Demyelination Of Corpus Callosum Research Articles

Pathologic TDP-43 downregulates myelin gene expression in the monkey brain.

Growing evidence indicates that non-neuronal oligodendrocyte plays an important role in Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In patient's brain, the impaired myelin structure is a pathological feature with the observation of TDP-43 in cytoplasm of oligodendrocyte. However, the mechanism underlying the gain of function by TDP-43 in oligodendrocytes, which are vital for the axonal integrity, remains unclear. Recently, we found that the primate-specific cleavage of truncated TDP-43 fragments occurred in cytoplasm of monkey neural cells. This finding opened up the avenue to investigate the myelin integrity affected by pathogenic TDP-43 in oligodendrocytes. In current study, we demonstrated that the truncated TDP-35 in oligodendrocytes specifically, could lead to the dysfunctional demyelination in corpus callosum of monkey. As a consequence of the interaction of myelin regulatory factor with the accumulated TDP-35 in cytoplasm, the downstream myelin-associated genes expression was downregulated at the transcriptional level. Our study aims to investigate the potential effect on myelin structure injury, affected by the truncated TDP-43 in oligodendrocyte, which provided the additional clues on the gain of function during the progressive pathogenesis and symptoms in TDP-43 related diseases.

5Z-7-Oxozaenol attenuates cuprizone-induced demyelination in mice through microglia polarization regulation.

Demyelination is a key factor in axonal degeneration and neural loss, leading to disability in multiple sclerosis (MS) patients. Transforming growth factor beta activated kinase 1 (TAK1) is a critical molecule involved in immune and inflammatory signaling pathways. Knockout of microglia TAK1 can inhibit autoimmune inflammation of the brain and spinal cord and improve the outcome of MS. However, it is unclear whether inhibiting TAK1 can alleviate demyelination. Eight-week-old male c57bl/6j mice were randomly divided into five groups: (a) the control group, (b) the group treated with cuprizone (CPZ) only, (c) the group treated with 5Z-7-Oxozaenol (OZ) only, and (d) the group treated with both cuprizone and 15 μg/30 μg OZ. Demyelination in the mice of this study was induced by administration of CPZ (ig) at a daily dose of 400mg/kg for consecutive 5weeks. OZ was intraperitoneally administered at mentioned doses twice a week, starting from week 3 after beginning cuprizone treatment. Histology, rotarod test, grasping test, pole test, Western blot, RT-PCR, and ELISA were used to evaluate corpus callosum demyelination, behavioral impairment, oligodendrocyte differentiation, TAK1 signaling pathway expression, microglia, and related cytokines. Our results demonstrated that OZ protected against myelin loss and behavior impairment caused by CPZ. Additionally, OZ rescued the loss of oligodendrocytes in CPZ-induced mice. OZ inhibited the activation of JNK, p65, and p38 pathways, transformed M1 polarized microglia into M2 phenotype, and increased brain-derived neurotrophic factor (BDNF) expression to attenuate demyelination in CPZ-treated mice. Furthermore, OZ reduced the expression of proinflammatory cytokines and increases anti-inflammatory cytokines in CPZ-treated mice. These findings suggest that inhibiting TAK1 may be an effective approach for treating demyelinating diseases.

Microglial Neuroinflammation-Independent Reversal of Demyelination of Corpus Callosum by Arsenic in a Cuprizone-Induced Demyelinating Mouse Model.

Demyelination is the loss of myelin in CNS, resulting in damaged myelin sheath. Oxidative stress and neuroinflammation play a key role in inducing demyelinating diseases like MS; hence, controlling oxidative stress and neuroinflammation is important. Cuprizone (CPZ), a copper chelator, generates oxidative stress and neuroinflammation, thereby inducing demyelination. Therefore, the CPZ-induced demyelinating mouse model (CPZ model) is widely used in research. The present study was intended to unravel a mechanism of inhibition of demyelination by arsenic in a CPZ model, which is otherwise known for its toxicity. We investigated an alternative mechanism of inhibition of demyelination by arsenic through the reversal of SOD1 activity employing in silico analysis, analytical chemistry techniques, and in vitro and in vivo experiments. In vivo experiments showed protection of body weight, survivability, and myelination of the corpus callosum in CPZ and arsenic-co-exposed animals, where neuroinflammation was apparently not involved. In vitro experiments revealed that arsenic-mediated reversal of impaired SOD1 activity leads to reduced cellular ROS levels and better viability of primary oligodendrocytes. Reversal of SOD1 activity was also observed in the corpus callosum tissue isolated from experimental animals. In silico and analytical chemistry studies revealed that similar to copper, arsenic can potentially bind to CPZ and thereby make the copper freely available for SOD1 activity. Suitable neurobehavior tests further validated the protective effect of arsenic. Taken together, the present study revealed that arsenic protects oligodendrocytes and demyelination of corpus callosum by reversing CPZ-induced impaired SOD1 activity.

