve fibre in cases of internodal, paranodal and simultaneously of paranodal internodal demyelinations, each of them mild systematic or severe focal. The computations use our previous multi-layered model of the fibre. The results show that the abnormally greater increase of the hyperpolarizing electrotonus, shorter strength-duration time constants and greater axonal superexcitability in the recovery cycles are the characteristic features of the mildly systematically demyelinated cases. The small decrease of the polarizing electrotonic responses in the demyelinated zone in turn leads to a compensatory small increase of these responses outside the demyelinated zone of all severely focally demyelinated cases. The paper summarizes the insights gained from these modeling studies on the membrane property abnormalities underlying the variation in clinical symptoms of demyelination in Charcot-Marie-Tooth disease type 1A, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome and multifocal motor neuropathy. The model used provides an objective study of the mechanisms of these diseases which up till now have not been sufficiently well understood, because quite different assumptions have been given in the literature for the interpretation of the membrane property abnormalities obtained in hereditary, chronic and acquired demyelinating neuropathies.     

The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease

The pathophysiology of multiple sclerosis is reviewed, with emphasis on the axonal conduction properties underlying the production of symptoms, and the course of the disease. The major cause of the negative symptoms during relapses (e.g. paralysis, blindness and numbness) is conduction block, caused largely by demyelination and inflammation, and possibly by defects in synaptic transmission and putative circulating blocking factors. Recovery from symptoms during remissions is due mainly to the restoration of axonal function, either by remyelination, the resolution of inflammation, or the restoration of conduction to axons which persist in the demyelinated state. Conduction in the latter axons shows a number of deficits, particularly with regard to the conduction of trains of impulses and these contribute to weakness and sensory problems. The mechanisms underlying the sensitivity of symptoms to changes in body temperature (Uhthoff's phenomenon) are discussed. The origin of 'positive' symptoms, such as tingling sensations, are described, including the generation of ectopic trains and bursts of impulses, ephaptic interactions between axons and/or neurons, the triggering of additional, spurious impulses by the transmission of normal impulses, the mechanosensitivity of axons underlying movement-induced sensations (e.g. Lhermitte's phenomenon) and pain. The clinical course of the disease is discussed, together with its relationship to the evolution of lesions as revealed by magnetic resonance imaging and spectroscopy. The earliest detectable event in the development of most new lesions is a breakdown of the blood-brain barrier in association with inflammation. Inflammation resolves after approximately one month, at which time there is an improvement in the symptoms. Demyelination occurs during the inflammatory phase of the lesion. An important mechanism determining persistent neurological deficit is axonal degeneration, although persistent conduction block arising from the failure of repair mechanisms probably also contributes.     

CD8+ T Cells Cause Disability and Axon Loss in a Mouse Model of Multiple Sclerosis

Background

The objective of this study was to test the hypothesis that CD8⁺ T cells directly mediate motor disability and axon injury in the demyelinated central nervous system. We have previously observed that genetic deletion of the CD8⁺ T cell effector molecule perforin leads to preservation of motor function and preservation of spinal axons in chronically demyelinated mice.

Methodology/Principal Findings

To determine if CD8⁺ T cells are necessary and sufficient to directly injure demyelinated axons, we adoptively transferred purified perforin-competent CD8⁺ spinal cord-infiltrating T cells into profoundly demyelinated but functionally preserved perforin-deficient host mice. Transfer of CD8⁺ spinal cord-infiltrating T cells rapidly and irreversibly impaired motor function, disrupted spinal cord motor conduction, and reduced the number of medium- and large-caliber spinal axons. Likewise, immunodepletion of CD8⁺ T cells from chronically demyelinated wildtype mice preserved motor function and limited axon loss without altering other disease parameters.

Conclusions/Significance

In multiple sclerosis patients, CD8⁺ T cells outnumber CD4⁺ T cells in active lesions and the number of CD8⁺ T cells correlates with the extent of ongoing axon injury and functional disability. Our findings suggest that CD8⁺ T cells may directly injure demyelinated axons and are therefore a viable therapeutic target to protect axons and motor function in patients with multiple sclerosis.     

