Breastfeeding promotes oligodendrocyte precursor cells division and myelination in the demyelinated corpus callosum.

Demyelination alters the conduction of neuronal signals and hampers sensory-motor functions. Experimental and clinical evidence suggest that breastfeeding exerts a promyelinating impact on the maternal brain. The mechanism underlying this neuroprotective effect is not well-understood. In the present paper, we assessed the impact of rat lactation on lysolecithin-induced demyelination injury within the corpus callosum of lactating and non-lactating postpartum rats. We show that lactation enhanced the cell density of oligodendrocyte precursor cells (OPCs), but not that of activated microglia and astrocytes, within the demyelination lesion. Lactation also increased the expression of myelin markers involved in the initial stage of myelin recovery (Myelin-associated glycoprotein and 2',3'-cyclic nucleotide 3'-phosphodiesterase) and reduced the demyelination injury. Altogether, these data suggest that lactation creates a conducive promyelinating environment through increased OPCs cell division, enhanced expression of select myelin proteins, and reduced number of non-myelinated axons.

A plausible contributor to multiple sclerosis; presentation of antigenic myelin protein epitopes by major histocompatibility complexes.

BACKGROUND: Multiple sclerosis (MS) can be induced upon successful presentation of myelin antigens by MHC I/II. Antigenic similarity between the myelin and viral proteins may worsen the immunological responses. METHODOLOGY: Antigenic regions within myelin proteins; PLP1, MBP, MOG, and MAG were analyzed using SVMTrip and EMBOSS. Homology search identified sequence similarity between the predicted host epitopes and viral proteins. NetMHCpan predicted MHC I/II binding followed by peptide-protein docking through the HPEPDOCK server. Thereafter we analyzed conformational flexibility and stability of 15 protein-peptide complexes based on high docking scores. The binding free energy was calculated using conventional (MD) and Gaussian accelerated molecular dynamics simulation. RESULTS: PLP1, MBP, MAG and MOG contained numerous antigenic epitopes. MBP and MOG epitopes had sequence similarity to HHV-6 BALF5; EBNA1 and CMV glycoprotein M (gM), and EBV LMP2B, gp350/220; HHV-8 ORFs respectively. Many herpes virus proteins like tegument, envelope glycoproteins, and ORFs of EBV, CMV, HHV-6, and HHV-8 demonstrated sequence similarity with MAG and PLP1. Some antigenic peptides were also linear B-cell epitopes and influenced cytokine production by T-cell. MHC I allele HLA-B*57:01 bound to PLP1 peptide and HLA-A*68:02 bound to a MAG peptide strongly. MHC II alleles HLA-DRB1*04:05 and HLA-DR1*01:01 associated with MAG- and MOG-derived peptides, respectively, demonstrating high HPEPDOCK scores. MD simulations established stable binding of certain peptides with the MHC namely HLA-B*51:01-MBP(DYKSAHKGFKGVDAQGTLSKIFKL), HLA-B*57:01-PLP1(PDKFVGITYALTVVWLLVFACSAVPVYIYF), HLA-DR1*01:01-MOG(VEDPFYWVSPGVLVLLAVLPVLLLQITVGLVFLCLQYR) and HLA-DRB1*04:05-MAG(TWVQVSLLHFVPTREA). CONCLUSIONS: Cross-reactivity between self-antigens and pathogen derived immunodominant epitopes may induce MS. Our study supported the role of specific MHC alleles as a contributing MS risk factor.

Lead exposure of rats during and after pregnancy induces anti-myelin proteolytic activity: a potential mechanism for lead-induced neurotoxicity.

Toxic effects of lead (Pb) are principally manifested in the central nervous system (CNS) and a mounting body of evidence indicates that excessive chronic exposure to Pb participates in the pathological processes of numerous neurodegenerative disorders in humans.In this study we evaluated whether the prolonged pre- and postnatal exposure of rat pups to lead, administrated through ingestion in drinking water, as a typical environmental exposure, can determine alterations of the protein pattern of CNS myelin and the induction of myelin-associated proteinases. Pregnant dams were given distilled water or 0.3 mg/mL lead acetate in drinking water during gestation and lactation. At postnatal day (PND) 21, pups born from mothers poisoned with Pb continued the treatment with the metal. On PND 35 and 56, pups were sacrificed, and brains were subjected to myelin purification and extraction of myelin-associated proteinases. The SDS-PAGE analysis of protein pattern of myelin incubated in vitro with an oxidative system indicated that myelin proteins from Pb-treated pups were more sensitive to the toxicity of reactive oxygen species in comparison with those from untreated pups. The zymografic analysis of NaCl-extracts from myelin of Pb-treated pups showed a band of digestion of 54 kDa that increased in pups sacrificed at PND 56 in comparison with those sacrificed at PND 35 and correlated with the concentration of Pb, detected in purified myelin. The incubation of the NaCl-extract from Pb-treated pups with purified myelin basic protein (MBP) evidenced the presence of different MBP-degrading activities. These results suggest that Pb may influence the integrity of the myelin sheath, probably through the induction of anti-myelin proteinases.