Abstract TP17: SPAK Kinase Inhibitor ZT-1a Prevents Reactive Astrogliosis, Blood-Brain Barrier Breakdown, and Demyelination in a Mouse Model of VCID

Background: Blood-brain barrier (BBB) breakdown, reactive astrogliosis, and myelin losses are the key features of vascular contributions to cognitive impairment and dementia (VCID). However, the molecular and cellular mechanisms underlying VCID are not well understood. Stimulation of Na-K-Cl cotransport 1 (NKCC1) and its downstream kinase SPAK (the STE20/SPS1-related proline/alanine-rich kinase) causes intracellular Na + overload, astrocytic hypertrophy, and swelling. In this study, we investigated the effect of SPAK inhibitor ZT-1a on bilateral carotid artery stenosis (BCAS)-mediated reactive astrogliosis, BBB breakdown, demyelination, and cerebral blood flow (CBF) in mice. Methods: BCAS was induced in male mice using two metal microcoils twined around both carotid arteries. Sham or BCAS mice receiving vehicle or a selective SPAK inhibitor ZT-1a were monitored for changes in CBF by laser speckle imaging and cognitive functions by the novel object recognition test. Expression of NKCC1 and BBB proteins, reactive astrogliosis, and demyelination were examined by immunofluorescence staining. Results: BCAS mice exhibited sustained CBF reduction and cognitive function deficits along with significant demyelination in corpus callosum and external capsule 8 weeks after BCAS procedure. Compared to sham mice, the BCAS mice showed increased NKCC1 expression in GFAP + astrocytes, reduced expression of ZO-1 and Claudin-5 in GLUT1 + endothelial cells, decreased APC + mature oligodendrocyte and NG2 + oligodendrocyte progenitor cells. Interestingly, delayed administration of ZT-1a (4-8 weeks post-BCAS) prevented BCAS-induced reactive astrogliosis, BBB breakdown, demyelination, and significantly improved CBF and cognitive functions. Conclusion: Our study demonstrates that BCAS-induced stimulation of NKCC1 involves in reactive astrogliosis, BBB breakdown, OL death, and cognitive impairment. Inhibition of the SPAK-NKCC1 cascade by pharmacological inhibitor has therapeutic potential for VCID therapy. This research was supported by NIH R01 166199 Grant (M.I.H.B.).

Spontaneous remyelination following dimethyl sulfoxide-induced demyelination is accompanied by behavioral and neurological alteration in mice

Introduction: Dimethyl sulfoxide (DMSO) is a commonly used solvent that can be applied in experimental studies for preparation of hydrophobic solutions as well as in capacity of a cryopreservative in transplantology. According to modern data acquired from in vitro experiments, DMSO is able to change the structure of myelin by decreasing synthesis of its main components and inhibiting oligodendrocyte genesis. Aim of the study: We studied influence of DMSO on anxiety and compulsive-like behavior, pain perception, motor coordination and myelin quantity in the corpus callosum of the C57BL/6 mice brain after prolonged oral administration of the solvent and 4 weeks after administration was stopped. Materials and Methods: All the experiments were conducted on male inbreed C57BL/6 mice. DMSO was added to drinking water to achieve 0.01% concentration, and the obtained solution was administered ad libitum for 6 weeks. After 6 weeks of administration of DMSO and 4 weeks after administration of DMSO was stopped, anxiety-like behavior in open field test, compulsive-like behavior in marble burying test, motor coordination in rotarod test, pain perception in tail-immersion test, as well as myelin quantity in the corpus callosum were evaluated. Results: It was established that DMSO consumed for 6 weeks was associated with decrease in the myelin quantity in thecorpus callosum and thermal hyperalgesia in tail-immersion test. During 4-week period after DMSO administration was stopped, attenuation of demyelination was observed, followed by an increase in thermal hyperalgesia in tail-immersion test, as well as vertical locomotion and exploratory activity in open field test. Conclusions: 6-week ad libitum administration of 0.01% DMSO solution was associated with demyelination in corpus callosum of С57BL/6 mice, followed by thermal hyperalgesia. Cessation of DMSO led to spontaneous remyelination with an increase in thermal hyperalgesia, vertical locomotion and exploratory activity of mice.

