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 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.
Ahmad
Iram
I
Department of Pediatrics, University of Arizona, Tucson, USA.
Lope-Piedrafita
Silvia
S
Bi
Xiaoning
X
Hicks
Chad
C
Yao
Yueqin
Y
Yu
Clara
C
Chaitkin
Elizabeth
E
Howison
Christine M
CM
Weberg
Lyndon
L
Trouard
Theodore P
TP
Erickson
Robert P
RP
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000367:Age Factors; D000777:Anesthetics / Q000008:administration & dosage*; D000818:Animals; D016880:Anisotropy; D000943:Antigens, Differentiation / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002452:Cell Count / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D026901:Membrane Transport Proteins / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009542:Niemann-Pick Diseases / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011280:Pregnanolone / Q000008:administration & dosage*; D013997:Time Factors
D000777:Anesthetics; D000943:Antigens, Differentiation; D005904:Glial Fibrillary Acidic Protein; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; C036763:monocyte-macrophage differentiation antigen; D011280:Pregnanolone; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases