Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2000 Aug 1;20(15):5703-8.
doi: 10.1523/JNEUROSCI.20-15-05703.2000.

Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination

J L Mason  1 , P Ye, K Suzuki, A J D'Ercole, G K Matsushima
Affiliations

Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination

J L Mason et al. J Neurosci. .

Abstract

Metabolic insult results in apoptosis and depletion of mature oligodendrocytes during demyelination. To examine the role of insulin-like growth factor-1 (IGF-1) during acute demyelination and remyelination in the adult CNS, we exposed transgenic mice that continuously express IGF-1 (IGF-1 tg) to cuprizone intoxication. Demyelination was observed within the corpus callosum in both wild-type and IGF-1 tg mice 3 weeks after exposure to cuprizone. Wild-type mice showed significant apoptotic mature oligodendrocytes and a dramatic loss of these cells within the lesion that resulted in near complete depletion and demyelination by week 5. In contrast, the demyelinated corpus callosum of the IGF-1 tg mice was near full recovery by week 5. This rapid recovery was apparently caused by survival of the mature oligodendrocyte population because apoptosis was negligible, and by week 4, the mature oligodendrocyte population was completely restored. Furthermore, despite demyelination in both wild-type and IGF-1 tg mice, oligodendrocyte progenitors accumulated only in the absence of mature oligodendrocytes and failed to accumulate if the mature oligodendrocytes remained as demonstrated in the IGF-1 tg mice. These results suggest that IGF-1 may be important in preventing the depletion of mature oligodendrocytes in vivo and thus facilitates an early recovery from demyelination.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Presence of IGF-1 within the corpus callosum of wild-type and IGF-1 tg mice fed cuprizone. Frozen brain sections from wild-type (A, C,E) and IGF-1 tg (B,D, F) mice were immunostained with anti-IGF-1 (green). Although few IGF-1+ cells were observed within the corpus callosum of the untreated control wild-type mice (A), a substantial number were observed in theIGF-1 tg mice (B). At 3 weeks, some IGF-1+ cells were present in wild-type mice (C), whereas large numbers appeared in theIGF-1 tg mice (D). At 5 weeks, a large accumulation of IGF-1+ cells was observed in the wild-type mice (E), whereas in IGF-1 tg mice the IGF-1+ cells appeared similar in number to untreated control mice. Scale bar, 15 μm.
Fig. 2.
Fig. 2.
Demyelination and remyelination in the corpus callosum of IGF-1 tg and wild-type mice. Electron micrographs show that nearly all axons within the corpus callosum are myelinated in both the untreated wild-type (A) and IGF-1 tg (B) mice. A large number of axons are demyelinated in both the wild-type (C) and IGF-1 tg(D) mice exposed to cuprizone for 3 weeks. At 5 weeks, almost all of the axons are demyelinated in the wild-type mice (E), whereas most of the axons are myelinated in the IGF-1 tg mice (F). Scale bar, 1.2 μm.
Fig. 3.
Fig. 3.
Percentage of myelinated axons within the corpus callosum of wild-type and IGF-1 tg mice. The percentage of myelinated axons within the corpus callosum of mice was determined by morphometric analysis of electron micrographs (300 axons per mouse were examined). The mean and SEM bars are plotted for each time point (n = 3) as examined in the wild-type (black bars) and IGF-1 tg (white bars) mice. (*p < 0.01; **p < 0.001 when comparing wild-type mice with IGF-1 tg mice.)
Fig. 4.
Fig. 4.
