ABSTRACT
Multiple sclerosis(MS) shows the pathological characteristics of "inflammatory injury of white matter" and "myelin repair disability" in the central nervous system(CNS). It is very essential for MS treatment and reduction of disease burden to strengthen repair, improve function, and reduce disability. Accordingly, different from the simple immunosuppression, we believe that key to strengthening remyelination and maintaining the "damage-repair" homeostasis of tissue is to change the current one-way immunosuppression strategy and achieve the "moderate pro-inflammation-effective inflammation removal" homeostasis. Traditional Chinese medicine shows huge potential in this strategy. Through literature research, this study summarized the research on remyelination, discussed the "mode-rate pro-inflammation-effective inflammation removal" homeostasis and the "damage-repair" homeostasis based on microglia, and summed up the key links in remyelination in MS. This review is expected to lay a theoretical basis for improving the function of MS patients and guide the application of traditional Chinese medicine.
Subject(s)
Humans , Multiple Sclerosis/pathology , Remyelination/physiology , Myelin Sheath/pathology , Inflammation/drug therapy , HomeostasisABSTRACT
The exacerbation of progressive multiple sclerosis (MS) is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells (OPCs). To discover novel therapeutic compounds for enhancing remyelination by endogenous OPCs, we screened for myelin basic protein expression using cultured rat OPCs and a library of small-molecule compounds. One of the most effective drugs was pinocembrin, which remarkably promoted OPC differentiation and maturation without affecting cell proliferation and survival. Based on these in vitro effects, we further assessed the therapeutic effects of pinocembrin in animal models of demyelinating diseases. We demonstrated that pinocembrin significantly ameliorated the progression of experimental autoimmune encephalomyelitis (EAE) and enhanced the repair of demyelination in lysolectin-induced lesions. Further studies indicated that pinocembrin increased the phosphorylation level of mammalian target of rapamycin (mTOR). Taken together, our results demonstrated that pinocembrin promotes OPC differentiation and remyelination through the phosphorylated mTOR pathway, and suggest a novel therapeutic prospect for this natural flavonoid product in treating demyelinating diseases.
Subject(s)
Animals , Mice , Rats , Cell Differentiation , Flavanones , Mice, Inbred C57BL , Myelin Sheath/metabolism , Oligodendroglia/metabolism , Remyelination , Signal Transduction , TOR Serine-Threonine Kinases/metabolismABSTRACT
The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells (OPCs) to differentiate, since OPCs and oligodendrocyte-lineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid (SA) is mainly derived from star anise, and is reported to have anti-influenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis (EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination. Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated mTOR. Taken together, our results demonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.
Subject(s)
Animals , Female , Rats , Apoptosis , Cell Differentiation , Cell Proliferation , Cells, Cultured , Demyelinating Diseases , Encephalitis , Encephalomyelitis, Autoimmune, Experimental , Mice, Inbred C57BL , Myelin Basic Protein , Metabolism , Neuroprotective Agents , Oligodendrocyte Precursor Cells , Metabolism , Remyelination , Shikimic Acid , TOR Serine-Threonine Kinases , MetabolismABSTRACT
SUMMARY: In spinal cord injury, radical treatment is still a persistent hope for patients and clinicians. Our study aimed to determine the different histological changes in central, cranial and caudal sites of compressed spinal cord as a result of neuroectodermal stem cells (NESCs) transplantation in rats. For extraction of NESCs, future brains were extracted from mice embryos (10-days old) and cultured. Eighty, male rats were divided randomly into control, sham (20 rats each); while 40 rats were subjected to compressed spinal cord injury (CSCI). Seven days after spinal cord injury, rats were subdivided into 2 groups (20 rats each); an untreated and treated with NESCs injected cranial and caudal to the site of the spinal cord injury. Rats were sacrificed 4 weeks after transplantations of NESCs and specimens from the spinal cord at the central, cranial and caudal to site of spinal cord injury were proceeded to be stained with haematoxylin & eosin, osmic acid and Immunohistochemistry of glial fibrillary acidic protein (GFAP). Sections of CSCI revealed areas of hemorrhages, necrosis and cavitation limited by reactive astrocytosis, with upregulation of GFAP expression. Evidence of remyelination and mitigation of histopathological features, reactive astrocytosis in CSCI sections were more pronounced in cranial than in caudal region. NESCs transplantation ameliorated the pathological changes, promoted remyelination.
RESUMEN: En la lesión de la médula espinal, el tratamiento radical aún sigue siendo el tratamiento preferente para los pacientes y los médicos. El objetivo de este estudio fue determinar los diferentes cambios histológicos en los sitios centrales, craneales y caudales de la médula espinal comprimida, como resultado del trasplante de células madre neuroectodérmicas (NESCs) en ratas. Para la extracción de NESCs, se extrajeron y cultivaron los cerebros de embriones de ratones de 10 días de edad. Se dividieron 80 ratas macho aleatoriamente en grupos control, simulado (20 ratas cada una); mientras que 40 ratas fueron sometidas a lesión de la médula espinal comprimida (CSCI). Siete días después de la lesión de la médula espinal, las ratas se subdividieron en 2 grupos (20 ratas cada uno); un grupo no tratado y un grupo tratado con NESCs inyectado craneal y caudal en el sitio de la lesión. Las ratas fueron sacrificadas 4 semanas después de los trasplantes de NESCs y las muestras de la médula espinal en el centro, craneal y caudal del sitio de lesión fueron teñidas con hematoxilina y eosina, ácido ósmico e inmunohistoquímica de la proteína ácida fibrilar glial (GFAP). Las secciones de CSCI revelaron áreas de hemorragias, necrosis y cavitación limitadas por astrocitosis reactiva, con una regulación positiva de la expresión de GFAP. Evidencia de remielinización y mitigación de características histopatológicas, astrocitosis reactiva en secciones de CSCI fue más pronunciada en la región craneal que en la caudal. El trasplante de NESC mejoró los cambios patológicos, promoviendo la remielinización.
Subject(s)
Animals , Male , Rats , Spinal Cord Injuries/surgery , Spinal Cord Injuries/pathology , Stem Cell Transplantation , Immunohistochemistry , Rats, Wistar , Ectoderm , Remyelination , Glial Fibrillary Acidic ProteinABSTRACT
The differentiation and maturation of oligodendrocyte precursor cells (OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1L (myelin transcription factor 1-like), mainly expressed in neurons, has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1L in neuron/glia antigen 2-positive (NG2) OPCs was significantly higher than that in mature CC1 oligodendrocytes. In primary cultured OPCs, overexpression of Myt1L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. ChIP assays showed that Myt1L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1L is an essential regulator of OPC differentiation, thereby supporting Myt1L as a potential therapeutic target for demyelinating diseases.