Functional central nervous system myelin repair in an adult mouse model of demyelination caused by proteolipid protein overexpression.
Two types of interventions to remyelinate the adult demyelinated central nervous system were investigated in heterozygous transgenic mice overexpressing the proteolipid protein gene. 1) A cocktail of trophic factors, "TS1," was directed toward the activation of the endogenous pool of neural progenitors to increase the number of myelinating oligodendrocytes (OL) in the brain. 2) A combinatorial approach in which OL progenitors were coinjected with TS1 into the corpus callosum of wild-type and He4e transgenic mice that displayed hindlimb paralysis. The levels of locomotor ability in these mice were evaluated after a single treatment. The data showed that a single administration of either one of the interventions had similar therapeutic effects, alleviating the symptoms of demyelination and leading to the recovery of hindlimb function. Histological and immunofluorescent examination of brain sections showed extensive remyelination that was sufficient to reverse hindlimb paralysis in transgenic mice. When the interventions were administered prior to hindlimb paralysis, He4e mice were able to walk up to 1 year of age without paralysis.
Espinosa-Jeffrey
A
A
IDDRCsp, Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. aespinosa@mednet.ucla.edu
Hitoshi
S
S
Zhao
P
P
Awosika
O
O
Agbo
C
C
Olaniyan
E
E
Garcia
J
J
Valera
R
R
Thomassian
A
A
Chang-Wei
R
R
Yamaguchi
M
M
de Vellis
J
J
Ikenaka
K
K
D000578:Amidines / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism* / Q000503:physiopathology*; D003337:Corpus Callosum / Q000378:metabolism / Q000637:transplantation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000502:physiology; D005732:Gangliosides / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal / Q000379:methods; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D016900:Neurofilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000737:chemistry; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
D000578:Amidines; D017077:Culture Media, Conditioned; D005732:Gangliosides; D036341:Intercellular Signaling Peptides and Proteins; D007381:Intermediate Filament Proteins; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D016900:Neurofilament Proteins; C047516:Plp1 protein, mouse; C031455:diamidino compound 253-50; C062875:ganglioside A2B5; D049452:Green Fluorescent Proteins