RRC ID |
2389
|
著者 |
Katsuno M, Adachi H, Doyu M, Minamiyama M, Sang C, Kobayashi Y, Inukai A, Sobue G.
|
タイトル |
Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy.
|
ジャーナル |
Nat Med
|
Abstract |
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease that affects males. It is caused by the expansion of a polyglutamine (polyQ) tract in androgen receptors. Female carriers are usually asymptomatic. No specific treatment has been established. Our transgenic mouse model carrying a full-length human androgen receptor with expanded polyQ has considerable gender-related motor impairment. This phenotype was abrogated by castration, which prevented nuclear translocation of mutant androgen receptors. We examined the effect of androgen-blockade drugs on our mouse model. Leuprorelin, a lutenizing hormone-releasing hormone (LHRH) agonist that reduces testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant androgen receptors in male transgenic mice. Moreover, leuprorelin treatment reversed the behavioral and histopathological phenotypes that were once caused by transient increases in serum testosterone. Flutamide, an androgen antagonist promoting nuclear translocation of androgen receptors, yielded no therapeutic effect. Leuprorelin thus seems to be a promising candidate for the treatment of SBMA.
|
巻・号 |
9(6)
|
ページ |
768-73
|
公開日 |
2003-6-1
|
DOI |
10.1038/nm878
|
PII |
nm878
|
PMID |
12754502
|
MeSH |
Androgen Antagonists / therapeutic use
Animals
Disease Models, Animal
Female
Flutamide / therapeutic use
Humans
Leuprolide / therapeutic use*
Male
Mice
Mice, Transgenic
Motor Activity / physiology
Muscle, Skeletal / metabolism
Muscle, Skeletal / pathology
Muscular Disorders, Atrophic / drug therapy*
Muscular Disorders, Atrophic / metabolism
Organ Size
Peptides / metabolism*
Phenotype
Receptors, Androgen / genetics
Receptors, Androgen / metabolism
Spinal Cord / metabolism
Spinal Cord / pathology
Testosterone / metabolism
Testosterone / pharmacology
|
IF |
36.13
|
引用数 |
203
|
WOS 分野
|
MEDICINE, RESEARCH & EXPERIMENTAL
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
リソース情報 |
実験動物マウス |
RBRC00344
RBRC00373 |