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1.
Neurotox Res ; 39(4): 1181-1188, 2021 Aug.
Article in English | MEDLINE | ID: mdl-33871814

ABSTRACT

Multiple sclerosis is a chronic demyelinating disease with a functional disturbance in the immune system and axonal damages. It was shown that Apamin as a blood-brain barrier shuttle acts as a Ca2+ activated K+ channels (SK channels) blocker. In this study, the effects of Apamin on oligodendrocyte differentiation markers were evaluated on an induced model of MS. Briefly, C57BL/6 male mice (22 ± 5 g) except the control group were fed with 0.2% (w/w) cuprizone pellets for 6 weeks. After cuprizone withdrawal, mice were divided randomly into six groups. Apamin (100 µg/kg/BW) was administered intraperitoneally as a co-treatment during phase I (demyelination) or post-treatment phase II (remyelination) twice a week. Mice were anesthetized, perfused with phosphate-buffered saline, then fixed brains were coronally sectioned and the changes in oligodendrocytes markers such as Olig2, PDGFR-α, and BrdU incorporation were assessed by immunohistochemistry assay. Apamin administration increased Olig2+ cells in phase I as compared to the control group (p < 0.0001). Also, a decreasing trend in PDGFRa+ cells observed after cuprizone withdrawal (p < 0.001). 5-Bromo-2'-deoxyuridine (BrdU) incorporation test was confirmed stimulation of oligodendrocyte progenitor cell proliferation in phase I in the Apamin exposed group (p < 0.0001), especially at the subventricular zone. This study highlights the potential therapeutic effects of Apamin as a bee venom-derived peptide on oligodendrocyte precursor proliferation and elevation in myelin content in an oxidative induced multiple sclerosis model due to cuprizone exposure.


Subject(s)
Bee Venoms/therapeutic use , Blood-Brain Barrier/drug effects , Cell Proliferation/drug effects , Cuprizone/toxicity , Multiple Sclerosis/drug therapy , Oligodendroglia/drug effects , Animals , Bee Venoms/pharmacology , Blood-Brain Barrier/chemistry , Blood-Brain Barrier/metabolism , Brain/drug effects , Brain/metabolism , Cell Proliferation/physiology , Chelating Agents/toxicity , Male , Mice , Mice, Inbred C57BL , Multiple Sclerosis/chemically induced , Multiple Sclerosis/metabolism , Oligodendrocyte Transcription Factor 2/analysis , Oligodendrocyte Transcription Factor 2/metabolism , Oligodendroglia/chemistry , Oligodendroglia/metabolism , Receptor, Platelet-Derived Growth Factor alpha/analysis , Receptor, Platelet-Derived Growth Factor alpha/metabolism
2.
J Neuropathol Exp Neurol ; 79(9): 959-965, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32770197

ABSTRACT

Mesenchymal chondrosarcoma (MC) is a rare aggressive mesenchymal sarcoma. Specific markers for the differential diagnosis of MCs remain to be developed. OLIG2 expression has been reported only in neuroepithelial tumors. Recently, OLIG2 expression was found to be involved in the development of NCOA2 fusion-positive alveolar rhabdomyosarcomas. Therefore, we investigated whether OLIG2 expression could be used as a diagnostic marker for MC. We report the clinical pathological and immunohistochemical features of 14 MCs. All tumors showed typical pathological features including biphasic patterns with sheets of primitive round mesenchymal cells and interspersed islands of cartilage. These tumors expressed BCL2, SOX9, and CD99. OLIG2 was robustly expressed in 12/14 of MCs. NCOA2 rearrangement was found in 12 cases. OLIG2 expression was not found in the NCOA2 rearrangement-negative MCs. Notably, OLIG2 expression was not detected in 52 neoplasms (8 Ewing sarcomas, 23 hemangiopericytomas, and 21 chondrosarcomas) that are frequently misdiagnosed as MC. Our findings provide convincing evidence that OLIG2 can serve as a reliable marker in the differential diagnosis of MC and may be a unique neurodevelopmental gene expression signature for the NCOA2 rearranged MCs.


