Rationale for treating oedema in Duchenne muscular dystrophy with eplerenone

Abstract

Recently we reported a cytoplasmic sodium overload to cause a severe osmotic oedema in Duchenne muscular dystrophy (DMD). Our results suggested that this dual overload of sodium ions and water precedes the dystrophic process and persists until fatty muscle degeneration is complete. The present paper addresses the questions as to whether these overloads are important for the pathogenesis of the disease, and if so, whether they can be treated. As a first step, we investigated the effects of various diuretic drugs on a cell model of DMD, i.e. rat diaphragm strips previously exposed to amphotericin B. We found that both carbonic anhydrase inhibitors and aldosterone antagonists were able to repolarise depolarised muscle fibres. Since carbonic anhydrase inhibitors are known to have acidifying effects and this might be detrimental to the ventilation of DMD patients, we mainly concentrated on the modern spironolactone derivative, eplerenone. This drug had a very high repolarizing power, the parameter considered by us as being most relevant for a beneficial effect. In a pilot study we administered this drug to a 22-yr-old female DMD patient who was bound to an electric wheelchair and has had no corticosteroid therapy before. Eplerenone decreased both cytoplasmic sodium and water overload and increased muscle strength and mobility. We conclude that eplerenone has beneficial effects on DMD muscle. In our opinion the cytoplasmic oedema is cytotoxic and should be treated before fatty degeneration takes place.

Figure 1.

X-ray of the female DMD patient after spondylodesis. The anterior-posterior and lateral x-rays of the whole spine show an extensive dorsal spondylodesis from third thoracic to first sacral vertebrae.

Figure 2.

MRI of the lower legs of the female DMD patient without and with eplerenone. In the T1-weighted MRI sequences (¹H T1-w), the patient's muscles showed a moderate fatty degeneration with a markedly pronounced (pseudo) hypertrophy before treatment with eplerenone (left). The fat-suppressed MRI sequences (¹H STIR) displayed an oedema that is reduced after treatment for 11 months (right). The ²³Na inversion recovery sequence exhibited higher signal intensities before treatment (left). The quantitative values for oedema and Na-signals are given in Table 1. Note that the right side of the patient is more affected than the left (smaller circumference, pronounced oedema). The bright circles in ²³Na-IR reflect the ²³Na signal of 51.3 mM NaCl trapped in 5% agarose while the signal of the contralateral tube containing an aequimolar NaCl solution is suppressed in the ²³Na-IR sequence but bright in the ¹H- STIR sequence.

Figure 3.

MRI of the lower legs of DMD and control, both age 7. Like in other DMD boys ≤ 7 years, the muscles revealed no fatty degeneration in the T1- weighted ¹H-MRI sequence (¹H T1-w). Compared to the control, his muscles are (pseudo)hypertrophic. As in all other DMD boys of any age, the fat-suppressed STIR ¹H-MRI sequence displayed a marked oedema (¹H STIR). The ²³Na inversion recovery sequence exhibited markedly higher signal intensities in the muscles of the DMD boy than in the control (²³Na-IR). The reference tubes show the same behaviour as in Fig. 2.

Figure 4.

Eplerenone effects on rat muscle strips partially depolarised according to a dystrophy model. A, B: The histograms present the distribution of resting membrane potentials of excised muscle fibres after exposure to eplerenone in a very low concentration (left) and a therapeutic concentration (right) (3 strips à 35 fibres for each concentration). Note that the addition of eplerenone in therapeutic concentrations shifted many fibres from the depolarised to the polarised state and thereby increased the fraction of polarised fibres. The eplerenone exposure started 30 min prior to the first potential measurement and remained for about one hour that was required for the measurement of a strip. c: Histograms of the fibres in the polarised state for various eplerenone concentrations, yielding an EC₅₀ of about 15 mg/L. D: Concentration-response curves for acetazolamide and dichlorophenamide (3-8 strips à 35 fibres for each concentration). Note that the fraction of polarised fibres is lower than for eplerenone.