Ganaxolone enhances microglial clearance activity and promotes remyelination in focal demyelination in the corpus callosum of ovariectomized rats.

AIM: Experimental studies have shown that the progesterone metabolite, allopregnanolone, is endowed with promyelinating effects. The mechanisms underlying these promyelinating effects are not well understood. Therefore, we explored the impact of allopregnanolone's synthetic analogue, ganaxolone, on remyelination and microglial activation following focal demyelination in the corpus callosum of ovariectomized rats. METHODS: Ovariectomized adult Sprague Dawley rats received a stereotaxic injection of 2 µL of 1% lysolecithin solution in the corpus callosum followed by daily injections of either ganaxolone (intraperitoneal injection [i.p.], 2.5 mg/kg) or vehicle. The demyelination lesion was assessed 3 and 7 days postdemyelination insult using Luxol fast blue staining and transmission electron microscopy. The expression levels of myelin proteins (MBP, MAG, MOG, CNPase) were explored using Western blot. The inflammatory response and clearance of damaged myelin were evaluated using immunofluorescent staining (Iba1, dMBP, GFAP) and multiplex enzyme-linked immunosorbent assay (IL-1ß, TNF-α, IL-4, IL-10, IL-6). RESULTS: Systemic administration of ganaxolone promoted remyelination of lysolecithin-induced demyelination, upregulated the expression of major myelin proteins, and enhanced microglial clearance of damaged myelin. Astrocytosis, as well as locally produced pro- and antiinflammatory cytokines, was not affected by ganaxolone treatment. CONCLUSION: Ganaxolone promotes remyelination in response to focal demyelination of the corpus callosum of ovariectomized rats. This effect is, at least in part, mediated by enhancing microglial clearance of myelin debris, which creates a conducive environment for a successful remyelination process.

Neuroactive steroids and diabetic complications in the nervous system.

Important complications of diabetes mellitus in the nervous system are represented by diabetic peripheral neuropathy and diabetic encephalopathy. In this context, an important link is represented by neuroactive steroids (i.e., steroids coming from peripheral glands and affecting nervous functionality as well as directly synthesized in the nervous system). Indeed, diabetes does not only affect the reproductive axis and consequently the levels of sex steroid hormones, but also those of neuroactive steroids. Indeed, as will be here summarized, the levels of these neuromodulators present in the central and peripheral nervous system are affected by the pathology in a sex-dimorphic way. In addition, some of these neuroactive steroids, such as the metabolites of progesterone or testosterone, as well as pharmacological tools able to increase their levels have been demonstrated, in experimental models, to be promising protective agents against diabetic peripheral neuropathy and diabetic encephalopathy.

Adipose tissue-derived stromal cells (ADSC) express oligodendrocyte and myelin markers, but they do not function as oligodendrocytes.

Mesenchymal cells cultured from the vasculo-stromal fraction of adipose tissue (ADSC) show adult stem cell characteristics and several groups have claimed generating neural cells from them. However, we have observed that many markers commonly used for the identification of neural cells are spontaneously expressed by ADSC in culture. In the present study, we have examined the expression of characteristic oligodendrocyte molecules in cultured ADSC, aiming to test if myelinating cells could be generated from accessible non-neural adult tissues. In basal growth conditions, rat ADSC spontaneously expressed CNPase, MBP, MOG, protein zero, GAP43, Sox10, and Olig2, as shown by immunocytrochemistry and western blot. A small population of cultured ADSC expressed membrane galactocerebroside (O1 antibody), but no cell stained with O4 antibody. RT-PCR analyses showed the expression of CNPase, MBP, DM20, and low levels of Olig2, Sox10, and Sox2 mRNA by rat ADSC. When rat ADSC were treated with combinations of factors commonly used in neural-inducing media (retinoic acid, dbcAMP, EGF, basic FGF, NT3, and/or PDGF), the number of O1-positive cells changed, but in no case, mRNA expression of Sox10 and Olig2 transcription factors approached CNS oligodendrocyte levels. In co-culture with rat dorsal root ganglion neurons, no sign of axonal myelination by rat ADSC was observed. These studies show that the expression of oligodendrocyte traits by cultured ADSC is not a proof of functional competence as oligodendroglia and suggest that in culture conditions, ADSC acquire intermediate, uncommitted phenotypes.

