Demyelinating Diseases
Corpus Callosum
Myelin Sheath
Oligodendroglia
Monoamine Oxidase Inhibitors
Chelating Agents
Microglia
Glial Fibrillary Acidic Protein
Gliosis
Astrocytes
Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination. (1/102)
Metabolic insult results in apoptosis and depletion of mature oligodendrocytes during demyelination. To examine the role of insulin-like growth factor-1 (IGF-1) during acute demyelination and remyelination in the adult CNS, we exposed transgenic mice that continuously express IGF-1 (IGF-1 tg) to cuprizone intoxication. Demyelination was observed within the corpus callosum in both wild-type and IGF-1 tg mice 3 weeks after exposure to cuprizone. Wild-type mice showed significant apoptotic mature oligodendrocytes and a dramatic loss of these cells within the lesion that resulted in near complete depletion and demyelination by week 5. In contrast, the demyelinated corpus callosum of the IGF-1 tg mice was near full recovery by week 5. This rapid recovery was apparently caused by survival of the mature oligodendrocyte population because apoptosis was negligible, and by week 4, the mature oligodendrocyte population was completely restored. Furthermore, despite demyelination in both wild-type and IGF-1 tg mice, oligodendrocyte progenitors accumulated only in the absence of mature oligodendrocytes and failed to accumulate if the mature oligodendrocytes remained as demonstrated in the IGF-1 tg mice. These results suggest that IGF-1 may be important in preventing the depletion of mature oligodendrocytes in vivo and thus facilitates an early recovery from demyelination. (+info)Absence of macrophage-inflammatory protein-1alpha delays central nervous system demyelination in the presence of an intact blood-brain barrier. (2/102)
Chemokines are small chemotactic cytokines that modulate leukocyte recruitment and activation during inflammation. Here, we describe the role of macrophage inflammatory protein-1alpha (MIP-1alpha) during cuprizone intoxication, a model where demyelination of the CNS features a large accumulation of microglia/macrophage without T cell involvement or blood-brain barrier disruption. RNase protection assays showed that mRNA for numerous chemokines were up-regulated during cuprizone treatment in wild-type, C57BL/6 mice. RANTES, inflammatory protein-10, and monocyte chemoattractant protein-1 showed greatest expression with initiation of insult at 1-2 wk of treatment, whereas MIP-1alpha and beta increased later at 4-5 wk, coincident with peak demyelination and cellular accumulation. The function of MIP-1alpha during demyelination was tested in vivo by exposing MIP-1alpha knockout mice (MIP-1alpha(-/-)) to cuprizone and comparing pathology to wild-type mice. Demyelination at 3.5 wk of treatment was significantly decreased in MIP-1alpha(-/-) mice ( approximately 36% reduction), a result confirmed by morphology at the electron microscopic level. The delay in demyelination was correlated to apparent decreases in microglia/macrophage and astrocyte accumulation and in TNF-alpha protein levels. It was possible that larger effects of the MIP-1alpha deficiency were being masked by other redundant chemokines. Indeed, RNase protection assays revealed increased expression of several chemokine transcripts in both untreated and cuprizone-treated MIP-1alpha(-/-) mice. Nonetheless, despite this possible compensation, our studies show the importance of MIP-1alpha in demyelination in the CNS and highlight its effect, particularly on cellular recruitment and cytokine regulation. (+info)Interleukin-1beta promotes repair of the CNS. (3/102)
Interleukin-1beta (IL-1beta) is a proinflammatory cytokine associated with the pathophysiology of demyelinating disorders such as multiple sclerosis and viral infections of the CNS. However, we demonstrate here that IL-1beta appears to promote remyelination in the adult CNS. In IL-1beta(-/-) mice, acute demyelination progressed similarly to wild-type mice and showed parallel mature oligodendrocyte depletion, microglia-macrophage accumulation, and the appearance of oligodendrocyte precursors. In contrast, IL-1beta(-/-) mice failed to remyelinate properly, and this appeared to correlate with a lack of insulin-like growth factor-1 (IGF-1) production by microglia-macrophages and astrocytes and to a profound delay of precursors to differentiate into mature oligodendrocytes. Thus, IL-1beta may be crucial to the repair of the CNS, presumably through the induction of astrocyte and microglia-macrophage-derived IGF-1. (+info)The protective role of nitric oxide in a neurotoxicant-induced demyelinating model. (4/102)
