First evaluation of the potential effectiveness in muscular dystrophy of a novel chimeric compound, BN 82270, acting as calpain-inhibitor and anti-oxidant

Rosa Burdi, Maria Paola Didonna, Bernadette Pignol, Beatrice Nico, Domenica Mangieri, Jean François Rolland, Claudia Camerino, Alberta Zallone, Paolo Ferro, Francesca Andreetta, Paolo Confalonieri, Annamaria De Luca

Research output: Contribution to journalArticle

Abstract

BN 82270 is a membrane-permeable prodrug of a chimeric compound (BN 82204) dually acting as calpain inhibitor and anti-oxidant. Acute in vivo injection of dystrophic mdx mice (30 mg/kg, s.c.) fully counteracted calpain overactivity in diaphragm. A chronic 4-6 weeks administration significantly prevented in vivo the fore limb force drop occurring in mdx mice exercised on treadmill. Ex vivo electrophysiological recordings showed that BN 82270 treatment contrasted the decrease in chloride channel function (gCl) in diaphragm, an index of spontaneous degeneration, while it was less effective on both exercise-impaired gCl and calcium-dependent mechanical threshold of the hind limb extensor digitorum longus (EDL) muscle fibres. The BN 82270 treated mdx mice showed a marked reduction of plasma creatine kinase and of the pro-fibrotic cytokine TGF-β1 in both hind limb muscles and diaphragm; however, the histopathological profile of gastrocnemious muscle was poorly ameliorated. In hind limb muscles of treated mice, the active form was detected by HPLC in the low therapeutic concentration range. In vitro exposure to 100 μM BN 82270 led to higher active form in diaphragm than in EDL muscle. This is the first demonstration that this class of chimeric compounds, dually targeting pathology-related events, exerts beneficial effects in muscular dystrophy. The drug/prodrug system may require posology adjustment to produce wider beneficial effects on all muscle types.

Original languageEnglish
Pages (from-to)237-248
Number of pages12
JournalNeuromuscular Disorders
Volume16
Issue number4
DOIs
Publication statusPublished - Apr 2006

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Keywords

  • Antioxidant activity
  • Calpains inhibition
  • Creatine kinase
  • Functional parameters
  • Hybrid compounds
  • Markers of fibrosis
  • Mdx mice
  • Muscular dystrophy
  • Skeletal muscle
  • Strength

ASJC Scopus subject areas

  • Clinical Neurology
  • Pediatrics, Perinatology, and Child Health
  • Developmental Neuroscience
  • Neurology

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