Potential molecular mimicry between the human endogenous retrovirus W family envelope proteins and myelin proteins in multiple sclerosis.

Multiple sclerosis is an autoimmune disease caused by the destruction of the myelin sheath in the central nervous system. The major target molecules for the immune response are the myelin basic protein, myelin oligodendrocyte glycoprotein and proteolipid protein but the aetiology of the disease is as yet poorly understood. The HLA Class II allele DRB1*1501 in particular as well as DRB5*0101 and the expression of human endogenous retroviral envelope proteins have been linked to multiple sclerosis but the molecular mechanisms relating these remain to be elucidated. We hypothesised that cross-reactive peptide epitopes in retroviral envelope proteins and myelin proteins that can be presented by the two Class II DR molecules may play a role in initiating multiple sclerosis. Sequence homologies between retroviral envelope and myelin proteins and in silico predictions of peptides derived from them that are able to bind to the two Class II alleles were examined to test the hypothesis. The results support the hypothesis that molecular mimicry in peptide epitopes from envelope proteins of the HERV-W family of endogenous retroviruses and myelin proteins is possible and could potentially trigger multiple sclerosis. Mimicry between syncytin-1, a HERV-W envelope protein that is expressed during placentation, and myelin proteins may also explain the higher prevalence of multiple sclerosis in women. Experiments to test the ability of the identified peptide epitopes to activate TH cells are required to confirm the present findings.

Stereotactic injection of shrna GSK-3ß-AAV promotes axonal regeneration after spinal cord injury.

Evidence suggested that glycogen synthase kinase-3ß (GSK-3ß) is involved in Nogo-66 inhibiting axonal regeneration in vitro, but its effect in vivo was poorly understood. We showed that stereotactic injection of shRNA GSK-3ß-adeno associated virus (GSK-3ß-AAV) diminished syringomyelia and promoted axonal regeneration after spinal cord injury (SCI), using stereotactic injection of shRNA GSK-3ß-AAV (tested with Western blotting and RT-PCR) into the sensorimotor cortex of rats with SCI and by the detection of biotin dextran amine (BDA)-labeled axonal regeneration. We also determined the right position to inject into the sensorimotor cortex. Our findings consolidate the hypothesis that downregulation of GSK-3ß promotes axonal regeneration after SCI.

MARK2 Rescues Nogo-66-Induced Inhibition of Neurite Outgrowth via Regulating Microtubule-Associated Proteins in Neurons In Vitro.

The ability of neurons in the adult mammalian central nervous system (CNS) to regenerate after injury is limited by inhibitors in CNS myelin. Nogo-66 is the most important myelin inhibitor but the mechanisms of Nogo-66 inhibition of neurite outgrowth remain poorly understood. Particularly, the relationship between Nogo-66 and microtubule-affinity regulating kinase 2 (MARK2) has not been examined. This study investigated the role of MARK2 in Nogo-66 inhibition and the function of MARK2 in neurite elongation in neurons in vitro. MARK2 and phosphorylated MARK2 at Ser212 (p-Ser212) alterations in Neuro 2a cells were assessed at different Nogo-66 exposure times; the relationships between MARK2 and microtubule-associated proteins (MAPs) were determined via the overexpression or interference of MARK2. Our study reports that Nogo-66 inhibited the expression of total MARK2 but also reduced Ser212 phosphorylation of MARK2, whereas levels of MAP1-b and tau varied depending on MARK2 overexpression or reduced expression. Furthermore, MARK2 increased the proportion of tyrosinated α-tubulin, thereby disrupting the stability of tubulin, most likely affecting axonal growth. In line with these results, overexpression of MARK2 promoted neurite elongation and therefore is able to rescue the inhibitory effect of Nogo-66 on neurite growth. In conclusion, the intracellular PKB/MARK2/MAPs/α-tubulin pathway appears to be essential for neurite elongation in neurons in vitro. These results suggest a critical role for MARK2 in overcoming Nogo-66-induced inhibition of axon outgrowth in neurons. Pharmacological activators of MARK2 may be applicable to promote successful axonal outgrowth following many types of CNS injuries.