Microglia/macrophages associate with demyelination within the corpus callosum of cuprizone-treated wild-type andIGF-1 tg mice. Paraffin-embedded brain sections from wild-type (A, C) and IGF-1 tg (B, D) mice were stained with RCA-1. No RCA-1+ cells were observed in the untreated control wild-type (A) and IGF-1 tg (B) mice. Large numbers of RCA-1+ cells (brown stain) were present in wild-type (C) and IGF-1 tg (D) mice fed cuprizone for 3 weeks. Scale bar, 25 μm.
Fig. 5.
Fig. 5.
The accumulation of microglia/macrophages in the corpus callosum of wild-type and IGF-1 tg mice during cuprizone feeding. The number of RCA-1+ cells of wild-type mice (black bars) and IGF-1 tgmice (white bars) was quantitated in triplicate and plotted as mean ± SEM (*p < 0.001 when comparing wild-type mice and IGF-1 tg mice).
Fig. 6.
Fig. 6.
Mature oligodendrocytes and apoptosis in the corpus callosum of wild-type and IGF-1 tg mice. Paraffin-embedded brain sections were immunostained with anti-GST-Pi (green cells;A–J), and some sections were also examined for the presence of apoptotic cells (red nuclei; G–J). Large numbers of GST-Pi+ cells were observed in untreated control wild-type (A) and IGF-1 tg(B) mice. At 3 weeks of exposure to cuprizone, there was a decrease in the number of GST-Pi+ cells in wild-type mice (C), whereas only a slight reduction was observed in the IGF-1 tg mice (D). At 5 weeks, only a few GST-Pi+ cells were observed in the wild-type mice (E), whereas normal numbers of these cells were observed in the IGF-1 tg mice (F). No apoptotic cells were observed in the untreated control wild-type (G) and IGF-1 tg(H) mice. At 3 weeks, a large number of apoptotic nuclei colocalized with GST-Pi+ cells (arrow) in wild-type mice (I), whereas no colocalization was observed in the IGF-1 tg mice (J). Scale bar, 25 μm.
Fig. 7.
Fig. 7.
Survival of mature oligodendrocytes inIGF-1 tg mice. The number of GST-Pi+mature oligodendrocytes (A) and the number of apoptotic mature oligodendrocytes (B) were quantitated for wild-type mice (black bars) andIGF-1 tg mice (white bars) from triplicate samples and plotted as mean ± SEM (*p < 0.001 when comparing wild-type mice withIGF-1 tg mice).
Fig. 8.
Fig. 8.
Accumulation of oligodendrocyte progenitors within the corpus callosum of wild-type but not IGF-1 tg mice during demyelination. Frozen brain sections from wild-type (A, C) and IGF-1 tg(B, D) mice were stained with the anti-NG2 antibody (green). Few NG2+ cells were observed in the untreated control wild-type (A) and IGF-1 tg(B) mice. Large numbers of NG2+ cells were present in wild-type mice exposed to cuprizone for 3 weeks (C). Few NG2+ cells were observed in the IGF-1 tg mice fed cuprizone for 3 weeks (D). Scale bar, 10 μm.
Fig. 9.
Fig. 9.
The accumulation of oligodendrocyte progenitors within the corpus callosum of wild-type and IGF-1 tgmice during cuprizone intoxication. The total number of NG2+ cells was quantitated in the corpus callosum of wild-type mice (white bars) and IGF-1 tgmice (black bars) from triplicate samples and plotted as mean ± SEM.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Barres BA, Schmid R, Sendnter M, Raff MC. Multiple extracellular signals are required for long-term oligodendrocyte survival. Development. 1993;118:283–295. - PubMed
    1. Cho KH, Kim MW, Kim SU. Tissue culture model of Krabbe's disease: psychosine cytotoxicity in rat oligodendrocyte cultures. Dev Neurosci. 1997;19:321–327. - PubMed
    1. Compston A. Remyelination of the central nervous system. Mult Scler. 1996;1:388–392. - PubMed
    1. Coetzee T, Fujita N, Dupree J, Shi R, Blight A, Suzuki K, Suzuki K, Popko B. Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional stability. Cell. 1996;86:209–219. - PubMed
    1. D'Ercole AJ, Ye P, Calikoglu AS, Gutierrez-Ospina G. The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol. 1996;13:227–255. - PubMed

Publication types

MeSH terms

LinkOut - more resources