Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelination through PTPσ

Pendleton, James; Shamblott, Michael J.; Gary, Devin S.; Belegu, Visar; Hurtado, Andrés; Malone, Misti; McDonald, John W.

doi:10.1016/j.expneurol.2013.04.003

Cited by 125 publications

(148 citation statements)

References 72 publications

Supporting

Mentioning

143

Contrasting

Unclassified

Order By: Relevance

“…In particular, astrocytes at the edge of active MS lesions up-regulate CSPGs such as versican, aggrecan and neurocan (Haylock-Jacobs et al, 2011;Haist et al, 2012;Lau et al, 2012). Significantly, there are several in vitro studies indicating that neurocan and aggrecan impair the outgrowth of oligodendrocyte process, OPC differentiation and myelination (Siebert and Osterhout, 2011;Pendleton et al, 2013). Here, the enhanced expression of CSPGs in astrocytes following exposure to TGFβ (Gris et al, 2007;Susarla et al, 2011) was down-regulated by Sativex administration.…”

Section: Discussionmentioning

confidence: 64%

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

Feliú

Moreno-Martet

Mecha

et al. 2015

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSE Sativex® is an oromucosal spray, containing equivalent amounts of Δ 9-tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD)-botanical drug substance (BDS), which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS). In this study, we investigated whether Sativex may also serve as a disease-modifying agent in the Theiler's murine encephalomyelitis virus-induced demyelinating disease model of MS. EXPERIMENTAL APPROACHA Sativex-like combination of phytocannabinoids and each phytocannabinoid alone were administered to mice once they had established MS-like symptoms. Motor activity and the putative targets of these cannabinoids were assessed to evaluate therapeutic efficacy. The accumulation of chondroitin sulfate proteoglycans (CSPGs) and astrogliosis were assessed in the spinal cord and the effect of Sativex on CSPGs production was evaluated in astrocyte cultures. KEY RESULTSSativex improved motor activity -reduced CNS infiltrates, microglial activity, axonal damage -and restored myelin morphology. Similarly, we found weaker vascular cell adhesion molecule-1 staining and IL-1β gene expression but an up-regulation of arginase-1. The astrogliosis and accumulation of CSPGs in the spinal cord in vehicle-infected animals were decreased by Sativex, as was the synthesis and release of CSPGs by astrocytes in culture. We found that CBD-BDS alone alleviated motor deterioration to a similar extent as Sativex, acting through PPARγ receptors whereas Δ 9 -THC-BDS produced weaker effects, acting through CB2 and primarily CB1 receptors. CONCLUSIONS AND IMPLICATIONSThe data support the therapeutic potential of Sativex to slow MS progression and its relevance in CNS repair. -tetrahydrocannabinol-botanical drug substance; Arg-1, arginase-1; CBD-BDS, cannabidiol-botanical drug substance; CSPGs, chondroitin sulfate proteoglycans; ECM, extracellular matrix; GAG chains, glycosaminoglycan chains; OPCs, oligodendrocyte precursor cells; TMEV-IDD, Theiler's murine encephalomyelitis virus-induced demyelinating disease; VCAM-1, vascular cell adhesion molecule-1; Sativex, Sativex-like combination of phytocannabinoids; XT-I, xylosyltransferase-I Abbreviations

show abstract

Section: Discussionmentioning

confidence: 64%

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

Feliú

Moreno-Martet

Mecha

et al. 2015

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…In addition to MAPK, several groups have also shown that CSPGs may signal through the Rho/ROCK pathway to exert inhibitory roles in the growth and regeneration of the axons (Lingor et al, 2007;Monnier et al, 2003). Recently, a receptor for CSPGs, PTPσ, was identified; it was determined that this receptor participates in the Rho/ROCK signaling pathway and allows CSPGs to suppress the outgrowth of OL processes and their capacity to remyelinate axons after SCI (Pendleton et al, 2013). However, the molecular basis for the interaction of CSPGs with the pre-OLs in the developing brain requires further exploration.…”

Section: Discussionmentioning

confidence: 98%

Chondroitin sulfate proteoglycans impede myelination by oligodendrocytes after perinatal white matter injury

Deng

Sun

et al. 2015

Experimental Neurology

View full text Add to dashboard Cite

“…Although it is possible that the active population of NG2+ ES cells shown here are early staged oligodendrocytes, we do not demonstrate in these studies that NG2 labeling is exclusive to a homogenous cell lineage. Additionally, our laboratory has recently published observations of CSPGs modulating NG2+ oligodendrocyte process extension and myelination but not differentiation through the tyrosine phosphatase s receptor [60]. Whether CSPG affects the MMP-9 degradative mechanism of NG2+ cells is a topic for future experiments.…”

Section: Discussionmentioning

confidence: 99%

NG2+ Progenitors Derived From Embryonic Stem Cells Penetrate Glial Scar and Promote Axonal Outgrowth Into White Matter After Spinal Cord Injury

Vadivelu

Stewart

et al. 2015

Stem Cells Translational Medicine

Self Cite

View full text Add to dashboard Cite

The glial scar resulting from spinal cord injury is rich in chondroitin sulfate proteoglycan (CSPG), a formidable barrier to axonal regeneration. We explored the possibility of breaching that barrier by first examining the scar in a functional in vitro model. We found that embryonic stem cell-derived neural lineage cells (ESNLCs) with prominent expression of nerve glial antigen 2 (NG2) survived, passed through an increasingly inhibitory gradient of CSPG, and expressed matrix metalloproteinase 9 (MMP-9) at the appropriate stage of their development. Outgrowth of axons from ESNLCs followed because the migrating cells sculpted pathways in which CSPG was degraded. The degradative mechanism involved MMP-9 but not MMP-2. To confirm these results in vivo, we transplanted ESNLCs directly into the cavity of a contused spinal cord 9 days after injury. A week later, ESNLCs survived and were expressing both NG2 and MMP-9. Their axons had grown through long distances (>10 mm), although they preferred to traverse white rather than gray matter. These data are consistent with the concept that expression of inhibitory CSPG within the injury scar is an important impediment to regeneration but that NG2+ progenitors derived from ESNLCs can modify the microenvironment to allow axons to grow through the barrier. This beneficial action may be partly due to developmental expression of MMP-9. We conclude that it might eventually be possible to encourage axonal regeneration in the human spinal cord by transplanting ESNLCs or other cells that express NG2. STEM CELLS

show abstract

Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelination through PTPσ

Cited by 125 publications

References 72 publications

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

Chondroitin sulfate proteoglycans impede myelination by oligodendrocytes after perinatal white matter injury

NG2+ Progenitors Derived From Embryonic Stem Cells Penetrate Glial Scar and Promote Axonal Outgrowth Into White Matter After Spinal Cord Injury

Contact Info

Product

Resources

About

Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelination through PTPσ

Cited by 125 publications

References 72 publications

A Sativex®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

A Sativex®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

Chondroitin sulfate proteoglycans impede myelination by oligodendrocytes after perinatal white matter injury

NG2+ Progenitors Derived From Embryonic Stem Cells Penetrate Glial Scar and Promote Axonal Outgrowth Into White Matter After Spinal Cord Injury

Contact Info

Product

Resources

About

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis