Bortezomib (PS-341) Treatment Decreases Inflammation and Partially Rescues the Expression of the Dystrophin-Glycoprotein Complex in GRMD Dogs

Autor(es)

Araujo, Karla P. C. ^[1] ; Bonuccelli, Gloria ^{[2, 3]} ; Duarte, Caio N. ^[1] ; Gaiad, Thais P. ^[4] ; Moreira, Dayson F. ^[5] ; Feder, David ^[6] ; Belizario, Jose E. ^[5] ; Miglino, Maria A. ^[1] ; Lisanti, Michael P. ^{[2, 7]} ; Ambrosio, Carlos E. ^[8]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Vet Med & Anim Sci, Dept Surg, Sao Paulo - Brazil

^[2] Thomas Jefferson Univ, Dept Stem Cell Biol & Regenerat Med & Canc Biol, Philadelphia, PA 19107 - USA

^[3] Ist Ortoped Rizzoli, Lab Orthopaed Pathophysiol & Regenerat Med, Bologna - Italy

^[4] Univ Fed Vales Jequitinhonha & Mucuri, Dept Physiotherapy, Fac Biol Sci & Hlth, Diamantina, MG - Brazil

^[5] Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo - Brazil

^[6] ABC Sch Med, Dept Pharmacol, Santo Andre, SP - Brazil

^[7] Univ Manchester, Breakthrough Breast Canc Res Unit, Inst Canc Sci, Manchester, Lancs - England

^[8] Univ Sao Paulo, Dept Vet Med, Fac Anim Sci & Food Engn, Pirassununga, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 8, n. 4 APR 8 2013.
• Citações Web of Science: 20

Resumo

Golden retriever muscular dystrophy (GRMD) is a genetic myopathy corresponding to Duchenne muscular dystrophy (DMD) in humans. Muscle atrophy is known to be associated with degradation of the dystrophin-glycoprotein complex (DGC) via the ubiquitin-proteasome pathway. In the present study, we investigated the effect of bortezomib treatment on the muscle fibers of GRMD dogs. Five GRMD dogs were examined; two were treated (TD- Treated dogs) with the proteasome inhibitor bortezomib, and three were control dogs (CD). Dogs were treated with bortezomib using the same treatment regimen used for multiple myeloma. Pharmacodynamics were evaluated by measuring the inhibition of 20S proteasome activity in whole blood after treatment and comparing it to that in CD. We performed immunohistochemical studies on muscle biopsy specimens to evaluate the rescue of dystrophin and dystrophin-associated proteins in the muscles of GRMD dogs treated with bortezomib. Skeletal tissue from TD had lower levels of connective tissue deposition and inflammatory cell infiltration than CD as determined by histology, collagen morphometry and ultrastructural analysis. The CD showed higher expression of phospho-NF kappa B and TGF-beta 1, suggesting a more pronounced activation of anti-apoptotic factors and inflammatory molecules and greater connective tissue deposition, respectively. Immunohistochemical analysis demonstrated that dystrophin was not present in the sarcoplasmic membrane of either group. However, bortezomib-TD showed higher expression of alpha- and beta-dystroglycan, indicating an improved disease histopathology phenotype. Significant inhibition of 20S proteasome activity was observed 1 hour after bortezomib administration in the last cycle when the dose was higher. Proteasome inhibitors may thus improve the appearance of GRMD muscle fibers, lessen connective tissue deposition and reduce the infiltration of inflammatory cells. In addition, proteasome inhibitors may rescue some dystrophin-associated proteins in the muscle fiber membrane. (AU)

• Processo FAPESP: 06/53056-0 - Uso de prednisona e Bortezomib (PS-341) em cães da raça Golden Retriever afetados oela distrofia muscular progressiva (GRMD) avaliação da viabilidade da terapia e resstruturacao da distrofina muscular
• Beneficiário: Karla Patrícia Cardoso Araújo
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 06/61563-9 - Avaliacao histologica e ultra-estrutural de fibras musculares de caes de raca golden retriever afetados pela distrofia muscular progressiva (grmd) tratados com prednisona e bortezomib (ps-341).
• Beneficiário: Caio Nogueira Duarte
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 06/59060-9 - Uso de prednisona e bortezomib (PS-341) em cães da Raça Golden Retriever afetados pela distrofia muscular progressiva (GRMD) avaliação da viabilidade da terapia e reestruturação da distrofina muscular
• Beneficiário: Maria Angelica Miglino
• Modalidade de apoio: Auxílio à Pesquisa - Regular