Regulation of DM-20 mRNA expression and intracellular translocation of glutathione-S-transferase pi isoform during oligodendrocyte differentiation in the adult rat spinal cord.

We previously demonstrated that NG2-positive oligodendrocyte precursor cells (OPCs) do not express DM-20 mRNA and identified a distinct DM-20 mRNA-positive cell population expressing glutathione-S-transferase pi isoform (GST-pi) in the nucleus (GST-pi(Nuc)) of the adult rat spinal cord. As GST-pi intranuclear localization correlates with progenitor cell properties, we examined the differentiation status of this cell population under the intensive 5-bromo-2'-deoxyuridine (BrdU) administration method, consisting of intraperitoneal BrdU injections every 2 h for 48 h. We observed that a certain population of proliferating/proliferated cells expressed DM-20 mRNA, and sometimes two proliferating/proliferated cells were observed still attached to each other. We performed triple staining for BrdU, DM-20 mRNA, and NG2 and found pairs of neighboring BrdU-positive cells, which were considered to originate from the same progenitor cells and where both cells expressed DM-20 mRNA. Triple staining for BrdU, DM-20 mRNA, and GST-pi detected proliferating/proliferated cells exhibiting the GST-pi(Nuc)/DM-20 mRNA-positive expression pattern. These findings suggested the presence of a GST-pi(Nuc)/DM-20 mRNA-positive oligodendrocyte-lineage progenitor cell population in the adult rat spinal cord. However, we did not find any pair of neighboring BrdU-positive cells with this expression pattern. These observations collectively support the idea that GST-pi(Nuc)/DM-20 mRNA-expressing cells are the progeny of NG2-positive OPCs rather than a novel type of oligodendrocyte-lineage progenitor cells and that DM-20 mRNA expression is dynamically regulated during differentiation of OPCs into oligodendrocytes.

Rab27a/Slp2-a complex is involved in Schwann cell myelination.

Myelination of Schwann cells in the peripheral nervous system is an intricate process involving myelin protein trafficking. Recently, the role and mechanism of the endosomal/lysosomal system in myelin formation were emphasized. Our previous results demonstrated that a small GTPase Rab27a regulates lysosomal exocytosis and myelin protein trafficking in Schwann cells. In this present study, we established a dorsal root ganglion (DRG) neuron and Schwann cell co-culture model to identify the signals associated with Rab27a during myelination. First, Slp2-a, as the Rab27a effector, was endogenously expressed in Schwann cells. Second, Rab27a expression significantly increased during Schwann cell myelination. Finally, Rab27a and Slp2-a silencing in Schwann cells not only reduced myelin protein expression, but also impaired formation of myelin-like membranes in DRG neuron and Schwann cell co-cultures. Our findings suggest that the Rab27a/Slp2-a complex affects Schwann cell myelination in vitro.

Cerebrovascular disease in ageing and Alzheimer's disease.

Cerebrovascular disease (CVD) and Alzheimer's disease (AD) have more in common than their association with ageing. They share risk factors and overlap neuropathologically. Most patients with AD have Aß amyloid angiopathy and degenerative changes affecting capillaries, and many have ischaemic parenchymal abnormalities. Structural vascular disease contributes to the ischaemic abnormalities in some patients with AD. However, the stereotyped progression of hypoperfusion in this disease, affecting first the precuneus and cingulate gyrus, then the frontal and temporal cortex and lastly the occipital cortex, suggests that other factors are more important, particularly in early disease. Whilst demand for oxygen and glucose falls in late disease, functional MRI, near infrared spectroscopy to measure the saturation of haemoglobin by oxygen, and biochemical analysis of myelin proteins with differential susceptibility to reduced oxygenation have all shown that the reduction in blood flow in AD is primarily a problem of inadequate blood supply, not reduced metabolic demand. Increasing evidence points to non-structural vascular dysfunction rather than structural abnormalities of vessel walls as the main cause of cerebral hypoperfusion in AD. Several mediators are probably responsible. One that is emerging as a major contributor is the vasoconstrictor endothelin-1 (EDN1). Whilst there is clearly an additive component to the clinical and pathological effects of hypoperfusion and AD, experimental and clinical observations suggest that the disease processes also interact mechanistically at a cellular level in a manner that exacerbates both. The elucidation of some of the mechanisms responsible for hypoperfusion in AD and for the interactions between CVD and AD has led to the identification of several novel therapeutic approaches that have the potential to ameliorate ischaemic damage and slow the progression of neurodegenerative disease.

