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

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 microg 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.

• Authors: Iram Ahmad, Silvia Lope-Piedrafita, Xiaoning Bi, Chad Hicks, Yueqin Yao, Clara Yu, Elizabeth Chaitkin, Christine M Howison, Lyndon Weberg, Theodore P Trouard, Robert P Erickson
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 82 Issue 6 Pg. 811-21 (Dec 15 2005) ISSN: 0360-4012 [Print] United States
• PMID: 16273542 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anesthetics
• Antigens, Differentiation
• Glial Fibrillary Acidic Protein
• Membrane Transport Proteins
• Npc1l1 protein, mouse
• monocyte-macrophage differentiation antigen
• Pregnanolone
• 2',3'-Cyclic-Nucleotide Phosphodiesterases

Topics

• 2',3'-Cyclic-Nucleotide Phosphodiesterases (metabolism)
• Age Factors
• Anesthetics (administration & dosage)
• Animals
• Anisotropy
• Antigens, Differentiation (metabolism)
• Body Weight (drug effects)
• Brain (drug effects, pathology)
• Cell Count (methods)
• Cell Survival (drug effects)
• Demyelinating Diseases (drug therapy, etiology)
• Disease Models, Animal
• Drug Administration Schedule
• Glial Fibrillary Acidic Protein (metabolism)
• Immunohistochemistry (methods)
• Magnetic Resonance Imaging (methods)
• Membrane Transport Proteins (deficiency)
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Motor Activity (drug effects)
• Niemann-Pick Diseases (complications, drug therapy, genetics, pathology)
• Pregnanolone (administration & dosage)
• Time Factors