Marchiafava–Bignami disease after the white matter lesions: A case report

AbstractMarchiafava–Bignami disease (MBD) is an uncommon alcoholism‐related neuropsychiatric disorder, featured with symmetrical demyelination of part or whole corpus callosum (CC). Previous studies reported follow‐up neuroimaging changes with necrosis, cystic degeneration, and atrophy of the CC after the diagnosis of MBD, but it is unclear whether the white matter is damaged before MBD. We report a case of alcoholic MBD whose magnetic resonance imaging revealed structural lesions in the white matter before the typical demyelination of CC during MBD, which support the prior hypothesis that chronic hazardous drinking may initially lead to microstructure abnormalities of the white matter and CC through some possible mechanisms, then microstructure lesions in the CC, and white matter deterioration into extensive demyelination, that is MBD. In future clinical practice, when patients with chronic alcoholism seek treatment for neuropsychiatric disorders, they may need to undergo repeated MRI scans to reveal progressive neuroimaging features before and after MBD.

Korean Red Ginseng extract ameliorates demyelination by inhibiting infiltration and activation of immune cells in cuprizone-administrated mice

BackgroundKorean Red Ginseng (KRG), the steamed root of Panax ginseng, has pharmacological activities for immunological and neurodegenerative disorders. But, the role of KRGE in multiple sclerosis (MS) remains unclear. PurposeTo determine whether KRG extract (KRGE) could inhibit demyelination in corpus callosum (CC) of cuprizone (CPZ)-induced murine model of MS MethodsMale adult mice were fed with a standard chow diet or a chow diet supplemented with 0.2% (w/w) CPZ ad libitum for six weeks to induce demyelination while were simultaneously administered with distilled water (DW) alone or KRGE-DW (0.004%, 0.02 and 0.1% of KRGE) by drinking. ResultsAdministration with KRGE-DW alleviated demyelination and oligodendrocyte degeneration associated with inhibition of infiltration and activation of resident microglia and monocyte-derived macrophages as well as downregulation of proinflammatory mediators in the CC of CPZ-fed mice. KRGE-DW also attenuated the level of infiltration of Th1 and Th17) cells, in line with inhibited mRNA expression of IFN-γ and IL-17, respectively, in the CC. These positive effects of KRGE-DW mitigated behavioral dysfunction based on elevated plus maze and the rotarod tests. ConclusionThe results strongly suggest that KRGE-DW may inhibit CPZ-induced demyelination due to its oligodendroglial protective and anti-inflammatory activities by inhibiting infiltration/activation of immune cells. Thus, KRGE might have potential in therapeutic intervention for MS.

The preventive effect of Zingiber officinale essential oil on demyelination of corpus callosum in a cuprizone rat model of multiple sclerosis.

Multiple sclerosis (MS) is the most prevalent neurological disability among young adults. Anti-inflammatory drugs have shown to be effective in MS. The anti-inflammatory and antioxidative properties of Zingiber officinale (ginger) have been shown and proven in many phytotherapy studies. This study aimed to evaluate effects of ginger essential oil on preventing myelin degradation in a rat model of MS. In this study, we divided 49 rats into 7 groups; 4 control and 3 experimental groups that received 3 different dose of ginger essential oil (50, 100, and 150 mg/kg/day) for treatment of cuprizone-induced demyelinated rats. Basket test and transmission electron microscopy were performed in this study. Olig2 and Mbp genes and proteins were respectively evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Histologically, cuprizone created demyelination in the corpus callosum fibers. Remyelination of fibers was seen in the group treated with the medium dose of ginger essence, by toluidine blue staining. transmission electron microscopy (TEM) revealed increased thickness of the myelin of fibers in all 3 treated groups (p<0.05). Feeding by the medium dose of ginger essence significantly increased the levels of Mbp and Olig2 genes (p<0.05). ELISA test showed that 100 mg/kg/day of ginger caused a significant difference between experimental and the cuprizone-induced groups (p<0.05). Our findings suggested that administration of ginger essential oil prevented demyelination and improved remyelination of rats` corpus callusom and can be used as an effective substance in the prevention of MS.

