Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti‐inflammatory effects in mdx mice with Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is the most common inherited muscular dystrophy. Patients experience DMD in their 20s from cardiac or respiratory failure related to progressive muscle wasting. Currently, the only treatments for the symptoms of DMD are available. Muscle fibrosis, a DMD feature, leads to reduced muscle function and muscle mass, and hampers pharmaceutical therapeutic efficacy. Although antifibrotic agents may be useful, none is currently approved. Phosphodiesterase 4 (PDE4) inhibitors have exhibited antifibrotic effects in human and animal models. In this study, we showed beneficial effects of the PDE4 inhibitor piclamilast in the DMD mdx mouse. Piclamilast reduced the mRNA level of profibrotic genes, including collagen 1A1, in the gastrocnemius and diaphragm, in the mdx mouse, and significantly reduced the Sirius red staining area. The PDE5 inhibitors sildenafil and tadalafil ameliorated functional muscle ischemia in boys with DMD, and sildenafil reversed cardiac dysfunction in the mdx mouse. Single-treatment piclamilast or sildenafil showed similar antifibrotic effects on the gastrocnemius; combination therapy showed a potent antifibrotic effect, and piclamilast and combination therapy increased peroxisome proliferator-activated receptor γ coactivator-1α mRNA in mouse gastrocnemius. In summary, we confirmed that piclamilast has significant antifibrotic effects in mdx mouse muscle and is a potential treatment for muscle fibrosis in DMD.-Nio, Y., Tanaka, M., Hirozane, Y., Muraki, Y., Okawara, M., Hazama, M., Matsuo, T. Phosphodiesterase 4 inhibitor and phosphodiesterase 5 inhibitor combination therapy has antifibrotic and anti-inflammatory effects in mdx mice with Duchenne muscular dystrophy.

Effect of the Phosphodiesterase 5 Inhibitor Sildenafil on Ischemia-Reperfusion-Induced Muscle Mitochondrial Dysfunction and Oxidative Stress

“…In line with our results, Nio et al [48] reported only a slight mRNA expression of PDE5 in gastrocnemius and, contrary to data obtained in the lung and the heart, oral sildenafil at a single dose of 30 mg/kg did not increase cGMP in such muscle [48]. Thus, a low physiological level of intracellular cGMP and/or a low amount of PDE type 5 in the gastrocnemius muscle might suggest a longer or greater exposure to sildenafil in order to protect skeletal muscle.…”

PAN‐selective inhibition of cAMP‐phosphodiesterase 4 (PDE4) induces gastroparesis in mice

“…First, in humans and animal species that can vomit, systemic administration of PDE4 inhibitors is generally associated with a narrow therapeutic window in that similar doses produce both various therapeutic effects (eg, anti‐inflammatory benefits) as well as emesis and nausea. Similarly, we show here that doses as low as 0.04 mg/kg Rolipram (Figure 5B) and 0.2 mg/kg Piclamilast (Figure 5C) induce acute gastric retention in mice, whereas a dose of 1 mg/kg Piclamilast induces gastric retention in the ad libitum model (Figure 3A), which is at or below the doses generally used to produce anti‐inflammatory benefits in these animals 79‐84 …”

Ameliorative effect of phosphodiesterase 4 and 5 inhibitors in deoxycorticosterone acetate‐salt hypertensive uni‐nephrectomized KKA y mice

“…By contrast, compound A significantly suppressed pro‐fibrotic mRNA expression in the kidneys of DOCA‐salt KKA y mice. In a previous study, we also reported that another PDE4 inhibitor, piclamilast, increased plasma cAMP levels along with increased cAMP levels in skeletal muscle 41 . We, therefore, postulated that increased cAMP may contribute to the anti‐fibrotic effects; however, were unable to conclude on its direct ameliorative effect on fibrosis.…”

“…In a previous study, we also reported that another PDE4 inhibitor, piclamilast, increased plasma cAMP levels along with increased cAMP levels in skeletal muscle. 41 We, therefore, postulated that increased cAMP may contribute to the anti-fibrotic effects; however, were unable to conclude on its direct ameliorative effect on fibrosis. We then sought to further confirm the anti-fibrotic effect of elevated cAMP levels in vitro using kidney cells.…”

“…Resveratrol (RSV), a natural plant polyphenolic compound, also exhibits antioxidant, anti‐inflammatory, and anti‐fibrotic properties in mammalian cells and animal models 43 . RSV activates energy metabolism via signaling pathways involving the PGC‐1α pathway through inhibition of PDEs and cAMP levels in skeletal muscles 41,44‐46 . Hence, the ameliorative effect of compound A on DN may also be partially derived from podocyte protection through ROS inhibition via SOD2 and PGC1α activation.…”