Poloxamer 188
Poloxamer 188, a "molecular band-aid" to close holes in membranes.
An attempt to rescue heart muscle cells in cardiomyopathy opens a way to close the holes in the membranes of dystrophic muscle membranes. This new approach to a Duchenne therapy was reported by Joseph Metzger of the University of Michigan in Ann Arbor at the PPMD conference in 2006. .
The absence of dystrophin in mdx mice as well as in Duchenne boys not only affects skeletal muscles but has also severe consequences for the correct function of cardiac muscles. The use of a specially designed polymer, the poloxamer 188 or P 188, had been shown to influence positively the heart function of mdx mice. To exactly measure this protective effect in isolated mdx heart muscle cells, single cells were connected with their ends to two very thin movable carbon fibers. As these cardiac muscles are about thousand times shorter than the skeletal muscle cells of mice, the distance between the two micro carbon fibers can only be varied between 1.8 and 2.2 μm, thousandths of a millimeter. In this way, it could be shown that, whereas normal cells could be stretched and relaxed for many hours, mdx fibers have a reduced cellular compliance, they are more resistant to extension, get into a hypercontraction, break away from the carbon fibers and finally die.
With this completely new microscopic test method, it could be shown that P 188 can restore the compliance of the cardiac muscle cells from mdx mice and also from the dystrophic GRMD dog. In-vivo application of P 188 to living mdx mice blocks their acute heart failure which could be measured with mini catheters in the hearts of living mice beating about 600 times a minute. P 188 is an artificial co-polymer, it consists of a core of 35 small hydrophobic, water repellent, units and two wings of 75 units each of a hydrophilic, water attracting structure.
Dr. Metzger called this a molecular albatross, whose central water-insoluble structure plugs the holes of the membrane whose interior is also hydrophobic, while the two hydrophilic wings act like the sticky ends of a bandaid by binding to the hydrophilic surface of the intact membrane around the holes. This molecular band-aid thus seals the holes at least temporarily so that no calcium ions can pass which would activate calpain and other proteindegrading enzymes. It is obvious, that this protective effect of polaxamer 188 on cardiac muscles could also be important for the repair of dystrophic skeletal muscle cells. This has been tried, however the first results were not as good as expected. Research on this approach is now in progress and could lead to another possibility for a Duchenne therapy.
From Günter Scheuerbrandt Report of the PPMD Conference 2006