Experimental Demyelination and Remyelination of Murine Spinal Cord by Focal Injection of Lysolecithin

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system characterized by plaque formation containing lost ...

Hotchkiss Brain Institute at University of Calgary

The extracellular matrix (ECM) is a complex network of scaffolding molecules that also plays an important role in cell signalling, migration and tissue structure. In the central nervous system (CNS), the ECM is integral to the efficient development/guidance and survival of neurons and axons. However, changes in distribution of the ECM in the CNS may significantly enhance pathology in CNS disease or following injury. One group of ECM proteins that is important for CNS homeostasis is the chondroitin sulphate proteoglycans (CSPGs). Up-regulation of these molecules has been demonstrated to be both desirable and detrimental following CNS injury. Taking cues from arthritis, where there is a strong anti-CSPG immune response, there is evidence that suggests that CSPGs may influence immunity during CNS pathological conditions. This review focuses on the role of CSPGs in CNS pathologies as well as in immunity, both from a viewpoint of how they may inhibit repair and exacerbate damage in the CNS, and how they are involved in activation and function of peripheral immune cells, particularly in multiple sclerosis. Lastly, we address how CSPGs may be manipulated to improve disease outcomes.

Chondroitin sulphate proteoglycans: extracellular matrix proteins that regulate immunity of the central nervous system.

Enriched rehabilitation (ER; environmental enrichment plus skilled reaching) improves recovery after middle cerebral artery occlusion (MCAo) in rats. Fundamental issues such as whether ER is effective in other models, optimal rehabilitation intensity, and underlying recovery mechanisms have not been fully assessed.

A critical threshold of rehabilitation involving brain-derived neurotrophic factor is required for poststroke recovery.

Failure of remyelination is a critical impediment to recovery in multiple sclerosis (MS). Chondroitin sulfate proteoglycans (CSPGs) have been reported to accumulate in MS lesions, and we thus examined the functional roles of CSPGs on oligodendrocyte precursor cells (OPCs), oligodendrocytes, and remyelination.

Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by infiltration of immune cells and progressive damage to myelin and axons. All therapeutics used to treat MS have been developed to target an overactive immune response, with aims to reduce disease activity. Chronic demyelinated axons are further prone to irreversible damage and death, and it is imperative that new therapies address this critical issue. Remyelination, the generation of new myelin in the adult nervous system, is an endogenous repair mechanism that restores function of denuded axons and delays their deterioration. Although remyelination can be extensive in some patients, the majority of cases limit repair only to the acute phase of disease. A significant current drive in new MS therapeutics is to identify targets that can promote remyelination by boosting endogenous oligodendrocyte precursor cells to form new myelin. Also, a number of inhibitory pathways have been identified in chronic MS lesions that prevent oligodendrocyte precursor cells from being properly recruited to demyelinated lesions or interfere with their differentiation to myelin-forming oligodendrocytes. In this review, we introduce the phenomenon of remyelination from the view of experimental models and studies in MS patients, describe a potential role in remyelination for currently available MS mediations, and discuss many avenues that are being actively studied to promote remyelination. The next frontier in MS therapeutics will supplement immunomodulation with agents that directly foster myelin repair, with aims to delay disease progression and recover lost neurological functions.

Remyelination therapy for multiple sclerosis.

Acute trauma to the central nervous system (CNS) can result in permanent damage and loss of function related to the poor regeneration of injured axons. Injured axons encounter several barriers to regeneration, such as the glial scar at the injury site. The glial scar contains extracellular matrix (ECM) macromolecules deposited by reactive astrocytes in response to injury. The scar ECM is rich in chondroitin sulfate proteoglycans (CSPGs), macromolecules that inhibit axonal growth. CSPGs consist of a core protein with attachment sites for glycosaminoglycan (GAG) chains. An extensive literature demonstrates that enzymatic removal of the GAG chains by chondroitinase ABC permits some axonal regrowth; however, the remaining intact core proteins also possess inhibitory domains. Because metalloproteinases can degrade core proteins of CSPGs, we have evaluated five matrix metalloproteinases (MMPs) and a related protease-a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4)-for their capacity to overcome CSPG inhibition of neuritic growth in culture. The metalloproteinases were selected for their known expression after CNS injuries. Of the MMPs, MMP-3, -7 and -8 reduced or abolished inhibition of neurite outgrowth on a purified CSPG substrate and on an astrocyte-derived ECM. ADAMTS-4 also attenuated CSPG inhibition of neurites and had the additional benefits of neither degrading laminin nor causing neurotoxicity. The efficacy of ADAMTS-4 matched that of blocking the EGFR signaling previously reported to mediate CSPG inhibition. These findings highlight ADAMTS-4 as a superior protease for overcoming CSPG inhibition of axonal regeneration in the CNS.