Demyelination is often associated with acute inflammatory events involving the recruitment-activation of microglia/macrophage, astrocytes, and leukocytes. The ultimate role of inflammatory products in demyelinating disease and in the survival of oligodendrocytes, the myelin forming cells, is unresolved. The current study examines the role of inducible NO synthase (iNOS)-derived NO in a neurotoxicant-induced model of demyelination. NO levels were greatly elevated in the midline corpus callosum during demyelination in genetically intact C57BL/6 mice, and this NO was due solely to the induction of iNOS, as the correlates of NO were not found in mice lacking iNOS. C57BL/6 mice lacking iNOS exhibited more demyelination, but did not display an increased overall cellularity in the corpus callosum, attributable to an unimpeded microglia/macrophage presence. An enhanced course of pathology was noted in mice lacking iNOS. This was associated with a greater depletion of mature oligodendrocytes, most likely due to apoptosis of oligodendrocytes. Microglia and astrocytes did not undergo apoptosis during treatment. Our results suggest a moderately protective role for NO during acute inflammation-association demyelination. (+info)Absence of fibroblast growth factor 2 promotes oligodendroglial repopulation of demyelinated white matter. (5/102)
This study takes advantage of fibroblast growth factor 2 (FGF2) knock-out mice to determine the contribution of FGF2 to the regeneration of oligodendrocytes in the adult CNS. The role of FGF2 during spontaneous remyelination was examined using two complementary mouse models of experimental demyelination. The murine hepatitis virus strain A59 (MHV-A59) model produces focal areas of spinal cord demyelination with inflammation. The cuprizone neurotoxicant model causes extensive corpus callosum demyelination without a lymphocytic cell response. In both models, FGF2 expression is upregulated in areas of demyelination in wild-type mice. Surprisingly, in both models, oligodendrocyte repopulation of demyelinated white matter was significantly increased in FGF2 -/- mice compared with wild-type mice and even surpassed the oligodendrocyte density of nonlesioned mice. This dramatic result indicated that the absence of FGF2 promoted oligodendrocyte regeneration, possibly by enhancing oligodendrocyte progenitor proliferation and/or differentiation. FGF2 -/- and +/+ mice had similar oligodendrocyte progenitor densities in normal adult CNS, as well as similar progenitor proliferation and accumulation during demyelination. To directly analyze progenitor differentiation, glial cultures from spinal cords of wild-type mice undergoing remyelination after MHV-A59 demyelination were treated for 3 d with either exogenous FGF2 or an FGF2 neutralizing antibody. Elevating FGF2 favored progenitor proliferation, whereas attenuating endogenous FGF2 activity promoted the differentiation of progenitors into oligodendrocytes. These in vitro results are consistent with enhanced progenitor differentiation in FGF2 -/- mice. These studies demonstrate that the FGF2 genotype regulates oligodendrocyte regeneration and that FGF2 appears to inhibit oligodendrocyte lineage differentiation during remyelination. (+info)Insulin-like growth factor (IGF) signaling through type 1 IGF receptor plays an important role in remyelination. (6/102)
We examined the role of IGF signaling in the remyelination process by disrupting the gene encoding the type 1 IGF receptor (IGF1R) specifically in the mouse brain by Cre-mediated recombination and then exposing these mutants and normal siblings to cuprizone. This neurotoxicant induces a demyelinating lesion in the corpus callosum that is reversible on termination of the insult. Acute demyelination and oligodendrocyte depletion were the same in mutants and controls, but the mutants did not remyelinate adequately. We observed that oligodendrocyte progenitors did not accumulate, proliferate, or survive within the mutant mice, compared with wild type, indicating that signaling through the IGF1R plays a critical role in remyelination via effects on oligodendrocyte progenitors. (+info)Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination. (7/102)
To investigate insulin-like growth factor I (IGF-I) and IGF-I receptor gene expression during experimental demyelination and myelin regeneration, young mice were fed cuprizone (( bis(cyclohexanone) oxaldihydrazone )). This copper-chelating agent produces demyelination in the corpus callosum and superior cerebellar peduncles, and when treatment is stopped, there is rapid remyelination. At intervals during cuprizone treatment and recovery, brain sections were hybridized with specific probes and immunostained with antibodies to determine the localization and relative amounts of IGF-I and IGF-I receptor mRNAs and peptides. In untreated littermates, IGF-I and IGF-I receptor mRNAs and peptides were not detected in white matter. In cuprizone-treated mice, high levels of both IGF-I mRNA and peptide were expressed by astrocytes in areas of myelin breakdown. Astrocyte IGF-I expression decreased rapidly during recovery and oligodendroglial expression of myelin-related genes increased. In severely demyelinated areas, immature oligodendroglia exhibited a transient increase in IGF-I receptor mRNA and peptide immunoreactivity during early recovery. This highly specific pattern of IGF-I induction in astrocytes during demyelination and the expression of the IGF-I receptor in regenerating oligodendrocytes during recovery suggest that IGF-I functions in the regulation of oligodendrocyte and myelin metabolism in vivo. (+info)Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration. (8/102)
