Chronic Dosing with Membrane Sealant Poloxamer 188 NF Improves Respiratory Dysfunction in Dystrophic Mdx and Mdx/Utrophin-/- Mice.

Abstract

Poloxamer 188 NF (national formulary (NF) grade of P-188) improves cardiac muscle function in the mdx mouse and golden retriever muscular dystrophy models. However in vivo effects on skeletal muscle have not been reported. We postulated that P-188 NF might protect diaphragm muscle membranes from contraction-induced injury in mdx and mdx/utrophin-/- (dko) muscular dystrophy models. In the first study 7-month old mdx mice were treated for 22 weeks with subcutaneous (s.c.) injections of saline or P-188 NF at 3 mg/Kg. In the second, dkos were treated with saline or P-188 NF (1 mg/Kg) for 8 weeks beginning at age 3 weeks. Prednisone was the positive control in both studies. Respiratory function was monitored using unrestrained whole body plethysmography. P-188 NF treatment affected several respiratory parameters including tidal volume/BW and minute volume/BW in mdx mice. In the more severe dko model, P-188 NF (1 mg/Kg) significantly slowed the decline in multiple respiratory parameters compared with saline-treated dko mice. Prednisone's effects were similar to those seen with P-188 NF. Diaphragms from P-188 NF or prednisone treated mdx and dko mice showed signs of muscle fiber protection including less centralized nuclei, less variation in fiber size, greater fiber density, and exhibited a decreased amount of collagen deposition. P-188 NF at 3 mg/Kg s.c. also improved parameters of systolic and diastolic function in mdx mouse hearts. These results suggest that P-188 NF may be useful in treating respiratory and cardiac dysfunction, the leading causes of death in Duchenne muscular dystrophy patients.

• Authors: Bruce E Markham, Stace Kernodle, Jean Nemzek, John E Wilkinson, Robert Sigler
• Journal: PloS one (PLoS One) Vol. 10 Issue 8 Pg. e0134832 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26248188 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Drug Carriers
• Utrophin
• Poloxamer
• Prednisone

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Diaphragm (pathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Carriers (chemistry)
• Half-Life
• Heart (physiology)
• Hemodynamics (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred mdx
• Mice, Knockout
• Muscle Fibers, Skeletal (physiology)
• Muscular Dystrophy, Duchenne (drug therapy, physiopathology)
• Plethysmography
• Poloxamer (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Prednisone (pharmacology, therapeutic use)
• Utrophin (deficiency, genetics)