Abstract Details

Title Spironolactone Treatment in a Cell Culture Model of Spinal and Bulbar Muscular Atrophy

Topic Anterior Horn

Presentation(s) P02 - (-)

Poster/Presentation
Number 174

Objective

Background BACKGROUND: This study addresses the lack of effective treatment for SBMA and uncertainty around the mechanism of neurodegeneration in this disease. Castration, which removes the AR ligand testosterone, is effective in animal models, but it is not an acceptable option in humans. Other androgen-reducing drugs, such as leuprorelin and dutasteride, have mixed effects.

Design/Methods DESIGN/METHODS: We used MN1 and PC12 cell models to assess the action of spironolactone on cells without the AR, with the normal AR, and with the SBMA mutant AR, and compared with the effects of dihydrotestosterone (DHT) in these same cell types.

Results RESULTS: Spironolactone binds the AR and causes about two thirds as much AR nuclear localization as DHT. AR inclusions, resembling those formed in response to DHT, are formed in response to spironolactone in PC12 cells with the mutant AR although fewer than with DHT. Co-administration of spironolactone and DHT causes greater nuclear localization of the AR, and formation of more inclusions in PC12 cells, than administration of either alone.

Conclusions CONCLUSIONS: In these cell models, spironolactone appears to act as a partial AR agonist, one that does not inhibit the effect of DHT. This finding raises the possibility that spironolactone is not an androgen antagonist, but rather is a selective androgen receptor modulator. In light of this latter possibility, more research is needed to discover whether spironolactone may be protective or pathogenic in animal models and humans with SBMA.

Authors/Disclosures
Alva M. Burke, MD (National Hospital for Neurology and Neurosorgery) PRESENTER	No disclosure on file
Kenneth H. Fischbeck, MD, FAAN (NINDS, NIH, Neurogenetics)	Dr. Fischbeck has received research support from NINDS/NIH. Dr. Fischbeck has received intellectual property interests from a discovery or technology relating to health care. Dr. Fischbeck has a non-compensated relationship as a Scientific Review Board member with Kennedy's Disease Association that is relevant to AAN interests or activities. Dr. Fischbeck has a non-compensated relationship as a Scientific Council member with Association Francaise contre les Myopathies that is relevant to AAN interests or activities. Dr. Fischbeck has a non-compensated relationship as a Independent Review Committee member with Target ALS that is relevant to AAN interests or activities. Dr. Fischbeck has a non-compensated relationship as a Scientific Advisory Board member, Musculoskeletal Diseases with Novartis that is relevant to AAN interests or activities. Dr. Fischbeck has a non-compensated relationship as a Senior Clinical Consultant with n-Lorem Foundation that is relevant to AAN interests or activities. Dr. Fischbeck has a non-compensated relationship as a Scientific Advisory Committee member with Stanford GNE myopathy program that is relevant to AAN interests or activities. Dr. Fischbeck has a non-compensated relationship as a Scientific Advisory Board member with Hereditary Disease Foundation that is relevant to AAN interests or activities. Dr. Fischbeck has a non-compensated relationship as a Scientific Advisory Board member with Packard Center for ALS Research that is relevant to AAN interests or activities. Dr. Fischbeck has a non-compensated relationship as a Scientific Advisory Board member with Huntington's Disease Society of America that is relevant to AAN interests or activities. Dr. Fischbeck has a non-compensated relationship as a TACT review panel member with TREAT-NMD that is relevant to AAN interests or activities.
Emilio Portaccio	Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Emilio Portaccio has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Biogen. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck Serono. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Janssen. Emilio Portaccio has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS Cellgene.
Christopher Grunseich, MD (National Institutes of Health)	The institution of Dr. Grunseich has received research support from AnnJi Pharmaceuticals.

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