Tumor necrosis factor alpha (TNFalpha), a proinflammatory cytokine, was shown previously to promote remyelination and oligodendrocyte precursor proliferation in a murine model for demyelination and remyelination. We used Affymetrix microarrays in this study to identify (1) changes in gene expression that accompany demyelination versus remyelination and (2) changes in gene expression during the successful remyelination of wild-type mice versus the unsuccessful attempts in mice lacking TNFalpha. Alterations in inflammatory genes represented the most prominent changes, with major histocompatibility complex (MHC) genes dramatically enhanced in microglia and astrocytes during demyelination, remyelination, and as a consequence of TNFalpha stimulation. Studies to examine the roles of these genes in remyelination were then performed using mice lacking specific genes identified by the microarray. Analysis of MHC-II-null mice showed delayed remyelination and regeneration of oligodendrocytes, whereas removal of MHC-I had little effect. These data point to the induction of MHC-II by TNFalpha as an important regulatory event in remyelination and emphasize the active inflammatory response in regeneration after pathology in the brain. (+info)The most common demyelinating diseases include:
1. Multiple sclerosis (MS): An autoimmune disease that affects the CNS, including the brain, spinal cord, and optic nerves. MS causes inflammation and damage to the myelin sheath, leading to a range of symptoms such as muscle weakness, vision problems, and cognitive difficulties.
2. Acute demyelination: A sudden, severe loss of myelin that can be caused by infections, autoimmune disorders, or other factors. This condition can result in temporary or permanent nerve damage.
3. Chronic inflammatory demyelination (CIDP): A rare autoimmune disorder that causes progressive damage to the myelin sheath over time. CIDP can affect the CNS and the peripheral nervous system (PNS).
4. Moore's disease: A rare genetic disorder that results in progressive demyelination of the CNS, leading to a range of neurological symptoms including muscle weakness, seizures, and cognitive difficulties.
5. Leukodystrophies: A group of genetic disorders that affect the development or function of myelin-producing cells in the CNS. These conditions can cause progressive loss of myelin and result in a range of neurological symptoms.
Demyelinating diseases can be challenging to diagnose, as the symptoms can be similar to other conditions and the disease progression can be unpredictable. Treatment options vary depending on the specific condition and its severity, and may include medications to reduce inflammation and modulate the immune system, as well as rehabilitation therapies to help manage symptoms and improve quality of life.
Gliosis is made up of glial cells, which are non-neuronal cells that provide support and protection to neurons. When neural tissue is damaged, glial cells proliferate and form a scar-like tissue to fill in the gap and repair the damage. This scar tissue can be made up of astrocytes, oligodendrocytes, or microglia, depending on the type of injury and the location of the damage.
Gliosis can have both beneficial and harmful effects on the brain. On one hand, it can help to prevent further damage by providing a physical barrier against invading substances and protecting the surrounding neural tissue. It can also promote healing by bringing in immune cells and growth factors that aid in the repair process.
On the other hand, gliosis can also have negative effects on brain function. The scar tissue can disrupt normal communication between neurons, leading to impaired cognitive and motor function. In addition, if the scar tissue is too extensive or severe, it can compress or displaces surrounding neural tissue, leading to long-term neurological deficits or even death.
There are several ways to diagnose gliosis, including magnetic resonance imaging (MRI), positron emission tomography (PET), and histopathology. Treatment options for gliosis depend on the underlying cause of the condition and can include medications, surgery, or a combination of both.
In summary, gliosis is a type of scar tissue that forms in the brain and spinal cord as a result of damage to neural tissue. It can have both beneficial and harmful effects on brain function, and diagnosis and treatment options vary depending on the underlying cause of the condition.
