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

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 lg 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 RotaRod performance. T2-weighted MRI and diffusion tensor imaging (DTI) of treated mice showed values of signal intensity and fractional anisotropy closer to those of wildtype 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. V C 2005 Wiley-Liss, Inc.