TY - JOUR
T1 - Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice
AU - Ahmad, Iram
AU - Lope-Piedrafita, Silvia
AU - Bi, Xiaoning
AU - Hicks, Chad
AU - Yao, Yueqin
AU - Yu, Clara
AU - Chaitkin, Elizabeth
AU - Howison, Christine M.
AU - Weberg, Lyndon
AU - Trouard, Theodore P.
AU - Erickson, Robert P.
PY - 2005/12/15
Y1 - 2005/12/15
N2 - Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1 -/- mice). We confirmed previous results showing that a single injection of 250 μg of allopregnanolone on postnatal day 7 significantly extended the life span of Npc1-/- mice. This caused a marked difference in the weight curves of the treated mice but no statistical difference in the Rota-Rod performance. T2-weighted MRI and diffusion tensor imaging (DTI) of treated mice showed values of signal intensity and fractional anisotropy closer to those of wild-type mice than those of untreated Npc1 -/- mice. Neuropathology showed that day-7 treatment markedly suppressed astrocyte reaction and significantly reduced microglial activation. Furthermore, the steroid treatment also increased myelination in brains of Npc1-/- mice. Similar effects of allopregnanolone treatment were observed in Npc1-/-, mdr1a-/- double-mutant mice, which have a deficient blood-brain barrier, resulting in increased steroid uptake. The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1-/- mice, and the beneficial effects were found to be greater than with the single injection at day 7. We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1-/- mice, presumably by effects on myelination or neuronal connectivity.
AB - Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1 -/- mice). We confirmed previous results showing that a single injection of 250 μg of allopregnanolone on postnatal day 7 significantly extended the life span of Npc1-/- mice. This caused a marked difference in the weight curves of the treated mice but no statistical difference in the Rota-Rod performance. T2-weighted MRI and diffusion tensor imaging (DTI) of treated mice showed values of signal intensity and fractional anisotropy closer to those of wild-type mice than those of untreated Npc1 -/- mice. Neuropathology showed that day-7 treatment markedly suppressed astrocyte reaction and significantly reduced microglial activation. Furthermore, the steroid treatment also increased myelination in brains of Npc1-/- mice. Similar effects of allopregnanolone treatment were observed in Npc1-/-, mdr1a-/- double-mutant mice, which have a deficient blood-brain barrier, resulting in increased steroid uptake. The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1-/- mice, and the beneficial effects were found to be greater than with the single injection at day 7. We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1-/- mice, presumably by effects on myelination or neuronal connectivity.
KW - Magnetic resonance imaging
KW - Mouse models
KW - Neurodegeneration
KW - Neurosteroids
KW - Niemann-Pick C
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U2 - 10.1002/jnr.20685
DO - 10.1002/jnr.20685
M3 - Article
C2 - 16273542
AN - SCOPUS:28544432842
SN - 0360-4012
VL - 82
SP - 811
EP - 821
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
IS - 6
ER -