Overcoming neurite-inhibitory chondroitin sulfate proteoglycans in the astrocyte matrix.

The extracellular matrix (ECM) occupies a notable proportion of the CNS and contributes to its normal physiology. Alterations to the ECM occur after neural injury (for example, in multiple sclerosis, spinal cord injury or Alzheimer's disease) and can have drastic consequences. Of note, injury-induced changes in chondroitin sulphate proteoglycans (CSPGs)--a family of ECM proteoglycans--can lead to the inhibition of myelin repair. Here, we highlight the pathophysiological roles of the brain's ECM, particularly those of CSPGs, after neural insults and discuss how the ECM can be targeted to promote remyelination.

Pathophysiology of the brain extracellular matrix: a new target for remyelination.

After spinal cord injury (SCI) there is prolonged and dispersed oligodendrocyte cell death that is responsible for widespread demyelination. To regenerate this lost myelin, many investigators have transplanted myelin-producing cells as a treatment for contusive SCI. There are several documented examples of cellular transplantation improving function after injury, with the degree of myelin regeneration correlating with functional recovery. On the basis of these findings, remyelination is hypothesized to be a beneficial strategy to promote recovery after injury. As cellular transplantation is now entering clinical trials for treatment of SCI, it is important to dissect carefully whether accelerating remyelination after SCI is a valid clinical target. In this review we will discuss the consequences of demyelination and the potential benefits of remyelination as it relates to injury. Prolonged demyelination is hypothesized to enhance axonal vulnerability to degeneration, and is thereby thought to contribute to the axonal degeneration that underlies the permanent functional losses associated with SCI. Currently, strategies to promote remyelination after SCI are largely limited to cellular transplantation. This review discusses those strategies as well as new, and largely untested, modes of therapy that aim to coax endogenous cells residing adjacent to the injury site to differentiate in order to replace lost myelin.

Remyelination after spinal cord injury: is it a target for repair?

Over 30 years ago a cry rang out through the proverbial halls of academia; "The clinician scientist is an endangered species." These prophetic words have been reverberated in the ears of every specialty and every general medical organization in deafening tones. Why is the role of the clinician scientist or clinician investigator so important that this phrase has been repeated subsequently in medical and educational journals? Simply put, the clinician scientist bridges the ravine between the ever-growing mountain of scientific knowledge and the demanding patient centered clinical care. Here, we describe the current educational model established by the University of Calgary, Leaders in Medicine Program. Our program seeks to train future physicians and clinician scientists by incorporating training in basic science, translational and clinical research with clinical and medical education in a longitudinal program to students of traditional MD/PhD, MD/MSc or MD/MBA stream as well as interested Doctor of Medicine students.

A prescription that addresses the decline of basic science education in medical school.

Laquinimod is an emerging oral medication for multiple sclerosis (MS) that reduces brain atrophy and progression of disability in two Phase III clinical trials. The mechanism of these effects is unclear. Persistent activation of microglia occurs in MS and contributes to injury. Thus, we investigated whether laquinimod alters properties of microglia in culture and in experimental autoimmune encephalomyelitis (EAE), and whether this reduces neurodegeneration.

Michael B. Keough

Department of Clinical Neurosciences

Hotchkiss Brain Institute at University of Calgary

Experimental Demyelination and Remyelination of Murine Spinal Cord by Focal Injection of Lysolecithin

Michael B. Keough

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Clinical Neurosciences

Hotchkiss Brain Institute at University of Calgary

Experimental Demyelination and Remyelination of Murine Spinal Cord by Focal Injection of Lysolecithin

Department of Clinical Neurosciences