关于健康成人左右运动神经传导参数的比较

目的:研究正常人左、右侧的末梢神经传导特点及易损伤性,探讨生活习惯与末梢神经潜在性损伤的内在关联,提高电生理诊断准确率。方法:100名志愿者为对象,检测正中、尺、胫和腓神经的复合肌肉动作电位(CMAP)、F波,观察左、右侧的神经传导参数及左右差值与生活习惯之间的联系。结果:左侧尺、胫运动神经传导速度(MCV)慢于右侧(P值各为0.013、0.011)。MCV≤X-1S尺神经组的远端潜伏期(D Lat)、F波最短潜伏期(F-Lat)延长于MCV>X-1S组(P值均为0.000)。MCV≤X-1S胫神经组的近端波幅(P Amp)低于MCV>X-1S组(P=0.000)。右侧腓神经D Lat延长于左侧(P=0.007),D Lat≥X+1S腓神经组的MCV、F-Lat平均值慢或延长于D Lat相似文献   

Prostacyclin promotes oligodendrocyte precursor recruitment and remyelination after spinal cord demyelination

Adult oligodendrocyte precursor cells (OPCs) are located adjacent to demyelinated lesion and contribute to myelin repair. The crucial step in remyelination is the migration of OPCs to the demyelinated area; however, the mechanism of OPC migration remains to be fully elucidated. Here we show that prostacyclin (prostaglandin I₂, PGI₂) promotes OPC migration, thereby promoting remyelination and functional recovery in mice after demyelination induced by injecting lysophosphatidylcholine (LPC) into the spinal cord. Prostacyclin analogs enhanced OPC migration via a protein kinase A (PKA)-dependent mechanism, and prostacyclin synthase expression was increased in the spinal cord after LPC injection. Notably, pharmacological inhibition of prostacyclin receptor (IP receptor) impaired remyelination and motor recovery, whereas the administration of a prostacyclin analog promoted remyelination and motor recovery after LPC injection. Our results suggest that prostacyclin could be a key molecule for facilitating the migration of OPCs that are essential for repairing demyelinated areas, and it may be useful in treating disorders characterized by demyelination.     

The effect of temperature on a simulated systematically paranodally demyelinated nerve fiber

The temperature dependence (from 10° to 50°C) of the intracellular action potentials' parameters as well as of the ionic currents' kinetics in normal and demyelinated nerve fiber is studied. The simulation of the conduction in the normal fiber is based on the Frankenhaeuser and Huxley (1964) and Goldman and Albus (1968) equations, while in the case of a demyelinated fiber according to the same equations modified by Stephanova (1988). The temperature coefficients (Q ₁₀) for the rate constants as well as for the sodium and potassium permeabilities are introduced. It is shown that increased temperature blocks conduction in the simulated demyelinated fiber at temperatures much lower than the blocking temperature for the normal fiber. When temperature is increased, the amplitude as well as the wavelength and the asymmetry of the potential decrease. The relationship between conduction velocity and temperature is non-linear. The velocity increases when the temperature approaches the blocking temperature, after which abruptly drops. At a given degree of demyelination with increasing temperatures, the ionic currents' flow and the membrane conduction respectively increase, but, at lower temperatures, when the degree of the demyelination is increased, the conduction is blocked.     

Differences in Membrane Properties in Simulated Cases of Demyelinating Neuropathies: Internodal Focal Demyelinations with Conduction Block

The aim of this study is to investigate the membrane properties (potentials and axonal excitability indices) in the case of myelin wrap reduction (96%) in one, two and three consecutive internodes along the length of human motor nerve fibre. The internodally focally demyelinated cases (termed as IFD1, IFD2 and IFD3, respectively, with one, two and three demyelinated internodes are simulated using our previous double cable model of the fibre. The progressively greater increase of focal loss of myelin lamellae blocks the invasion of the intracellular potentials into the demyelinated zones. For all investigated cases, the radial decline of the extracellular potential amplitudes increases with the increase of the radial distance and demyelination, whereas the electrotonic potentials show a decrease in the slow part of the depolarizing and hyperpolarizing responses. The time constants are shorter and the rheobases higher for the IFD2 and IFD3 cases than for the normal case. In the recovery cycles, the same cases have less refractoriness, greater supernormality and less late subnormality than the normal case. The simulated membrane abnormalities can be observed in vivo in patients with demyelinating forms of Guillain-Barré syndrome. The study provides new information about the pathophysiology of acquired demyelinating neuropathies.     

Differences in Membrane Properties in Simulated Cases of Demyelinating Neuropathies: Internodal Focal Demyelinations without Conduction Block

The membrane properties (intracellular, extracellular, electrotonic potentials, strength-duration time constants, rheobasic currents and recovery cycles), which can now be measured in healthy subjects and patients with demyelinating neuropathies, are investigated in simulated cases of focal reduction (70%) of the myelin sheath in one, two and three successive internodal segments along the length of human motor fibres. The internodally focally demyelinated cases (termed as IFD1, IFD2 and IFD3, respectively) are simulated using our previous double cable model of the fibres. The results show that the intracellular potentials are with reduced amplitude and slowed conduction velocity in the vicinity of demyelinated segments, however the segmental conduction block is not achieved. The radial decline of the extracellular potential amplitudes slightly increases with the increase of the radial distance and demyelination. In contrast, the electrotonic potentials, strength-duration time constants and rheobases are normal. In the recovery cycles, the refractoriness, supernormality and less late subnormality are close to the normal, showing that the pathology is relatively minor. The obtained abnormalities in the potentials and excitability properties provide new information about the pathophysiology of the demyelinated human motor axons and can be observed in vivo in patients with acquired demyelinating neuropathies.     

Electrophysiology of the peripheral nerve net in the polyclad flatworm Freemania litoricola.

1. A diffuse-conducting system close to the dorsal epithelium of the polyclad flatworm Freemania litoricola is described. Tactile stimuli elicit small action potentials which can be conducted around lesions through the body wall. The potentials can occur in bursts or barrages. 2. This conducting system appears to be insensitive to Mg2+ ions. 3. Conduction velocities (0-26--71 m/sec) vary over the animal. Conduction spread in the anterior half of the animal appears to be greater than that in the posterior portion. 4. Response decrement to repeated stimulation can be recorded in the peripheral system but it is not clear if this is due to habituation or fatigue. 5. Conduction from the peripheral net to the brain occurs. Some central units appear to pick up information only, or mainly, through the anterior nerves, while other units can respond to information conducted through the network to nerves of the contralateral side. 6. Different possibilities to account for this system are discussed, and it is suggested that the animals either possess a unique Mg2+ insensitive synaptic nerve-net or else the network is electrically coupled.     

Book Review

Electronic Conduction and Mechanoelectrical Transduction in Biological Materials. Edited By Boguslaw Lipinski Marcel Dekker, Inc. New York, New York     

Intranasal HB-EGF administration favors adult SVZ cell mobilization to demyelinated lesions in mouse corpus callosum

In the adult rodent brain, the subventricular zone (SVZ) represents a special niche for neural stem cells; these cells proliferate and generate neural progenitors. Most of these migrate along the rostral migratory stream to the olfactory bulb, where they differentiate into interneurons. SVZ-derived progenitors can also be recruited spontaneously to damaged brain areas to replace lost cells, including oligodendrocytes in demyelinated lesions. In this study, we searched for factors able to enhance this spontaneous recruitment of endogenous progenitors. Previous studies have suggested that epidermal growth factor (EGF) could stimulate proliferation, migration, and glial differentiation of SVZ progenitors. In the present study we examined EGF influence on endogenous SVZ cell participation to brain repair in the context of demyelinated lesions. We induced a focal demyelinated lesion in the corpus callosum by lysolecithin injection and showed that intranasal heparin-binding epidermal growth factor (HB-EGF) administration induces a significant increase in SVZ cell proliferation together with a stronger SVZ cell mobilization toward the lesions. Besides, HB-EGF causes a shift of SVZ-derived progenitor cell differentiation toward the astrocytic lineage. However, due to the threefold increase in cell recruitment by EGF treatment, the absolute number of SVZ-derived oligodendrocytes in the lesion of treated mice is higher than in controls. These results suggest that enhancing SVZ cell proliferation could be part of future strategies to promote SVZ progenitor cell mobilization toward brain lesions.     