Semaglutide, a novel glucagon-like peptide-1 agonist, amends experimental autoimmune encephalomyelitis-induced multiple sclerosis in mice: Involvement of the PI3K/Akt/GSK-3β pathway.

Multiple sclerosis (MS) is a disabling neurodegenerative disease that causes demyelination and axonal degeneration of the central nervous system. Current treatments are partially effective in managing MS relapses and have a negligible impact on treating MS cognitive deficits and cannot enhance neuronal remyelination, imposing a need for a new MS remedy. Semaglutide, a novel glucagon-like peptide-1 agonist, has recently displayed a neuroprotective effect on several neurodegenerative diseases, suggesting that it may have a protective effect in MS. Therefore, this study was conducted to investigate the influence of semaglutide on experimental autoimmune encephalomyelitis (EAE)-induced MS in mice. Here, EAE was induced in mice using spinal cord homogenate, which eventually altered the mice's cognitive and motor functions, similar to what is observed in MS. Interestingly, intraperitoneally administered semaglutide (25nmol/kg/day) amended EAE-induced cognitive and motor deficits observed in novel object recognition, open field, rotarod, and grip strength tests. Moreover, histological examination revealed that semaglutide treatment attenuated hippocampal damage and corpus callosum demyelination caused by EAE. Additionally, biochemical testing revealed that semaglutide activates the PI3K/Akt axis, which eventually hampers GSK-3β activity. GSK-3β activity inhibition attenuates demyelination and triggers remyelination through CREB/BDNF; furthermore, it boosts Nrf2 and SOD levels, protecting the mice from EAE-induced oxidative stress. Additionally, GSK-3β inhibition minimizes neuroinflammation, as reflected by decreased NF-kβ and TNF-α levels. In conclusion, semaglutide has a neuroprotective effect in EAE-induced MS in mice, which is mediated by activating the ramified PI3K/Akt/GSK-3β pathway.

The effect of Zingiber Officinale Extract on Preventing Demyelination of Corpus Callosum in a Rat Model of Multiple Sclerosis

Background:Multiple sclerosis is the most prevalent neurological disability of young adults. Anti-inflammatory drugs have relative effects on MS. The anti-inflammatory and antioxidative effects of Zingiber officinale (ginger) have been proven in some experimental and clinical investigations. The aim of this study was to evaluate the effects of ginger extract on preventing myelin degradation in a rat model of MS. Methods: Forty nine male Wistar rats were used in this study and divided into four control groups: the normal group, cuprizone-induced group, sham group (CPZ + NaCMC), standard control group (fingolimod + cuprizone), including three experimental groups of CPZ, each receiving three different doses of ginger extract: 150, 300, and 600mg/kg /kg/day.Results:Ginger extract of 600 mg/kg prevented CC from demyelination; however, a significant difference was observed in the fingolimod group (p < 0.05). Difference in the CPZ group was quite significant (p < 0.05).Conclusion:Treatment with ginger inhibited demyelination and alleviated remyelination of corpus callosum in rats. Therefore, it could serve as a therapeutic agent in the MS.

Locomotor and histological changes in a cuprizone-induced animal model of multiple sclerosis: comparison between alpha-tocopherol and fingolimod.

Background and purpose:Fingolimod is a sphingosine 1-phosphate receptor modulator used to treat multiple sclerosis (MS). Alpha-tocopherol (AT) has been found to improve motor function in an animal model of MS. In the present study, the effects of AT and fingolimod on the locomotor function and histological evidence of demyelination were compared in a cuprizone-induced rat model of MS.Experimental approach:Female Sprague-Dawley rats (8 weeks) were fed with 0.2% (w/w) cuprizone diet for 5 weeks followed by intraperitoneal injections of fingolimod (3 mg/Kg; group F, n = 10) and alpha- tocopherol (100 mg/Kg; group A, n = 10). Vehicle-treated rats (group V, n = 10) were treated intraperitoneally with 1% ethanol in saline on weeks 6 and 7. Open field and beam walking tests were carried out every 10 days. The mean area of demyelination in the corpus callosum was quantified using Luxol fast blue stained histological sections of the forebrain.Findings/Results:The mean speed of movement was increased by 54% and 50% in groups F and A compared to group V. Total distance moved was increased by 61% and 52.7% in groups F and A compared to group V. Mean time to walk the beam was reduced in group A by 52% compared to group V. Mean frequency of crossing lines from the inner squares to outer squares was reduced in groups A and F compared to group V. Mean area of demyelination in corpus callosum showed 62% reduction in group A compared to group V.Conclusion and implications:Both fingolimod and AT treatments improved the locomotor function. However, AT treatment reduced the areas of demyelination in higher proportion and improved motor coordination and exploratory behavior.