Demyelinating disease
Glycolipid
Remyelination
Cerebroside
Neurotrophin mimetics
Hes3 signaling axis
GPR84
Ilorin
Cerebral edema
Oligodendrocyte progenitor cell
List of MeSH codes (D02)
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The contribution of myelin to magnetic susceptibility-weighted contrasts in high-field MRI of the brain - PubMed
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ABORTIFACIENT AGENTS ABORTIFACIENT AGENTS
Remyelination8
- 4. The Effect of Stereotactic Injections on Demyelination and Remyelination: a Study in the Cuprizone Model. (nih.gov)
- 7. Demyelination and remyelination in anatomically distinct regions of the corpus callosum following cuprizone intoxication. (nih.gov)
- 8. G protein-coupled receptor 30 contributes to improved remyelination after cuprizone-induced demyelination. (nih.gov)
- 12. rHIgM22 enhances remyelination in the brain of the cuprizone mouse model of demyelination. (nih.gov)
- 16. Quantitative temporal changes in DTI values coupled with histological properties in cuprizone-induced demyelination and remyelination. (nih.gov)
- 18. Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model. (nih.gov)
- Likewise, electron microscopy showed cuprizone-induced demyelination in the corpus callosum and nearly complete remyelination after cuprizone removal. (elsevierpure.com)
- 8. ghaiad, H. R., M. M. Nooh, M. M. El-Sawalhi, and A. A. Shaheen, "Resveratrol Promotes Remyelination in Cuprizone Model of Multiple Sclerosis: Biochemical and Histological Study. (cu.edu.eg)
Corpus callosum2
- After a 4-week cuprizone diet, cuprizone was removed and PBS or rhGas6 (400 ng/ml, 4 μg/ml and 40 μg/ml) was delivered by osmotic mini-pump into the corpus callosum of C57Bl6 mice for 14 days. (elsevierpure.com)
- 10. Neural Stem Cells of the Subventricular Zone Contribute to Neuroprotection of the Corpus Callosum after Cuprizone-Induced Demyelination. (nih.gov)
Mice6
- C57BL/6J mice were maintained on a cuprizone-containing or control diet and sacrificed at specific time points after initiation of treatment. (nih.gov)
- tissue: brain age: adult genotype: B6N.129-Rpl22tm1.1Psam x B6.Synapsin1-Cre treatment: Cuprizone chow mice at 6 weeks on chow. (nih.gov)
- 17. Anatomical Distribution of Cuprizone-Induced Lesions in C57BL6 Mice. (nih.gov)
- We established an experimental system to measure the response latency of cortical neurons and examined changes in nerve conduction in cuprizone-induced demyelinating mice and in myelin basic protein-deficient shiverer mice. (elsevierpure.com)
- The results of these electrophysiological assessments imply that different demyelinating mechanisms, differentially affecting axon conduction, are present in the cuprizone-treated and shiverer mice, and may provide new insights to understanding the pathophysiology of demyelination in animal models in the CNS. (elsevierpure.com)
- A cuprizone (CPZ) -induced schizophrenic mice model was established. (jneuropsychiatry.org)
Myelin1
- Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. (semanticscholar.org)
Murine2
- Cortical demyelination is prominent in the murine cuprizone model and is strain-dependent. (semanticscholar.org)
- In the present study, we used a murine model of cuprizone-induced demyelination to broaden the application of PBR as a marker of brain injury and to validate the relationship between PBR levels and glial cell types. (nih.gov)
Oligodendrocyte1
- 13. Lineage tracing reveals dynamic changes in oligodendrocyte precursor cells following cuprizone-induced demyelination. (nih.gov)
Brain2
- Our findings indicate that brain PBR levels increased as a function of dose and duration of cuprizone treatment and it was detectable prior to observable demyelination. (nih.gov)
- 1991. A comparison of spongiosis induced in the brain by hexachlorophene, cuprizone and triethyl tin in the Sprague-Dawley rat. (nih.gov)
Enhances1
- Interestingly, CDK5 exerts positive regulation in CPZ-induced autophagy, revealing that CDK5 overexpression enhances LC3â ¡ level and autophagosome formation in company with cuprizone treatment, while CDK5 knockdown works conversely. (jneuropsychiatry.org)
Pathology1
- 6. The cuprizone model: regional heterogeneity of pathology. (nih.gov)
Dose1
- In vitro, cuprizone dose- and time-dependently induces excessive autophagy and autophagic flux, therefore depresses cell viability in oligodendrocytes. (jneuropsychiatry.org)
Treatment1
- The data show that rhGas6 treatment resulted in more efficient repair following cuprizone-induced injury. (elsevierpure.com)
Study1
- In this study, we tested the hypothesis that administration of recombinant human Gas6 (rhGas6) protein into the CNS improves recovery following cuprizone withdrawal. (elsevierpure.com)
Demyelination3
- In the present study, we used a murine model of cuprizone-induced demyelination to broaden the application of PBR as a marker of brain injury and to validate the relationship between PBR levels and glial cell types. (nih.gov)
- Our findings indicate that brain PBR levels increased as a function of dose and duration of cuprizone treatment and it was detectable prior to observable demyelination. (nih.gov)
- In this study, the contribution of myelin to both T(2)* and frequency contrasts is investigated using a mouse model of demyelination based on a cuprizone diet. (nih.gov)