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H C Hoyos, Mariel Marder, R Ulrich, V Gudi, M Stangel, G A Rabinovich, L A Pasquini, J M Pasquini
The aim of this work was to combine our previously published results with our new data to show how galectin-3 (Gal-3) controls myelin integrity and function, promotes oligodendroglial cell differentiation, and regulates microglial responses to limit cuprizone- (CPZ)-induced demyelination and foster remyelination. In this study, 8-week-old Gal-3-deficient (Lgals3 (-/-)) and wild type (WT) mice were fed a diet containing 0.2 % CPZ w/w for 6 weeks, after which CPZ was withdrawn in order to allow remyelination...
2016: Advances in Experimental Medicine and Biology
Qianying Zhang, Zhike Li, Shuangchan Wu, Xiaofei Li, Ying Sang, Jian Li, Yunhui Niu, Hong Ding
Multiple sclerosis (MS) is a demyelinating disease occurring in the central nervous system. In the present study, we evaluated the function of myricetin on the alleviation of behavioral dysfunction and myelin protection in the cuprizone-induced demyelination model. Mice were daily fed with fodder including 0.2% cuprizone and were administrated myricetin (100 mg kg(-1)) by gavage administration for 5 weeks. The treatment of myricetin ameliorated hyper-locomotion and behavior impairment induced by cuprizone toxicity...
October 12, 2016: Food & Function
Arjun Saha, Susan Buntz, Paula Scotland, Li Xu, Pamela Noeldner, Sachit Patel, Amy Wollish, Aruni Gunaratne, Tracy Gentry, Jesse Troy, Glenn K Matsushima, Joanne Kurtzberg, Andrew E Balber
Microglia and monocytes play important roles in regulating brain remyelination. We developed DUOC-01, a cell therapy product intended for treatment of demyelinating diseases, from banked human umbilical cord blood (CB) mononuclear cells. Immunodepletion and selection studies demonstrated that DUOC-01 cells are derived from CB CD14(+) monocytes. We compared the ability of freshly isolated CB CD14(+) monocytes and DUOC-01 cells to accelerate remyelination of the brains of NOD/SCID/IL2Rγ(null) mice following cuprizone feeding-mediated demyelination...
August 18, 2016: JCI Insight
Caroline Guglielmetti, Debbie Le Blon, Eva Santermans, Angelica Salas-Perdomo, Jasmijn Daans, Nathalie De Vocht, Disha Shah, Chloé Hoornaert, Jelle Praet, Jurgen Peerlings, Firat Kara, Christian Bigot, Zhenhua Mai, Herman Goossens, Niel Hens, Sven Hendrix, Marleen Verhoye, Anna M Planas, Zwi Berneman, Annemie van der Linden, Peter Ponsaerts
Detrimental inflammatory responses in the central nervous system are a hallmark of various brain injuries and diseases. With this study we provide evidence that lentiviral vector-mediated expression of the immune-modulating cytokine interleukin 13 (IL-13) induces an alternative activation program in both microglia and macrophages conferring protection against severe oligodendrocyte loss and demyelination in the cuprizone mouse model for multiple sclerosis (MS). First, IL-13 mediated modulation of cuprizone induced lesions was monitored using T2 -weighted magnetic resonance imaging and magnetization transfer imaging, and further correlated with quantitative histological analyses for inflammatory cell influx, oligodendrocyte death, and demyelination...
September 29, 2016: Glia
T Draheim, A Liessem, M Scheld, F Wilms, M Weißflog, B Denecke, T W Kensler, A Zendedel, C Beyer, M Kipp, C J Wruck, A Fragoulis, T Clarner
Oxidative stress critically contributes to the pathogenesis of a variety of neurodegenerative diseases such as multiple sclerosis. Astrocytes are the main regulators of oxidative homeostasis in the brain and dysregulation of these cells likely contributes to the accumulation of oxidative damage. The nuclear factor erythroid 2-related factor 2 (Nrf2) is the main transcriptional regulator of the anti-oxidant stress defense. In this study, we elucidate the effects of astrocytic Nrf2-activation on brain-intrinsic inflammation and lesion development...
September 19, 2016: Glia
Manabu Makinodan, Daisuke Ikawa, Yuki Miyamoto, Junji Yamauchi, Kazuhiko Yamamuro, Yasunori Yamashita, Michihiro Toritsuka, Sohei Kimoto, Kazuki Okumura, Takahira Yamauchi, Shin-Ichi Fukami, Hiroki Yoshino, Akio Wanaka, Toshifumi Kishimoto
Recent studies have revealed that social experience affects myelination. These findings have important implications for disorders that feature abnormal myelination, such as multiple sclerosis (MS), as previous studies have shown that psychosocial stress exacerbates the pathobiology of MS. However, most studies have focused on psychosocial stress during the demyelination phase of MS and have not investigated the effects of social experience on remyelination. Thus, the current study sought to determine whether social experience can alter remyelination after myelin depletion...