Abstract- Poster

Marchiafava - Bignami disease is a progressive alcoholism related neurologic disease characterized by corpus callosum demyelination, necrosis and subsequent atrophy which occasionally occurs in non alcoholics but chronically malnourished. Among the many brain alterations promoted by chronic ethanol consumption, brain shrinkage due to cortical atrophy is the most striking one, it is related to alcoholic dementia and to atrophy of the corpus callosum. Although clearly dependent on age, brain shrinkage is more intense among heavy drinkers. MBD is a rare complication of chronic alcoholism and malnutrition which is most prevalent in men between 40 and 60 years of age. We are presenting here a case of 32year old alcoholic came to us with chief complaints of memory disturbances, decreased selfcare, decreased interaction with family members, provoked anger, sleep disturbances and disoriented to time and place for 2 months, with history of chronic alcohol consumption. A provisional diagnosis of Delirium was made and started him on Tab. Haloperidol 1.5 mg HS, T. Pregabalin 75 mg BD, T. Memantine 5mg OD, Thiamine and folic acid supplements for 7 days which showed no improvement in symptoms, on imaging found to have thinning of Corpus Callosum.

Marchiafava- Bignami disease (MBD): A rare case report

Marchiafava-Bignami disease (MBD) is a rare neuro degenerative disease characterized by demyelination of corpus callosum. Clinical diagnosis of MBD is challenging due to its nonspecific neurological manifestations. It’s promptly diagnosed by brain Magnetic Resonance Imaging (MRI). Prompt treatment with high dose thiamine could be lifesaving. Here we report a 68 year old male with chronic alcoholism who was diagnosed to have MBD and successfully treated with high doses of intravenous thiamine administration.

Differential Role of p53 in Oligodendrocyte Survival in Response to Various Stresses: Experimental Autoimmune Encephalomyelitis, Cuprizone Intoxication or White Matter Stroke.

Promoting oligodendrocyte viability has been proposed as a therapeutic strategy for alleviating many neuronal diseases, such as multiple sclerosis and stroke. However, molecular pathways critical for oligodendrocyte survival under various stresses are still not well known. p53 is a strong tumor suppressor and regulates cell cycle, DNA repair and cell death. Our previous studies have shown that p53 plays an important role in promoting neuronal survival after insults, but its specific role in oligodendrocyte survival is not known. Here, we constructed the mice with oligodendrocyte-specific p53 loss by crossing TRP53flox/flox mice and CNP-cre mice, and found that p53 was dispensable for oligodendrocyte differentiation and myelin formation under physiological condition. In the experimental autoimmune encephalomyelitis (EAE) model, p53 loss of function, specifically in oligodendrocytes, did not affect the EAE disease severity and had no effect on demyelination in the spinal cord of the mice. Interestingly, p53 deficiency in oligodendrocytes significantly attenuated the demyelination of corpus callosum and alleviated the functional impairment of motor coordination and spatial memory in the cuprizone demyelination model. Moreover, the oligodendrocyte-specific loss of p53 provided protection against subcortical white matter damage and mitigated recognition memory impairment in mice in the white matter stroke model. These results suggest that p53 plays different roles in the brain and spinal cord or in response to various stresses. Thus, p53 may be a therapeutic target for oligodendrocyte prevention in specific brain injuries, such as white matter stroke and multiple sclerosis.

Abstract P761: Reducing Reactive Astrocytes Improves Cognitive Function in a Mouse Model of Vascular Cognitive Impairment and Dementia

