title: GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy.
abstract: Anabolic drugs may counteract muscle wasting and dysfunction in Duchenne muscular dystrophy (DMD); however, steroids have unwanted side effects. We focused on GLPG0492, a new non-steroidal selective androgen receptor modulator that is currently under development for musculo-skeletal diseases such as sarcopenia and cachexia. GLPG0492 was tested in the exercised mdx mouse model of DMD in a 4-week trial at a single high dose (30 mg/kg, 6 day/week s.c.), and the results were compared with those from the administration of α-methylprednisolone (PDN; 1 mg/kg, i.p.) and nandrolone (NAND, 5 mg/kg, s.c.). This assessment was followed by a 12-week dose-dependence study (0.3-30 mg/kg s.c.). The outcomes were evaluated in vivo and ex vivo on functional, histological and biochemical parameters. Similar to PDN and NAND, GLPG0492 significantly increased mouse strength. In acute exhaustion tests, a surrogate of the 6-min walking test used in DMD patients, GLPG0492 preserved running performance, whereas vehicle- or comparator-treated animals showed a significant increase in fatigue (30-50%). Ex vivo, all drugs resulted in a modest but significant increase of diaphragm force. In parallel, a decrease in the non-muscle area and markers of fibrosis was observed in GLPG0492- and NAND-treated mice. The drugs exerted minor effects on limb muscles; however, electrophysiological biomarkers were ameliorated in extensor digitorum longus muscle. The longer dose-dependence study confirmed the effect on mdx mouse strength and resistance to fatigue and demonstrated the efficacy of lower drug doses on in vivo and ex vivo functional parameters. These results support the interest of further studies of GLPG0492 as a potential treatment for DMD.
authors.affiliation: Sezione di Farmacologia, Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Bari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cozzoli
authors.forename: Roberta Francesca
authors.initials: RF
authors.lastname: Capogrosso
authors.forename: Valeriana Teresa
authors.initials: VT
authors.lastname: Sblendorio
authors.forename: Maria Maddalena
authors.initials: MM
authors.lastname: Dinardo
authors.forename: Catherine
authors.initials: C
authors.lastname: Jagerschmidt
authors.forename: Florence
authors.initials: F
authors.lastname: Namour
authors.forename: Giulia Maria
authors.initials: GM
authors.lastname: Camerino
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Luca
mesh_terms: D000728:Androgens / Q000627:therapeutic use*; D000818:Animals; D005938:Glucocorticoids / Q000627:therapeutic use; D006827:Hydantoins / Q000627:therapeutic use*; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009277:Nandrolone / Q000627:therapeutic use; D010805:Physical Conditioning, Animal; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: C577110:4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile; D000728:Androgens; D005938:Glucocorticoids; D006827:Hydantoins; D011944:Receptors, Androgen; D009277:Nandrolone; D008775:Methylprednisolone