Subject(s)
Biomarkers, Tumor/analysis , Bone Neoplasms/diagnosis , Chondrosarcoma, Mesenchymal/diagnosis , Oligodendrocyte Transcription Factor 2/analysis , Adult , Bone Neoplasms/genetics , Bone Neoplasms/pathology , Child , Chondrosarcoma, Mesenchymal/genetics , Chondrosarcoma, Mesenchymal/pathology , Female , Gene Rearrangement , Humans , Immunohistochemistry , Male , Middle Aged , Nuclear Receptor Coactivator 2/genetics , Oligodendrocyte Transcription Factor 2/metabolism , Young Adult
3.
Cancer Med ; 9(3): 1069-1078, 2020 02.
Article in English | MEDLINE | ID: mdl-31568682

ABSTRACT

AIMS: Glioblastoma (GBM) is the most common and lethal malignant brain tumor in adults. Glioma stem cells (GSCs) are implicated in this poor prognosis and in radio(chemo-)resistance. We have previously demonstrated that among potentially highly specific GSC markers oligodendrocyte lineage transcription factor 2 (OLIG2) appears to be the most specific and cyclin D2 (CCND2) the only one related to cell cycle regulation. The purpose of this work was to investigate the clinical significance and the evolution of OLIG2 and CCND2 protein expression in GBM. METHODS AND RESULTS: Immunohistochemical expression analysis of Olig2 and Ccnd2 was carried out on a cohort of human paired GBM samples comparing initial resections with local recurrent tumors after radiation therapy (RT) alone or radio-chemotherapy with temozolomide (RT-TMZ). Uni- and multivariate logistic regression analysis revealed that significant risk factors predicting early mortality (<12 months) are: subtotal surgery for recurrence, time to recurrence <6 months, Ccnd2 nuclear expression at initial surgery ≥30%, and Olig2 nuclear expression <30% at second surgery after RT alone and RT-TMZ. CONCLUSIONS: We demonstrated that patients for whom nuclear expression of Olig2 becomes low (<30%) after adjuvant treatments have a significantly shorter time to recurrence and survival reflecting most probably a proneural to mesenchymal transition of the GSCs population. We also highlighted the fact that at initial surgery, high nuclear expression (≥30%) of CCND2, a G1/S regulator specific of GSCs, has a prognostic value and is associated with early mortality (<12 months).


Subject(s)
Brain Neoplasms/mortality , Cyclin D2/metabolism , Glioblastoma/mortality , Neoplasm Recurrence, Local/therapy , Neoplastic Stem Cells/pathology , Oligodendrocyte Transcription Factor 2/metabolism , Adult , Aged , Brain/cytology , Brain/pathology , Brain/surgery , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Cell Nucleus/pathology , Chemoradiotherapy, Adjuvant/methods , Cyclin D2/analysis , Female , Glioblastoma/pathology , Glioblastoma/therapy , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Neoplastic Stem Cells/cytology , Oligodendrocyte Transcription Factor 2/analysis , Prognosis , Retrospective Studies , Risk Factors , Survival Analysis , Temozolomide/therapeutic use , Time Factors , Treatment Outcome
4.
J Vet Med Sci ; 82(1): 68-76, 2020 Jan 17.
Article in English | MEDLINE | ID: mdl-31787662

ABSTRACT

Patients with hypoglycemic coma show abnormal signals in the white matter on magnetic resonance imaging. However, the precise pathological changes in the white matter caused by hypoglycemic coma remain unclear in humans and experimental animals. This study aimed to reveal the distribution and time course of histopathological and immunohistochemical changes occurring in the white matter during the early stages of hypoglycemic coma in rats. Insulin-induced hypoglycemic coma of 15-30-min duration was induced in rats, followed by recovery using a glucose solution. Rat brains were collected after 6 and 24 hr and after 3, 5, 7, and 14 days. The brains were submitted for histological and immunohistochemical analysis for neurofilament 200 kDa (NF), myelin basic protein, olig-2, Iba-1, and glial fibrillary acidic protein (GFAP). Vacuolation was observed in the fiber bundles of the globus pallidus on days 1-14. Most of the vacuoles were located in GFAP-positive astrocytic processes or the extracellular space and appeared to be edematous. Additionally, myelin pallor and a decrease in NF-positive signals were observed on day 14. Microgliosis and astrogliosis were also detected. Observations similar to the globus pallidus, except for edema, were noted in the internal capsule. In the corpus callosum, a mild decrease in NF-positive signals, microgliosis, and astrogliosis were observed. These results suggest that after transient hypoglycemic coma, edema and/or degeneration occurred in the white matter, especially in the globus pallidus, internal capsule, and corpus callosum in the early stages.