Inflammation and reactive astrocytes are pathologic features in vascular cognitive impairment and dementia (VCID). However, there are no effective therapies to reduce chronic hypoperfusion-induced reactive astrocytes and neuroinflammation and cognitive deficits in VCID. Activation of Na + /H + exchanger 1 (NHE1) in astrocytes mediates Na + influx in exchange of H + efflux, causing hypertrophy and swelling of reactive astrocytes after acute brain injury. Whether pharmacological blockade of NHE1 protein can reduce reactive astrocytes and improve cognitive deficits remains untested. Bilateral carotid artery stenosis (BCAS) with microcoils as a murine VCID model was induced in adult male C57BL/6 mice. BCAS procedures led to sustained reduction (30-40%) in cerebral blood flow (CBF) and deficits in special working memory by 30 days post-surgery (p &lt; 0.05). Compared with sham control mice, BCAS mice displayed demyelination in corpus callosum (CC) and external capsule (EC) at 30 days post-surgery (p &lt; 0.05). There were significantly increased GFAP + astrocytes and Iba1 + microglia in CC, EC and hippocampus in BCAS brain at 30 days post-surgery (p &lt; 0.05). Interestingly, those GFAP + astrocytes and Iba1 + microglia exhibited elevated NHE1 protein expression in these brain regions (p &lt; 0.05). These results suggest that NHE1 protein may play a role in chronic hypoperfusion-induced reactive astrocyte transformation and microglia activation. We administered saline vehicle (Veh) or NHE1 inhibitor HOE642 during 30 days post-BCAS (via either i.p. or osmotic mini-pump). The Veh- and HOE642-treated BCAS mice caused similar reduction in CBF. Compared to the Veh controls, both HOE642 treatment regimens significantly improved cognitive performance at 30 days post-surgery (p &lt; 0.05). Causative relationship between blockade of NHE1 protein activation and reducing glia-mediated inflammation and demyelination are under investigation by immunostaining assessments and ex-vivo MRI DTI analysis. Taken together, our study suggests that elevation of NHE1 protein activity plays a role in glial activation in the murine VCID model. Pharmacological blockade of NHE1 protein shows efficacy in reducing cerebral hypoperfusion-induced chronic brain injury and cognitive impairment.

Metformin promotes CNS remyelination and improves social interaction following focal demyelination through CBP Ser436 phosphorylation

Individuals with demyelinating diseases often experience difficulties during social interactions that are not well studied in preclinical models. Here, we describe a novel juvenile focal corpus callosum demyelination murine model exhibiting a social interaction deficit. Using this preclinical murine demyelination model, we discover that application of metformin, an FDA-approved drug, in this model promotes oligodendrocyte regeneration and remyelination and improves the social interaction. This beneficial effect of metformin acts through stimulating Ser436 phosphorylation in CBP, a histone acetyltransferase. In addition, we found that metformin acts through two distinct molecular pathways to enhance oligodendrocyte precursor (OPC) proliferation and differentiation, respectively. Metformin enhances OPC proliferation through early-stage autophagy inhibition, while metformin promotes OPC differentiation into mature oligodendrocytes through activating CBP Ser436 phosphorylation. In summary, we identify that metformin is a promising remyelinating agent to improve juvenile demyelination-associated social interaction deficits by promoting oligodendrocyte regeneration and remyelination.

Slit1 Protein Regulates SVZ-Derived Precursor Mobilization in the Adult Demyelinated CNS.

Slit1 is a secreted axon guidance molecule, also involved in adult neurogenesis. In physiological conditions, Slit1 loss promotes ectopic dispersal of SVZ-derived neural precursors (SVZ-NPCs) into periventricular structures such as the corpus callosum. Demyelination of the corpus callosum triggers SVZ-NPC migration to ectopic locations and their recruitment by the lesion, suggesting a possible role for Slit1 in SVZ-NPCs ectopic dispersal regulation in pathological conditions. Here, we have investigated the function of Slit1 protein in the recruitment of SVZ-NPCs after CNS demyelination. We find that the dynamics of oligodendrogenesis and temporal profile of developmental myelination in Slit1–/– mice are similar to Slit1+/− controls. SVZ micro-dissection and RT-PCR from wild-type mice, show that Slits and Robos are physiologically regulated at the transcriptional level in response to corpus callosum demyelination suggesting their role in the process of SVZ-NPC ectopic migration in demyelinating conditions. Moreover, we find that the number of SVZ-NPCs recruited by the lesion increases in Sli1–/– mice compared to Slit1+/− mice, leading to higher numbers of Olig2+ cells within the lesion. Time-lapse video-microscopy of immuno-purified NPCs shows that Slit1-deficient cells migrate faster and make more frequent directional changes than control NPCs, supporting a cell-autonomous mechanism of action of Slit1 in NPC migration. In conclusion, while Slit1 does not affect the normal developmental process of oligodendrogenesis and myelination, it regulates adult SVZ-NPC ectopic migration in response to demyelination, and consequently oligodendrocyte renewal within the lesion.

