Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice

Iram Ahmad, Silvia Lope-Piedrafita, Xiaoning Bi, Chad Hicks, Yueqin Yao, Clara Yu, Elizabeth Chaitkin, Christine M. Howison, Lyndon Weberg, Theodore "Ted" Trouard, Robert P. Erickson

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)811-821
Number of pages11
JournalJournal of Neuroscience Research
Volume82
Issue number6
DOIs
StatePublished - Dec 15 2005

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Pregnanolone
Demyelinating Diseases
Injections
Niemann-Pick Diseases
Therapeutics
Weight Loss
Steroids
Magnetic Resonance Imaging
Diffusion Tensor Imaging
Gangliosides
Anisotropy
Blood-Brain Barrier
Astrocytes
Neurodegenerative Diseases

Keywords

  • Magnetic resonance imaging
  • Mouse models
  • Neurodegeneration
  • Neurosteroids
  • Niemann-Pick C

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice. / Ahmad, Iram; Lope-Piedrafita, Silvia; Bi, Xiaoning; Hicks, Chad; Yao, Yueqin; Yu, Clara; Chaitkin, Elizabeth; Howison, Christine M.; Weberg, Lyndon; Trouard, Theodore "Ted"; Erickson, Robert P.

In: Journal of Neuroscience Research, Vol. 82, No. 6, 15.12.2005, p. 811-821.

Research output: Contribution to journalArticle

Ahmad, I, Lope-Piedrafita, S, Bi, X, Hicks, C, Yao, Y, Yu, C, Chaitkin, E, Howison, CM, Weberg, L, Trouard, TT & Erickson, RP 2005, 'Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice', Journal of Neuroscience Research, vol. 82, no. 6, pp. 811-821. https://doi.org/10.1002/jnr.20685
Ahmad, Iram ; Lope-Piedrafita, Silvia ; Bi, Xiaoning ; Hicks, Chad ; Yao, Yueqin ; Yu, Clara ; Chaitkin, Elizabeth ; Howison, Christine M. ; Weberg, Lyndon ; Trouard, Theodore "Ted" ; Erickson, Robert P. / Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice. In: Journal of Neuroscience Research. 2005 ; Vol. 82, No. 6. pp. 811-821.
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abstract = "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.",
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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 "Ted"

AU - Erickson, Robert P.

PY - 2005/12/15

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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.

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