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

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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.