Subject(s)
Hypoglycemia/pathology , Insulin Coma/pathology , White Matter/pathology , Animals , Astrocytes/pathology , Calcium-Binding Proteins/analysis , Cerebrum/pathology , Glial Fibrillary Acidic Protein , Gliosis , Glucose , Insulin/pharmacology , Intermediate Filaments , Male , Microglia/pathology , Myelin Basic Protein/analysis , Oligodendrocyte Transcription Factor 2/analysis , Rats, Sprague-Dawley , White Matter/cytology
5.
Med Sci Monit ; 23: 4834-4840, 2017 Oct 09.
Article in English | MEDLINE | ID: mdl-28989170

ABSTRACT

BACKGROUND The pathogenesis of schizophrenia is complex and oligodendrocyte abnormality is an important component of the pathogenesis found in schizophrenia. This study was designed to evaluate the function of olig2 in cuprizone-induced schizophrenia-like symptoms in a mouse model, and to assess the related mechanisms. MATERIAL AND METHODS The schizophrenia-like symptoms were modeled by administration of cuprizone in mice. Open-field and elevated-plus maze tests were applied to detect behavioral changes. Adenovirus encoding olig2 siRNA was designed to silence olig2 expression. Real-time PCR and western blotting were applied to detect myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), glial fibrillary acidic protein (GFAP) and olig2 expressions. RESULTS Open field test showed that the distance and time spent in the center area were significantly decreased in cuprizone mice (model mice) when compared with control mice (p<0.05). By contrast, olig2 silence could significantly increase the time and distance spent in the center area compared with the model mice (p<0.05). As revealed by elevated-plus maze test, the mice in the model group preferred the open arm and spent more time and distance in the open arm compared with control mice (p<0.05), while olig2 silence significantly reversed the abnormalities (p<0.05). Mechanically, MBP and CNPase expression were reduced in the model group compared with the control (p<0.05). However, olig2 silence reversed the reduction caused by cuprizone modeling (p<0.05). In addition, GFAP was elevated after cuprizone modeling compared with control (p<0.05), and was significantly inhibited by olig2 silence compared with model (p<0.05). CONCLUSIONS Cuprizone-induced schizophrenia-like symptoms involved olig2 upregulation. The silence of olig2 could prevent changes, likely through regulating MBP, CNPase, and GFAP expressions.


Subject(s)
Oligodendrocyte Transcription Factor 2/therapeutic use , Schizophrenia/metabolism , 2',3'-Cyclic-Nucleotide Phosphodiesterases/analysis , 2',3'-Cyclic-Nucleotide Phosphodiesterases/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Brain/pathology , Cuprizone/administration & dosage , Disease Models, Animal , Glial Fibrillary Acidic Protein/analysis , Glial Fibrillary Acidic Protein/metabolism , Mice , Mice, Inbred C57BL , Myelin Basic Protein/analysis , Myelin Basic Protein/metabolism , Myelin Sheath/metabolism , Nerve Tissue Proteins/metabolism , Oligodendrocyte Transcription Factor 2/analysis , Oligodendrocyte Transcription Factor 2/physiology , Oligodendroglia/pathology , Oligodendroglia/physiology , Schizophrenia/chemically induced , Up-Regulation
6.
Brain Pathol ; 27(1): 26-35, 2017 01.
Article in English | MEDLINE | ID: mdl-26748554

ABSTRACT

The histopathological spectrum of human epileptogenic brain lesions is widespread including common and rare variants of cortical malformations. However, 2-26% of epilepsy surgery specimens are histopathologically classified as nonlesional. We hypothesized that these specimens include also new diagnostic entities, in particular when presurgical magnetic resonance imaging (MRI) can identify abnormal signal intensities within the anatomical region of seizure onset. In our series of 1381 en bloc resected epilepsy surgery brain specimens, 52 cases could not be histopathologically classified and were considered nonlesional (3.7%). An increase of Olig2-, and PDGFR-alpha-immunoreactive oligodendroglia was observed in white matter and deep cortical layers in 22 of these patients (42%). Increased proliferation activity as well as heterotopic neurons in white matter were additional histopathological hallmarks. All patients suffered from frontal lobe epilepsy (FLE) with a median age of epilepsy onset at 4 years and 16 years at epilepsy surgery. Presurgical MRI suggested focal cortical dysplasia (FCD) in all patients. We suggest to classify this characteristic histopathology pattern as "mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE)." Further insights into pathomechanisms of MOGHE may help to bridge the diagnostic gap in children and young adults with difficult-to-treat FLE.


Subject(s)
Epilepsy, Frontal Lobe/pathology , Malformations of Cortical Development/pathology , Oligodendroglia/pathology , Adolescent , Adult , Age of Onset , Cell Division , Child , Child, Preschool , Drug Resistant Epilepsy/diagnostic imaging , Drug Resistant Epilepsy/pathology , Drug Resistant Epilepsy/surgery , Epilepsy, Frontal Lobe/diagnostic imaging , Epilepsy, Frontal Lobe/surgery , Female , Humans , Hyperplasia , In Situ Hybridization, Fluorescence , Magnetic Resonance Imaging , Male , Malformations of Cortical Development/diagnostic imaging , Middle Aged , Neuroimaging , Oligodendrocyte Transcription Factor 2/analysis , Young Adult
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