September 9, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Rentaro Okazaki, Toru Doi, Kentaro Hayakawa, Kazuhito Morioka, Osamu Imamura, Kunio Takishima, Makoto Hamanoue, Yasuhiro Sawada, Motoshi Nagao, Sakae Tanaka, Toru Ogata
BACKGROUND: Brain inflammation is a crucial component of demyelinating diseases such as multiple sclerosis. Although the initiation of inflammatory processes by the production of cytokines and chemokines by immune cells is well characterized, the processes of inflammatory aggravation of demyelinating diseases remain obscure. Here, we examined the contribution of Erk2, one of the isoforms of the extracellular signal-regulated kinase, to demyelinating inflammation. METHODS: We used the cuprizone-induced demyelinating mouse model...
2016: Journal of Neuroinflammation
Katharina Marie Höflich, Cordian Beyer, Tim Clarner, Christoph Schmitz, Stella Nyamoya, Markus Kipp, Tanja Hochstrasser
Axonal damage has been identified as a significant contributor to permanent clinical disability in multiple sclerosis. In the context of demyelinating disorders, this destructive event can be the result of inflammation, demyelination and/or the activation of innate defense cells such as microglia or monocytes. The relative contribution of each of these variables to acute axonal injury is, however, unknown. In the present study, we compared the extent of acute axonal damage in three different murine demyelination models using anti-amyloid precursor protein (APP) immunohistochemistry...
November 1, 2016: Brain Research
Juliane Wolter, Lorenz Schild, Fabian Bock, Andrea Hellwig, Ihsan Gadi, Moh D Mohanad Al-Dabet, Satish Ranjan, Raik Rönicke, Peter P Nawroth, Karl-Uwe Petersen, Christian Mawrin, Khurrum Shahzad, Berend Isermann
BACKGROUND: Studies with human samples and in rodents established a function of coagulation proteases in neuro-inflammatory demyelinating diseases, e.g. in multiple sclerosis (MS) and experimental autoimmune encephalitis (EAE). Surprisingly, approaches to increase aPC plasma levels as well as antibody mediated inhibition of PC/aPC ameliorated EAE in mice. Hence, the role of aPC generation in demyelinating diseases and potential mechanisms involved remain controversial. Furthermore, it is not known whether loss of aPC has pathological consequences at baseline, e...
September 3, 2016: Journal of Thrombosis and Haemostasis: JTH
Guiyun Mi, Yunyun Gao, Shuai Liu, Enmao Ye, Yanyan Li, Xiao Jin, Hongju Yang, Zheng Yang
The cuprizone (CPZ) model has been widely used for the studies of de-and remyelination. The CPZ-exposed mice show oligodendrocyte precursor cells (OPCs) increase and mature oligodendrocytes decrease, suggesting an imbalance between proliferation and differentiation of OPCs. In the first experiment of this study, we examined the expression of cell cycle related genes in brains of mice following CPZ administration for 5 weeks by means of microarray assay. In addition, we performed a double labeling of BrdU and Ki-67 to calculate cell cycle exit index in the mice...
October 17, 2016: Cell Cycle
Éva Sághy, Éva Sipos, Péter Ács, Kata Bölcskei, Krisztina Pohóczky, Ágnes Kemény, Zoltán Sándor, Éva Szőke, György Sétáló, Sámuel Komoly, Erika Pintér
Multiple sclerosis is a chronic inflammatory, demyelinating degenerative disease of the central nervous system. Current treatments target pathological immune responses to counteract the inflammatory processes. However, these drugs do not restrain the long-term progression of clinical disability. For this reason, new therapeutic approaches and identification of novel target molecules are needed to prevent demyelination or promote repair mechanisms. Transient Receptor Potential Ankyrin 1 (TRPA1) is a nonselective cation channel with relatively high Ca(2+) permeability...
August 29, 2016: Glia
James M Hillis, Julie Davies, Mayara Vieira Mundim, Osama Al-Dalahmah, Francis G Szele
BACKGROUND: Cuprizone leads to demyelination of the corpus callosum (CC) and activates progenitor cells in the adjacent subventricular zone (SVZ), a stem cell niche which contributes to remyelination. The healthy SVZ contains semi-activated microglia and constitutively expresses the pro-inflammatory molecule galectin-3 (Gal-3) suggesting the niche uniquely regulates inflammation. METHODS: We studied the inflammatory response to cuprizone in the SVZ and CC in Gal-3 knockout mice using immunohistochemistry and with the in vitro neurosphere assay...
2016: Journal of Neuroinflammation
Filip Petković, Iain L Campbell, Berta Gonzalez, Bernardo Castellano
Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Interleukin (IL)-6 is a pleiotropic cytokine with a potential role in MS. Here we used transgenic mice with astrocyte-targeted production of IL-6 (GFAP-IL6Tg) to study the effect of IL-6 in the cuprizone-induced demyelination paradigm, which is an experimental model of de- and re-myelination, both hallmarks of MS. Our results demonstrated that cuprizone-treated GFAP-IL6Tg mice showed a significant reduction in astroglial and especially microglial activation/accumulation in the corpus callosum in comparison with the corresponding cuprizone-treated wild type (WT)...
