Neurotrophin-3 specifically increases mature oligodendrocyte population and enhances remyelination after chemical demyelination of adult rat CNS

Jean, Isabelle; Lavialle, Céline; Barthelaix-Pouplard, Annick; Fressinaud, Catherine

doi:10.1016/s0006-8993(03)02510-1

Cited by 59 publications

(48 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NT-3 is known to stimulate the survival of OLGs and may play an important role in myelin regeneration after CNS injury and demyelination (Barres et al, 1993;McTigue et al, 1998;Jean et al, 2003;Saini et al, 2005). We have previously found that NT-3 stimulates the survival of OLG progenitors by a mechanism that involves the activation of an S1P-dependent pathway (Saini et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

Coelho

Payne²,

Bittman³

et al. 2007

J Pharmacol Exp Ther

169

132

View full text Add to dashboard Cite

The immunomodulator 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720) has promising therapeutic effects in multiple sclerosis (MS), a degenerative disease in which demyelination of the central nervous system is accompanied by death of oligodendrocytes (OLGs), the myelin-producing cells. In vivo phosphorylation of FTY720 generates an agonist for G protein-coupled receptors for sphingosine-1-phosphate, a lipid mediator that plays a crucial role in the stimulation of OLG survival by neurotrophin-3 (NT-3). The mechanisms underlying the action of FTY720 in MS are not clearly understood, although the effects of this drug in autoimmune diseases are thought to stem from its ability to reduce lymphocyte infiltration and inflammation. Interestingly, we now found that FTY720 also has a direct effect on OLG progenitors. Treatment of these cells with FTY720 causes activation of extracellular signal-regulated kinase 1/2 and Akt, accompanied by protection from apoptosis. However, FTY720 also arrested OLG differentiation. Importantly, this effect was counteracted by NT-3, which not only enhanced the survival of OLG progenitors induced by FTY720 but also stimulated their maturation. Altogether, these observations suggest that in addition to its immunosuppressive functions, FTY720 could also have a beneficial effect in MS by direct action on OLG progenitors. However, the finding that FTY720 blocks the differentiation of these cells raises the question of whether MS therapies with FTY720 should include the use of differentiation-enhancing factors such as NT-3. This approach would ensure both protection of existing OLG progenitor pools against immune-mediated insults as well as stimulation of remyelination by enhancing the maturation of these cells.Multiple sclerosis (MS) is a chronic degenerative and debilitating disease of the central nervous system (CNS) characterized by inflammation and demyelination (McQualter and Bernard, 2007). The pathological hallmarks of MS also include axonal degeneration (Trapp et al., 1999) and death of oligodendrocytes (OLGs) (Barnett and Prineas, 2004;Lucchinetti et al., 2004), the cells that make the myelin membrane in the CNS. Although the cause of MS remains unknown, the presence of serum antibodies against different myelin constituents and the existence of multiple inflammatory foci in brain and spinal cord support the idea of a predominant autoimmune component. For this reason, most therapeutic approaches involve the use of anti-inflammatory drugs and immunosuppressants.2-Amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720, also known as Fingolimod), is among the latest immunomodulatory agents under evaluation for the treatment of MS. This synthetic drug was developed by chemical modification of ISP-I (myriocin), a sphingosine-like metabolite produced by the fungus Isaria sinclairii. FTY720 has been shown to prolong allograft survival in different animal models of transplantation (Chiba et al., 1996) and exert a protective effect in animal models of autoimmune diseases (Ma...

show abstract

Section: Resultsmentioning

confidence: 99%

The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

Coelho

Payne²,

Bittman³

et al. 2007

J Pharmacol Exp Ther

169

132

View full text Add to dashboard Cite

show abstract

“…Furthermore, in a model of chemically induced demyelination, stereotaxic delivery of NT-3 into the corpus callosum increased the numbers of mature MBP 1 oligodendrocytes while significantly decreasing the volume of demyelinated lesions (Jean et al, 2003). Similarly, after a spinal cord contusion injury, transplanted grafts of fibroblasts expressing NT-3 and brain-derived Fig.…”

Section: Bone Morphogenic Proteinsmentioning

confidence: 88%

How factors secreted from astrocytes impact myelin repair

Moore

Abdullah

Brown

et al. 2010

J of Neuroscience Research

143

117

View full text Add to dashboard Cite

Over a century ago, hypertrophy of astrocytes was noted as a pathology of multiple sclerosis (MS) and was hypothesized to play an important role in this disease, yet the contribution of astrocytes has been largely underemphasized in the pathophysiology of CNS demyelination. Astrocytes perform many homeostatic functions within the developing and adult CNS, including enhancing formation and maintenance of the blood-brain barrier, moderating neuronal connections through the tripartite synapse, and perhaps even offering intercellular communication independently of neurons. Although there is a significant body of literature characterizing different types of MS lesions, the inflammatory demyelination in an active MS lesion is accompanied by the presence of macrophages, lymphocytes, and large reactive astrocytes. The astrocyte has long been viewed as a cell that promotes inflammation and demyelination, while also forming the glial scar, thus hindering remyelination and axon growth. Renewed interest in the astrocyte has been brought about by recent studies demonstrating that astrocytes can also function as cellular mediators of CNS myelination by promoting oligodendrocyte progenitor migration, proliferation, and differentiation. Thus, refining our knowledge of astrocytic functions in the regulation of CNS myelination may help us to better understand why remyelination fails in MS.

show abstract

“…In the spinal cord, these adult OPCs proliferate in response to demyelination (Carroll and Jennings, 1994;Keirstead et al, 1998;Redwine and Armstrong, 1998;Reynolds et al, 2001), and it is well documented that an array of growth factors, including BDNF and NT-3, increases their proliferation and survival in vitro (McMorris and McKinnon, 1996;Rubio et al, 2004). Previous studies based on ex vivo gene transfer (McTigue et al, 1998) or direct injection of NT-3 (Jean et al, 2003) showed that NT-3 promotes a fivefold increase in the number of proliferating OPCs after injury. We obtained similar results after transplantation of BDNF-transduced (4.6-fold) and NT-3-transduced (6.5-fold) SCs in demyelinated spinal cords.…”

Section: Discussionmentioning

confidence: 99%

Grafts of Brain-Derived Neurotrophic Factor and Neurotrophin 3-Transduced Primate Schwann Cells Lead to Functional Recovery of the Demyelinated Mouse Spinal Cord

Girard¹,

Bemelmans²,

Dufour³

et al. 2005

J. Neurosci.

100

View full text Add to dashboard Cite

Neurotrophin-3 specifically increases mature oligodendrocyte population and enhances remyelination after chemical demyelination of adult rat CNS

Cited by 59 publications

References 50 publications

The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

The Immunomodulator FTY720 Has a Direct Cytoprotective Effect in Oligodendrocyte Progenitors

How factors secreted from astrocytes impact myelin repair

Grafts of Brain-Derived Neurotrophic Factor and Neurotrophin 3-Transduced Primate Schwann Cells Lead to Functional Recovery of the Demyelinated Mouse Spinal Cord

Contact Info

Product

Resources

About