Treatment with a Nitric Oxide-Donating NSAID Alleviates Functional Muscle Ischemia in the Mouse Model of Duchenne Muscular Dystrophy

Abstract

In patients with Duchenne muscular dystrophy (DMD) and the standard mdx mouse model of DMD, dystrophin deficiency causes loss of neuronal nitric oxide synthase (nNOSμ) from the sarcolemma, producing functional ischemia when the muscles are exercised. We asked if functional muscle ischemia would be eliminated and normal blood flow regulation restored by treatment with an exogenous nitric oxide (NO)-donating drug. Beginning at 8 weeks of age, mdx mice were fed a standard diet supplemented with 1% soybean oil alone or in combination with a low (15 mg/kg) or high (45 mg/kg) dose of HCT 1026, a NO-donating nonsteroidal anti-inflammatory agent which has previously been shown to slow disease progression in the mdx model. After 1 month of treatment, vasoconstrictor responses to intra-arterial norepinephrine (NE) were compared in resting and contracting hindlimbs. In untreated mdx mice, the usual effect of muscle contraction to attenuate NE-mediated vasoconstriction was impaired, resulting in functional ischemia: NE evoked similar decreases in femoral blood flow velocity and femoral vascular conductance (FVC) in the contracting compared to resting hindlimbs (ΔFVC contraction/ΔFVC rest = 0.88±0.03). NE-induced functional ischemia was unaffected by low dose HCT 1026 (ΔFVC ratio = 0.92±0.04; P>0.05 vs untreated), but was alleviated by the high dose of the drug (ΔFVC ratio = 0.22±0.03; P<0.05 vs untreated or low dose). The beneficial effect of high dose HCT 1026 was maintained with treatment up to 3 months. The effect of the NO-donating drug HCT 1026 to normalize blood flow regulation in contracting mdx mouse hindlimb muscles suggests a putative novel treatment for DMD. Further translational research is warranted.

Nonsteroidal Anti‐Inflammatory Therapy: A Journey Toward Safety

“…However, it may not be the end for naproxcinod clinical development, since it recently received from FDA and European Medicines Agency (EMA) the orphan drug designation for the treatment of Duchenne muscular dystrophy . In fact, some animal studies have already shown the naproxcinod potential to delay the progression of muscular dystrophies . Furthermore, a recent agreement between NicOx and Fera Pharmaceuticals (USA) gives hope to the further development of naproxcinod to be commercialized in USA…”

Nutraceuticals and Their Potential to Treat Duchenne Muscular Dystrophy: Separating the Credible from the Conjecture

“…Pharmacological approaches to correct NO availability in dystrophic muscle include agents such as NSAIDS and phosphodiesterase 5 (PDE5) inhibitors which improve blood flow and slow disease progression resulting in reduced necrosis and inflammation [230,241,242]. PDE5 inhibitors, such as tadalafil and sildenafil, prolong the half-life of (cGMP) which is a downstream target of NO.…”

“…The use of NO donors to restore NO signaling in dystrophic muscle is attractive as they correct deficiencies in vascular regulation [242] and can also act to inhibit histone deacetylases which improves differentiation and regeneration [250]. This should be balanced by the potential for hyper-nitrosylation of ryanodine receptors that can reduce muscle force generation capacity [251,252].…”

Nitric oxide synthase deficiency and the pathophysiology of muscular dystrophy

“…; Thomas et al . ; Uaesoontrachoon et al . ), indicating that elevated NO production specifically at the sarcolemma is not required for NO‐mediated reduction of muscular dystrophy.…”

“…Pharmacological interventions also show that NO generated at sites remote from the sarcolemma can have beneficial effects in muscular dystrophy. Systemic elevations of NO levels by treatment with NO donors or NO donors in conjunction with anti-inflammatory agents ameliorate the dystrophic pathology in mdx mice (Voisin et al 2005;Brunelli et al 2007;Sciorati et al 2010;Mizunoya et al 2011;Thomas et al 2012;Uaesoontrachoon et al 2014), indicating that elevated NO production specifically at the sarcolemma is not required for NO-mediated reduction of muscular dystrophy. However, a detailed analysis of dystrophin constructs showed that constructs that increased membrane-associated nNOS (H2-R15 transgenic mdx mice) also reduced some features of mdx mouse pathology while a similar construct that did not increase nNOS at the membrane (H2-R19 mice) had a less ameliorative effect (Lai et al 2009); at first view, the finding suggested that nNOS localization at the membrane is J Physiol 592.21 important in reducing some features of mdx pathology.…”