The lack of dystrophin and the destruction of the DGC leads to a delocalization of the nitric oxide sinthase in myofibers (nNOS). This is believed to have a great MEK inhibitor impact in contracting muscles, where the proper formation of NO triggers vasodilatation and increases blood flow. Then a functional ischemia can be recurrent in dystrophin-less muscles and can strongly contribute to myofiber damage for hypoxia-reperfusion injury as well as metabolic distress. According to this view, drugs able Inhibitors,research,lifescience,medical to mimic NO action, either by enhancing its formation (L-arginine, NOdonors) or supporting its downstream signalling, exerts positive effect in mdx mice. The restoration of NO signalling also has additional advantages in increasing utrophin expression and in stimulating myogenic program, since follistatin is also under the control of NO (60, 61). Phosphodiesterase (PDE) inhibitors able to enhance the level of cyclic nucleotides also act through similar mechanisms, since NO signals via cGMP. Inhibitors Inhibitors,research,lifescience,medical of PDE5, other than ameliorating heart function in mdx mice, have also been shown to enhance exercise Inhibitors,research,lifescience,medical performance, that has been ascribed to an enhanced vasodilatation (62, 63). These
potential beneficial effect at muscle level should also be considered in DMD patients undergoing trials with sildenafil. Similar results have been obtained in our laboratories by the use of pentoxifylline, an aspecific inhibitor of phosphodiesterase. The action of this Inhibitors,research,lifescience,medical drug is likely the result of both the increase
in cGMP and cAMP, exerting then a wide action on many different parameters. In fact we found the ability of this drug to enhance exercise resistance and regeneration signs, as expected by a NO-like signalling, meanwhile reducing calcium influx and markers of oxidative stress and inflammation, likely via enhanced cAMP (10, 29). A trial with pentoxifylline in DMD patients was little successful due to relevant side effects of this aspecific drug. Stabilization of sarcolemma Inhibitors,research,lifescience,medical has also been attempted in the mdx mouse model. The use of aspecific compounds, such as poloxamer P188, or molecules able to enhance binding to and expression of integrins, such as laminin 111, although promising, raised concerns in relation to Calpain possible deregulation of the extracellular matrix and the unclear outcome in terms of fibrosis and muscle stiffness (64-66). Blocks of channels involved in calcium entry can be another reasonable approach; however the molecular identity of these channels, necessary to develop specific modulators, is still unclear. Mechanosenstive channels or various members of the TRP channel family, such as TRPC1 or TRPV2, have been indicated as possible candidates but a real evidence is still lacking (10, 67-68). Taurine, a safe aminoacid, has an interesting wide action in dystrophic muscle.