Extensive remyelination of the CNS leads to functional recovery

Duncan, I. D.; Brower, Aaron M.; Kondo, Yoichi; Curlee, Jr Jf; Schultz, RD

doi:10.1073/pnas.0812500106

Cited by 200 publications

(180 citation statements)

References 21 publications

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“…Of course, as remyelination has been linked to restoration of saltatory conduction 21 , the ultimate metric of repair would be functional recovery of neurological deficits. While remyelination has been linked to recovery of function in some species 22,23 , it has not become a standard procedure in murine lysolecithin studies. This is likely due to a lack of overt observable deficits from either dorsal or ventral lesions, compared to more robust demyelination models such as EAE and even cuprizone.…”

Section: Discussionmentioning

confidence: 99%

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

Keough

Jensen

2015

JoVE

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Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system characterized by plaque formation containing lost oligodendrocytes, myelin, axons, and neurons. Remyelination is an endogenous repair mechanism whereby new myelin is produced subsequent to proliferation, recruitment, and differentiation of oligodendrocyte precursor cells into myelin-forming oligodendrocytes, and is necessary to protect axons from further damage. Currently, all therapeutics for the treatment of multiple sclerosis target the aberrant immune component of the disease, which reduce inflammatory relapses but do not prevent progression to irreversible neurological decline. It is therefore imperative that remyelination-promoting strategies be developed which may delay disease progression and perhaps reverse neurological symptoms. Several animal models of demyelination exist, including experimental autoimmune encephalomyelitis and curprizone; however, there are limitations in their use for studying remyelination. A more robust approach is the focal injection of toxins into the central nervous system, including the detergent lysolecithin into the spinal cord white matter of rodents. In this protocol, we demonstrate that the surgical procedure involved in injecting lysolecithin into the ventral white matter of mice is fast, cost-effective, and requires no additional materials than those commercially available. This procedure is important not only for studying the normal events involved in the remyelination process, but also as a pre-clinical tool for screening candidate remyelination-promoting therapeutics.

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Section: Discussionmentioning

confidence: 99%

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

Keough

Jensen

2015

JoVE

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“…These data indicate that remyelination probably occurred in the corpus callosum after acute OLG death, although its extent was difficult to assess given that g-ratios of myelinated and remyelinated axons are very similar due to the small diameters of the majority of axons in this tract (Stidworthy et al, 2003). Overall remyelination in our model was not sufficient to cause functional recovery in the experimental mice before the experiment had to be terminated (Duncan et al, 2009). …”

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confidence: 96%

Genetically Induced Adult Oligodendrocyte Cell Death Is Associated with Poor Myelin Clearance, Reduced Remyelination, and Axonal Damage

Pohl¹,

Porcheri²,

Mueggler³

et al. 2011

J. Neurosci.

128

118

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Loss of oligodendrocytes is a feature of many demyelinating diseases including multiple sclerosis. Here, we have established and characterized a novel model of genetically induced adult oligodendrocyte death. Specific primary loss of adult oligodendrocytes leads to a well defined and highly reproducible course of disease development that can be followed longitudinally by magnetic resonance imaging. Histological and ultrastructural analyses revealed progressive myelin vacuolation, in parallel to disease development that includes motor deficits, tremor, and ataxia. Myelin damage and clearance were associated with induction of oligodendrocyte precursor cell proliferation, albeit with some regional differences. Remyelination was present in the mildly affected corpus callosum. Consequences of acutely induced cell death of adult oligodendrocytes included secondary axonal damage. Microglia were activated in affected areas but without significant influx of B-cells, T-helper cells, or T-cytotoxic cells. Analysis of the model on a RAG-1 (recombination activating gene-1)-deficient background, lacking functional lymphocytes, did not change the observed disease and pathology compared with immunecompetent mice. We conclude that this model provides the opportunity to study the consequences of adult oligodendrocyte death in the absence of primary axonal injury and reactive cells of the adaptive immune system. Our results indicate that if the blood-brain barrier is not disrupted, myelin debris is not removed efficiently, remyelination is impaired, and axonal integrity is compromised, likely as the result of myelin detachment. This model will allow the evaluation of strategies aimed at improving remyelination to foster axon protection.

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“…Compelling evidence in support of functional restoration by remyelination has recently been provided by an unusual demyelinating condition in cats in which the reversal of clinical signs is associated with spontaneous remyelination [21]. Taken together these observations imply that an effective means of restoring function and preventing axonal loss in MS is to promote remyelination.…”

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confidence: 97%

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

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Extensive remyelination of the CNS leads to functional recovery

Cited by 200 publications

References 21 publications

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

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

Genetically Induced Adult Oligodendrocyte Cell Death Is Associated with Poor Myelin Clearance, Reduced Remyelination, and Axonal Damage

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

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