Minocycline Ameliorates Depressive-Like Behavior and Demyelination Induced by Transient Global Cerebral Ischemia by Inhibiting Microglial Activation.

Global cerebral ischemia (GCI) commonly occurs in the elderly. Subcortical white matter lesions and oligodendrocyte (OLG) loss caused by cerebral ischemia have been implicated in the development of post-ischemic depression and cognitive impairment. OLGs are necessary for axonal myelination; the disrupted differentiation of OLG progenitor cells (OPCs) is associated with impaired remyelination. Evidence has indicated that increased levels of inflammatory cytokines released from activated microglia induce depression-like behaviors by affecting neurotransmitter pathways, but the mechanisms remain elusive. We explored the potential mechanisms that link microglia activation with GCI-induced depression and cognitive dysfunction by studying effects of minocycline on white matter damage, cytokine levels, and the monoaminergic neurotransmitters. An acute GCI animal model was generated through bilateral common carotid artery occlusion to induce ischemic inflammation and subcortical white matter damage. Minocycline, an inhibitor of microglia activation, was intraperitoneally administrated immediately after surgery and continued daily for additional six days. Minocycline shortened the immobile duration in tail suspension test and forced swimming test, while no improvement was found in Morris water maze test. The plasma levels of IL-1β, IL-6, TNF-α, HMGB1, and netrin-1 were significantly reduced with the treatment of minocycline. Minocycline treatment substantially reversed demyelination in corpus callosum and hippocampus, alleviated hippocampal microglia activation, and promoted OPCs maturation, while no effect was found on hippocampal neurodegeneration. Besides, the content of dopamine (DA) in the hippocampus was upregulated by minocycline treatment after GCI. Collectively, our data demonstrated that minocycline exerts an anti-depressant effect by inhibiting microglia activation, promoting OPCs maturation and remyelination. Increased DA in hippocampus may also play a role in ameliorating depressive behavior with minocycline treatment.

Distinctive functional deficiencies in axonal conduction associated with two forms of cerebral white matter injury.

AimsThis study determines whether assessment with compound action potentials (CAPs) can distinguish two different forms of cerebral white matter injury at the functional levels.MethodsA pure demyelination model was induced in C57/BL6 adult mice by dietary supplementation of cuprizone (0.2%) for 6 weeks. Callosal L‐N5‐(1‐Iminoethyl) ornithine (L‐NIO) hydrochloride (27 mg/mL) was injected into the corpus callosum (CC) to induce a focal white matter stroke (WMS), resulting in both demyelination and axonal injury. White matter integrity was assessed by performing CAP recording, electron microscopy, and immunohistological and luxol fast blue (LFB) staining.ResultsImmunohistological and electron microscopic analyses confirmed the induction of robust demyelination in CC with cuprizone, and mixed demyelination and axonal damage with L‐NIO. Electrophysiologically, cuprizone‐induced demyelination significantly reduced the amplitude of negative peak 1 (N1), but increased the amplitude of negative peak 2 (N2), of the CAPs compared to the sham controls. However, cuprizone did not affect the axonal conduction velocity. In contrast, the amplitude and area of both N1 and N2 along with N1 axonal conduction velocity were dramatically decreased in L‐NIO‐induced WMS.ConclusionsConcertedly, parameters of the CAPs offer a novel functional assessment strategy for cerebral white matter injury in rodent models.

The endocannabinoid 2-AG enhances spontaneous remyelination by targeting microglia

Remyelination is an endogenous process by which functional recovery of damaged neurons is achieved by reinstating the myelin sheath around axons. Remyelination has been documented in multiple sclerosis (MS) lesions and experimental models, although it is often incomplete or fails to affect the integrity of the axon, thereby leading to progressive disability. Microglia play a crucial role in the clearance of the myelin debris produced by demyelination and in inflammation-dependent OPC activation, two processes necessary for remyelination to occur. We show here that following corpus callosum demyelination in the TMEV-IDD viral murine model of MS, there is spontaneous and partial remyelination that involves a temporal discordance between OPC mobilization and microglia activation. Pharmacological treatment with the endocannabinoid 2-AG enhances the clearance of myelin debris by microglia and OPC differentiation, resulting in complete remyelination and a thickening of the myelin sheath. These results highlight the importance of targeting microglia during the repair processes in order to enhance remyelination.