August 18, 2016: Glia
Hajime Abe, Fumiyo Saito, Takeshi Tanaka, Sayaka Mizukami, Yousuke Watanabe, Nobuya Imatanaka, Yumi Akahori, Toshinori Yoshida, Makoto Shibutani
Both developmental and postpubertal cuprizone (CPZ) exposure impairs hippocampal neurogenesis in rats. We previously found that developmental CPZ exposure alters the expression of genes related to neurogenesis, myelination, and synaptic transmission in specific brain regions of offspring. Here, we examined neuronal and glial toxicity profiles in response to postpubertal CPZ exposure by using expression microarray analysis in the hippocampal dentate gyrus, corpus callosum, cerebral cortex, and cerebellar vermis of 5-week-old male rats exposed to 0, 120, and 600mg/kg CPZ for 28days...
November 1, 2016: Toxicology and Applied Pharmacology
Nina Wagenknecht, Birte Becker, Miriam Scheld, Cordian Beyer, Tim Clarner, Tanja Hochstrasser, Markus Kipp
There is a broad consensus that multiple sclerosis (MS) represents more than an inflammatory disease: it harbors several characteristic aspects of a classical neurodegenerative disorder, i.e., damage to axons, synapses, and nerve cell bodies. While several accepted paraclinical methods exist to monitor the inflammatory-driven aspects of the disease, techniques to monitor progression of early and late neurodegeneration are still in their infancy and have not been convincingly validated. It was speculated that the thalamus with its multiple reciprocal connections is sensitive to inflammatory processes occurring in different brain regions, thus acting as a "barometer" for diffuse brain parenchymal damage in MS...
September 2016: Journal of Molecular Neuroscience: MN
Kurt-Wolfram Sühs, Viktoria Gudi, Nils Eckermann, Richard Fairless, Refik Pul, Thomas Skripuletz, Martin Stangel
The N-methyl-d-aspartate receptor (NMDA-R) is crucial for synaptic transmission and plasticity. Over-activation, as well as complete blockade, of receptor function can lead to severe impairment. However, modest modulation of the receptor has been reported to be neuroprotective via endogenous regulation of the receptor and its subunit composition in response to pathophysiological conditions. As an important model for de- and remyelination in the central nervous system (CNS) we examined NMDA-R regulation in the mouse cuprizone model...
August 26, 2016: Neuroscience Letters
C Brian Bai, Sunny Sun, Andrew Roholt, Emily Benson, Dale Edberg, Satish Medicetty, Ranjan Dutta, Grahame Kidd, Wendy B Macklin, Bruce Trapp
Used in combination with immunomodulatory therapies, remyelinating therapies are a viable therapeutic approach for treating individuals with multiple sclerosis. Studies of postmortem MS brains identified greater remyelination in demyelinated cerebral cortex than in demyelinated brain white matter and implicated reactive astrocytes as an inhibitor of white matter remyelination. An animal model that recapitulates these phenotypes would benefit the development of remyelination therapeutics. We have used a modified cuprizone protocol that causes a consistent and robust demyelination of mouse white matter and cerebral cortex...
September 2016: Experimental Neurology
John A Olsen, Lauren A Kenna, Regine C Tipon, Michael G Spelios, Mark M Stecker, Eitan M Akirav
Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). Minimally invasive biomarkers of MS are required for disease diagnosis and treatment. Differentially methylated circulating-free DNA (cfDNA) is a useful biomarker for disease diagnosis and prognosis, and may offer to be a viable approach for understanding MS. Here, methylation-specific primers and quantitative real-time PCR were used to study methylation patterns of the myelin oligodendrocyte glycoprotein (MOG) gene, which is expressed primarily in myelin-producing oligodendrocytes (ODCs)...
August 2016: EBioMedicine
Nikoo Ghaffarian, Masoud Mesgari, Manuela Cerina, Kerstin Göbel, Thomas Budde, Erwin-Josef Speckmann, Sven G Meuth, Ali Gorji
BACKGROUND: Demyelination and remyelination are common pathological processes in many neurological disorders, including multiple sclerosis (MS). Clinical evidence suggests extensive involvement of the thalamocortical (TC) system in patients suffering from MS. METHODS: Using murine brain slices of the primary auditory cortex, we investigated the functional consequences of cuprizone-induced de- and remyelination on neuronal activity and auditory TC synaptic transmission in vitro...
2016: Journal of Neuroinflammation
In Young Choi, Laura Piccio, Patra Childress, Bryan Bollman, Arko Ghosh, Sebastian Brandhorst, Jorge Suarez, Andreas Michalsen, Anne H Cross, Todd E Morgan, Min Wei, Friedemann Paul, Markus Bock, Valter D Longo
Dietary interventions have not been effective in the treatment of multiple sclerosis (MS). Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs)...
June 7, 2016: Cell Reports
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