Multiple sclerosis involves an aberrant autoimmune response and
progressive failure of remyelination in the central nervous system.
Prevention of neural degeneration and subsequent disability requires
remyelination through the generation of new oligodendrocytes, but
current treatments exclusively target the immune system. Oligodendrocyte
progenitor cells are stem cells in the central nervous system and the
principal source of myelinating oligodendrocytes1.
These cells are abundant in demyelinated regions of patients with
multiple sclerosis, yet fail to differentiate, thereby representing a
cellular target for pharmacological intervention2.
To discover therapeutic compounds for enhancing myelination from
endogenous oligodendrocyte progenitor cells, we screened a library of
bioactive small molecules on mouse pluripotent epiblast
stem-cell-derived oligodendrocyte progenitor cells3, 4, 5.
Here we show seven drugs function at nanomolar doses selectively to
enhance the generation of mature oligodendrocytes from progenitor cells in vitro.
Two drugs, miconazole and clobetasol, are effective in promoting
precocious myelination in organotypic cerebellar slice cultures, and in vivo
in early postnatal mouse pups. Systemic delivery of each of the two
drugs significantly increases the number of new oligodendrocytes and
enhances remyelination in a lysolecithin-induced mouse model of focal
demyelination. Administering each of the two drugs at the peak of
disease in an experimental autoimmune encephalomyelitis mouse model of
chronic progressive multiple sclerosis results in striking reversal of
disease severity. Immune response assays show that miconazole functions
directly as a remyelinating drug with no effect on the immune system,
whereas clobetasol is a potent immunosuppressant as well as a
remyelinating agent. Mechanistic studies show that miconazole and
clobetasol function in oligodendrocyte progenitor cells through
mitogen-activated protein kinase and glucocorticoid receptor signalling,
respectively. Furthermore, both drugs enhance the generation of human
oligodendrocytes from human oligodendrocyte progenitor cells in vitro.
Collectively, our results provide a rationale for testing miconazole
and clobetasol, or structurally modified derivatives, to enhance
remyelination in patients.
progressive failure of remyelination in the central nervous system.
Prevention of neural degeneration and subsequent disability requires
remyelination through the generation of new oligodendrocytes, but
current treatments exclusively target the immune system. Oligodendrocyte
progenitor cells are stem cells in the central nervous system and the
principal source of myelinating oligodendrocytes1.
These cells are abundant in demyelinated regions of patients with
multiple sclerosis, yet fail to differentiate, thereby representing a
cellular target for pharmacological intervention2.
To discover therapeutic compounds for enhancing myelination from
endogenous oligodendrocyte progenitor cells, we screened a library of
bioactive small molecules on mouse pluripotent epiblast
stem-cell-derived oligodendrocyte progenitor cells3, 4, 5.
Here we show seven drugs function at nanomolar doses selectively to
enhance the generation of mature oligodendrocytes from progenitor cells in vitro.
Two drugs, miconazole and clobetasol, are effective in promoting
precocious myelination in organotypic cerebellar slice cultures, and in vivo
in early postnatal mouse pups. Systemic delivery of each of the two
drugs significantly increases the number of new oligodendrocytes and
enhances remyelination in a lysolecithin-induced mouse model of focal
demyelination. Administering each of the two drugs at the peak of
disease in an experimental autoimmune encephalomyelitis mouse model of
chronic progressive multiple sclerosis results in striking reversal of
disease severity. Immune response assays show that miconazole functions
directly as a remyelinating drug with no effect on the immune system,
whereas clobetasol is a potent immunosuppressant as well as a
remyelinating agent. Mechanistic studies show that miconazole and
clobetasol function in oligodendrocyte progenitor cells through
mitogen-activated protein kinase and glucocorticoid receptor signalling,
respectively. Furthermore, both drugs enhance the generation of human
oligodendrocytes from human oligodendrocyte progenitor cells in vitro.
Collectively, our results provide a rationale for testing miconazole
and clobetasol, or structurally modified derivatives, to enhance
remyelination in patients.
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