Analysis of clinical and electrophysiological features in patients with hereditary neuropathy with liability to pressure palsy diagnosed by gene analysis / 中华神经科杂志

Objective To study the clinical and electrophysiological features of the patients with hereditary neuropathy with liability to pressure palsy ( HNPP) diagnosed by gene analysis.Methods Seven patients from two HNPP families were assessed on medical history, physical examination, electrophysiology findings and gene analysis.Results A clinical manifestation of acute, painless, recurrent peripheral nerve palsies was typical for HNPP.Median, ulnar and peroneal nerves were usually affected.Electrophysiology study revealed that prolonged distal motor latency and slowing nerve conduction velocity were prominent.Gene studies exhibited a deletion of the peripheral myelination protein 22 gene in all the seven patients.Conclusions HNPP usually affects areas where nerves are subject to entrapment, and many episodes are preceded by minor compression on the affected nerve.As a reliable screening tool in detecting HNPP, the electrophysiological study shows that segmental demyelination is most commonly seen at common nerve entrapment sites.

Stereotactic injection of shrna GSK-3β-AAV promotes axonal regeneration after spinal cord injury / 华中科技大学学报（医学）（英德文版）

Evidence suggested that glycogen synthase kinase-3β (GSK-3β) is involved in Nogo-66 inhibiting axonal regeneration in vitro, but its effect in vivo was poorly understood. We showed that stereotactic injection of shRNA GSK-3β-adeno associated virus (GSK-3β-AAV) diminished syringomyelia and promoted axonal regeneration after spinal cord injury (SCI), using stereotactic injection of shRNA GSK-3β-AAV (tested with Western blotting and RT-PCR) into the sensorimotor cortex of rats with SCI and by the detection of biotin dextran amine (BDA)-labeled axonal regeneration. We also determined the right position to inject into the sensorimotor cortex. Our findings consolidate the hypothesis that downregulation of GSK-3β promotes axonal regeneration after SCI.

Chronic intermittent ethanol induced axon and myelin degeneration is attenuated by calpain inhibition.

Chronic alcohol consumption causes multifaceted damage to the central nervous system (CNS), underlying mechanisms of which are gradually being unraveled. In our previous studies, activation of calpain, a calcium-activated neutral protease has been found to cause detrimental alterations in spinal motor neurons following ethanol (EtOH) exposure in vitro. However, it is not known whether calpain plays a pivotal role in chronic EtOH exposure-induced structural damage to CNS in vivo. To test the possible involvement of calpain in EtOH-associated neurodegenerative mechanisms the present investigation was conducted in a well-established mouse model of alcohol dependence - chronic intermittent EtOH (CIE) exposure and withdrawal. Our studies indicated significant loss of axonal proteins (neurofilament light and heavy, 50-60%), myelin proteins (myelin basic protein, 20-40% proteolipid protein, 25%) and enzyme (2', 3'-cyclic-nucleotide 3'-phosphodiesterase, 21-55%) following CIE in multiple regions of brain including hippocampus, corpus callosum, cerebellum, and importantly in spinal cord. These CIE-induced deleterious effects escalated after withdrawal in each CNS region tested. Increased expression and activity of calpain along with enhanced ratio of active calpain to calpastatin (sole endogenous inhibitor) was observed after withdrawal compared to EtOH exposure. Pharmacological inhibition of calpain with calpeptin (25 µg/kg) prior to each EtOH vapor inhalation significantly attenuated damage to axons and myelin as demonstrated by immuno-profiles of axonal and myelin proteins, and Luxol Fast Blue staining. Calpain inhibition significantly protected the ultrastructural integrity of axons and myelin compared to control as confirmed by electron microscopy. Together, these findings confirm CIE exposure and withdrawal induced structural alterations in axons and myelin, predominantly after withdrawal and corroborate calpain inhibition as a potential protective strategy against EtOH associated CNS degeneration.

