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.
Subject(s)
Apoptosis/physiology , Demyelinating Diseases/physiopathology , Insulin-Like Growth Factor I/metabolism , Oligodendroglia/cytology , Acute Disease , Animals , Brain Chemistry/drug effects , Brain Chemistry/physiology , Cell Survival/physiology , Chelating Agents/poisoning , Corpus Callosum/pathology , Corpus Callosum/physiopathology , Cuprizone/poisoning , Demyelinating Diseases/chemically induced , Demyelinating Diseases/genetics , Female , Gene Expression/physiology , Insulin-Like Growth Factor I/genetics , Macrophages/cytology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Microglia/cytology , Recovery of Function/physiology , Stem Cells/cytologyABSTRACT
The status of blood-brain barrier (BBB) permeability was investigated in the twitcher, an authentic murine model of globoid cell leukodystrophy (GLD, Krabbe disease) and cuprizone-intoxicated mice. Although extensive demyelination was noted in the CNS of both mice and additionally, macrophage infiltration was pronounced in the twitcher, BBB remained intact to horseradish peroxidase. Thus, the change of microenvironment caused by demyelination is not necessarily a responsible factor for increased BBB permeability in the inflammatory demyelinating conditions.
