RRC ID 2389
Author Katsuno M, Adachi H, Doyu M, Minamiyama M, Sang C, Kobayashi Y, Inukai A, Sobue G.
Title Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy.
Journal 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.
Volume 9(6)
Pages 768-73
Published 2003-6
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 32.621
Times Cited 176
Mice B6D2-Tg(CAG-AR*97Q)7-8Sobu(RBRC00344) B6SJL-TgN(hAndR/CAGn)/1(RBRC00373)