Lipids in the nervous system: from biochemistry and molecular biology to patho-physiology.

Lipids in the nervous system accomplish a great number of key functions, from synaptogenesis to impulse conduction, and more. Most of the lipids of the nervous system are localized in myelin sheaths. It has long been known that myelin structure and brain homeostasis rely on specific lipid-protein interactions and on specific cell-to-cell signaling. In more recent years, the growing advances in large-scale technologies and genetically modified animal models have provided valuable insights into the role of lipids in the nervous system. Key findings recently emerged in these areas are here summarized. In addition, we briefly discuss how this new knowledge can open novel approaches for the treatment of diseases associated with alteration of lipid metabolism/homeostasis in the nervous system. This article is part of a Special Issue entitled Linking transcription to physiology in lipidomics.

Relationship study of the expressions of Slit2 and Nogo-A in rats with cerebral hemorrhage / 中国医师杂志

Objective To investigate the expressions of Slit2 and Nogo-A in the ipsilateral hippocampus after cerebral hemorrhage in rats.Methods A total of 64 adult Sprague-Dawley (SD) rats was randomly divided into control and model groups.Collagenase Ⅶ was used to induce cerebral hemorrhage model.Immunohistochemistry was used to detect the expressions of Slit2 and Nogo-A in hippocampus at the cerebral hemorrhage side at the time points (24 h,7 d,14 d,and 21 d).Results Compared to the control group,the expressions of Slit2 and Nogo-A were significantly enhanced in model group (P ＜0.01),with the highest level at the 7 d.Conclutions Cerebral hemorrhage can significantly enhance expressions of Slit2 and Nogo-A with a positive correlation of Slit2 and Nogo-A,which might have an important effect on the recovery of brain injury.

Animal models of autoimmune neuropathy.

The peripheral nervous system (PNS) comprises the cranial nerves, the spinal nerves with their roots and rami, dorsal root ganglia neurons, the peripheral nerves, and peripheral components of the autonomic nervous system. Cell-mediated or antibody-mediated immune attack on the PNS results in distinct clinical syndromes, which are classified based on the tempo of illness, PNS component(s) involved, and the culprit antigen(s) identified. Insights into the pathogenesis of autoimmune neuropathy have been provided by ex vivo immunologic studies, biopsy materials, electrophysiologic studies, and experimental models. This review article summarizes earlier seminal observations and highlights the recent progress in our understanding of immunopathogenesis of autoimmune neuropathies based on data from animal models.

Axonal loss in multiple sclerosis: causes and mechanisms.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and the leading cause of non-traumatic neurologic disability in young adults in the United States and Europe. The disease course is variable and starts with reversible episodes of neurologic disability which transforms into continuous and irreversible neurologic decline. It is well established that loss of axons and neurons is the major cause of the progressive neurologic decline that most MS patients endure. Current hypotheses support primary inflammatory demyelination as the underlying cause of axonal loss during earlier stages in MS. The transition to progressive disease course is thought to occur when a threshold of neuronal and axonal loss is reached and the compensatory capacity of the central nervous system is surpassed. Available immunomodulatory therapies are of little benefit to MS after entering this irreversible phase of the disease. Elucidation of mechanisms that are responsible for axonal loss is therefore essential for the development of therapies directed to stop neurologic decline in MS patients. The current chapter reviews existing data on mechanisms of axonal pathology in MS.

Demyelination in multiple sclerosis.

This review, focused on demyelination in multiple sclerosis, is divided in two parts. The first part addresses the many and not exclusive mechanisms leading to demyelination in the central nervous system. Although the hypothesis that a primary oligodendrocyte or myelin injury induces a secondary immune response in the central nervous system is still a matter of debate, most recent advances underline the influence of a primary immune response against myelin antigen(s), with a diversity of potential targets. Whereas multiple sclerosis was long considered as a T cell-mediated disease, the role of B lymphocytes is now increasingly recognized, and the influence of antibodies on tissue damage actively investigated. The second part of the review describes the axonal consequences of demyelination. Segmental demyelination results in conduction block or slowing of conduction through adaptative responses, notably related to modifications in the distribution of voltage gated sodium channels along the denuded axon. If demyelination persists, these changes, as well as the loss of trophic and metabolic support, will lead to irreversible axonal damage and loss. In this respect, favouring early myelin repair, during a window of time when axonal damage is still reversible, might pave the way for neuroprotection.