Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti-galactocerebroside: A comparative study

Woodruff, Rachel H.; Franklin, R. J. M.

doi:10.1002/(sici)1098-1136(19990201)25:3<216::aid-glia2>3.0.co;2-l

Cited by 279 publications

(265 citation statements)

References 52 publications

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“…On the contrary, in the absence of testosterone or a functional AR, astrocytes remained sparse and P0 + myelin was preferentially detected within the lesion. This observation is consistent with previous studies showing that Schwann cell remyelination occurs in areas of the CNS where astrocytes are absent (9,10).…”

Section: Discussionsupporting

confidence: 94%

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Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

Bielecki

Mattern²,

Ghoumari

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

101

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Lost myelin can be replaced after injury or during demyelinating diseases in a regenerative process called remyelination. In the central nervous system (CNS), the myelin sheaths, which protect axons and allow the fast propagation of electrical impulses, are produced by oligodendrocytes. The abundance and widespread distribution of oligodendrocyte progenitors (OPs) within the adult CNS account for this remarkable regenerative potential. Here, we report a key role for the male gonad, testosterone, and androgen receptor (AR) in CNS remyelination. After lysolecithin-induced demyelination of the male mouse ventral spinal cord white matter, the recruitment of glial fibrillary acidic protein-expressing astrocytes was compromised in the absence of testes and testosterone signaling via AR. Concomitantly, the differentiation of OPs into oligodendrocytes forming myelin basic protein (MBP) + and proteolipid protein-positive myelin was impaired. Instead, in the absence of astrocytes, axons were remyelinated by protein zero (P0) + and peripheral myelin protein 22-kDa (PMP22) + myelin, normally only produced by Schwann cells in the peripheral nervous system. Thus, testosterone favors astrocyte recruitment and spontaneous oligodendrocyte-mediated remyelination. This finding may have important implications for demyelinating diseases, psychiatric disorders, and cognitive aging. The testosterone dependency of CNS oligodendrocyte remyelination may have roots in the evolutionary history of the AR, because the receptor has evolved from an ancestral 3-ketosteroid receptor through gene duplication at the time when myelin appeared in jawed vertebrates.T he remyelination of axons is a complex process, involving interactions between different types of neural cells. It shows a peculiarity that has been observed in both experimental models and demyelinating diseases such as multiple sclerosis (MS) (1). Although most of the remyelination is normally accomplished by oligodendrocytes derived from oligodendrocyte progenitors (OPs), a variable proportion of central nervous system (CNS) axons can be remyelinated by cells with the immunophenotypic and ultrastructural characteristics of Schwann cells, the presence of which is normally limited to the peripheral nervous system (PNS). These cells indeed express protein zero (P0), a sensitive and specific marker of Schwann cells (2). Moreover, analysis by electron microscopy demonstrated that they have the typical morphology of myelinating Schwann cells (1-4). These ultrastructural findings indicate that the expression of P0 by part of the remyelinating cells is not merely ectopic, but that these cells may correspond to authentic Schwann cells. This observation was further supported by their expression of Schwann cell-specific transcription factors (5).Importantly, there is strong evidence that large numbers of the Schwann cells present in demyelinating CNS lesions are derived from OPs. The first evidence came from the transplantation of purified OPs into demyelinating CNS lesions, in which endogenous ...

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Section: Discussionsupporting

confidence: 94%

“…Thus, within a demyelinated lesion, oligodendrocyte remyelination occurs in regions where astrocytes are present, whereas Schwann cell remyelination preferentially occurs in the absence of astrocytes (7,9,10). Moreover, reducing astrocyte activation by a conditional genetic deletion promoted Schwann cell remyelination (1).…”

mentioning

confidence: 99%

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

Bielecki

Mattern²,

Ghoumari

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

101

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“…It is of our belief that the best model for studying remyelination is the direct injection of toxins, either lysolecithin, ethidium bromide, or others, into the caudal cerebral peduncles 18 or the spinal cord white matter. The former location is achieved only by precise 3-dimension stereotactic injection, and is limited to larger rodents (rats) due to the small size of the cerebellar peduncles.…”

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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“…A localized lesion was induced in the corpus callosum of 8-weekold mice (Fig. 3a-c), using the ethidium bromide injection paradigm (Woodruff and Franklin, 1999). The close proximity of the lesion to the SVZ was selected to determine whether stathmin expression would increase during the 3-4 d period after the injection, when oligodendrocyte progenitors begin to repopulate the lesion site (Levine and Reynolds, 1999).…”

Section: Stathmin Expression Is High In Primary Cultures Of Oligodendmentioning

confidence: 99%

Expression of Stathmin, a Developmentally Controlled Cytoskeleton-Regulating Molecule, in Demyelinating Disorders

Liu

Stadelmann²,

Moscarello³

et al. 2005

J. Neurosci.

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Understanding the biological relevance of reexpression of developmental molecules in pathological conditions is crucial for the development of new therapies. In this study, we report the increased expression of stathmin, a developmentally regulated tubulin-binding protein, in the brains of patients with multiple sclerosis (MS). In physiological conditions, stathmin immunoreactivity was observed in polysialic acid-neural cell adhesion molecule-positive migratory progenitors in the subventricular zone, and its expression progressively decreased as the cells matured into oligodendrocytes (OLs). In MS patients, however, stathmin levels were elevated in 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase-positive OLs, in 10 of 10 bioptic samples analyzed. Increased levels of stathmin were confirmed by Western blot analysis of normal-appearing white matter samples from MS brains. In addition, using mass spectrometry, stathmin was identified as the main component of a specific myelin protein fraction consistently increased in MS preparations compared with controls.To test the biological relevance of increased stathmin levels, primary OL progenitors were transfected using a myc-tagged stathmin cDNA and were allowed to differentiate. Consistent with a distinct role played by this molecule in cells of the OL lineage at different developmental stages, transient transfection in progenitors favored the bipolar migratory phenotype but did not affect survival. However, sustained stathmin levels in differentiating OLs, because of overexpression, resulted in enhanced apoptotic susceptibility.We conclude that stathmin expression in demyelinating disorders could have a dual role. On one hand, by favoring the migratory phenotype of progenitors, it may promote myelin repair. On the other hand, stathmin in mature OLs may indicate cell stress and possibly affect survival.

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Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti-galactocerebroside: A comparative study

Cited by 279 publications

References 52 publications

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

Unexpected central role of the androgen receptor in the spontaneous regeneration of myelin

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

Expression of Stathmin, a Developmentally Controlled Cytoskeleton-Regulating Molecule, in Demyelinating Disorders

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