Persistent reflection underlies ectopic activity in multiple sclerosis: a numerical study

Ectopic activity in multiple sclerosis (MS) patients has been traditionally attributed to hyperexcitability of the demyelinated axon segments. Here, we propose that the same outcome may be the result of persistent reflection—the continuous reactivation of the axonal nodes that limit a demyelinated internodal segment. Using computer simulations, we studied the patterns of impulse propagation for a wide range of electrophysiological conditions. In uniformly myelinated fibers, increasing the temperature enabled successful propagation with no blocks in more severe conditions of demyelination. Secondary activations that were originated at the paranodes were formed for temperatures lower than T = 305 K, and at the condition of high sodium channel excitability. Non-sustained and persistent reflections appeared in the case of focally demyelinated fibers, and only within a narrow range of parameters of high temperature and membrane excitability. Persistent reflection reached steady state in ionic currents within 4 ms, and was characterized with a very high activation frequency of 1.504 ± 0.039 kHz. We conclude that persistent reflection is a possible mechanism for ectopic activity in MS patients, being more prominent in higher temperatures and severe axonal demyelination. Eliminating these symptoms may be addressed by cooling the body or by applying pharmacological agents to alter excitability properties.     

Action potential refractory period in axonal demyelination: a computer simulation

Axonal demyelination leads to an increase in the refractory period for propagation of the action potential. Computer simulations were used to investigate the mechanism by which changes in the passive properties of the internodal membrane increase the refractory period. The properties of the voltage dependent ion channels can be altered to restore conduction in demyeliated nerve fibers. The ability of these alterations to decrease the refractory period of demyelinated model nerve fibers was compared. The model nerve fiber contained six nodes. The action potential was stimulated at node one and propagated to node six. The internode between nodes three and four was demyelinated in a graded manner. The absolute refractory period for propagation of the action potential through the demyelinated internode increased as the number of myelin wraps was reduced to less than 25% of the normal value. The increase in refractory period was found to be due to a reduction in the rate or repolarization of the action potential at node three. The delay in repolarization reduced the rate of recovery of inactivated Na channels and slowed the closing of K channels. The rate of repolarization of node three was reduced by the conduction delay for the depolarization of node four caused by demyelination of the preceeding internode. In these simulations the increase in refractory period due to demyelination was eliminated by slowing the onset of Na channel inactivation. A small reduction of the K conductance also decreased the refractory period. However, larger reductions eliminated this effect.     

IGF binding protein alterations on periplaque oligodendrocytes in multiple sclerosis: implications for remyelination

Why myelin repair greatly fails in multiple sclerosis (MS) is unclear. The insulin-like growth factor (IGF) system plays vital roles in oligodendrocyte development, survival, and myelin synthesis. We used immunohistochemistry to study IGF-I, IGF-I receptors and IGF binding proteins (IGFBPs) 1-6 on oligodendrocytes at the edges of chronic demyelinated plaques and normal appearing white matter of MS, and in cerebral white matter of controls without neurological disease. Oligodendrocytes in all conditions were immunoreactive for IGF-I, IGF-I receptors and IGFBPs-1-5. Oligodendrocytes at the edges of demyelinated plaques displayed enhanced immunoreactivity for IGF-I, IGF-I receptors, IGFBPs-1 and -6. Because increased expression of IGFBPs-1 and -6 has been associated with impaired synthesis of myelin proteins in oligodendrocyte lineage cells, pharmacological approaches to reduce their expression might be useful for promoting remyelination of axons in MS lesions.