title: Assessment of resveratrol, apocynin and taurine on mechanical-metabolic uncoupling and oxidative stress in a mouse model of duchenne muscular dystrophy: A comparison with the gold standard, α-methyl prednisolone.
abstract: Antioxidants have a great potential as adjuvant therapeutics in patients with Duchenne muscular dystrophy, although systematic comparisons at pre-clinical level are limited. The present study is a head-to-head assessment, in the exercised mdx mouse model of DMD, of natural compounds, resveratrol and apocynin, and of the amino acid taurine, in comparison with the gold standard α-methyl prednisolone (PDN). The rationale was to target the overproduction of reactive oxygen species (ROS) via disease-related pathways that are worsened by mechanical-metabolic impairment such as inflammation and over-activity of NADPH oxidase (NOX) (taurine and apocynin, respectively) or the failing ROS detoxification mechanisms via sirtuin-1 (SIRT1)-peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) (resveratrol). Resveratrol (100mg/kg i.p. 5days/week), apocynin (38mg/kg/day per os), taurine (1g/kg/day per os), and PDN (1mg/kg i.p., 5days/week) were administered for 4-5 weeks to mdx mice in parallel with a standard protocol of treadmill exercise and the outcome was evaluated with a multidisciplinary approach in vivo and ex vivo on pathology-related end-points and biomarkers of oxidative stress. Resveratrol≥taurine>apocynin enhanced in vivo mouse force similarly to PDN. All the compounds reduced the production of superoxide anion, assessed by dihydroethidium staining, with apocynin being as effective as PDN, and ameliorated electrophysiological biomarkers of oxidative stress. Resveratrol also significantly reduced plasma levels of creatine kinase and lactate dehydrogenase. Force of isolated muscles was little ameliorated. However, the three compounds improved histopathology of gastrocnemius muscle more than PDN. Taurine>apocynin>PDN significantly decreased activated NF-kB positive myofibers. Thus, compounds targeting NOX-ROS or SIRT1/PGC-1α pathways differently modulate clinically relevant DMD-related endpoints according to their mechanism of action. With the caution needed in translational research, the results show that the parallel assessment can help the identification of best adjuvant therapies.
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy; Department of Chemical, Toxicological and Pharmacological Drug Studies, Catholic University "Our Lady of Good Counsel", Tirana, Albania.
authors.forename: Roberta Francesca
authors.initials: RF
authors.lastname: Capogrosso
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Cozzoli
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Mantuano
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Giulia Maria
authors.initials: GM
authors.lastname: Camerino
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Ada Maria
authors.initials: AM
authors.lastname: Massari
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Valeriana Teresa
authors.initials: VT
authors.lastname: Sblendorio
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: De Bellis
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Tamma
authors.affiliation: Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari "Aldo Moro" Bari, Italy.
authors.forename: Arcangela
authors.initials: A
authors.lastname: Giustino
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nico
authors.affiliation: Department of Biomedical Sciences and Human Oncology, School of Medicine, University of Bari "Aldo Moro" Bari, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Montagnani
authors.affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy. Electronic address: annamaria.deluca@uniba.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: De Luca
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D004195:Disease Models, Animal; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013654:Taurine / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D016328:NF-kappa B; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D013267:Stilbenes; D013654:Taurine; C056165:acetovanillone; D019255:NADPH Oxidases; D056564:Sirtuin 1; D000077185:Resveratrol; D008775:Methylprednisolone
keywords: Anti-oxidants; Apocynin; Duchenne muscular dystrophy; Mdx mice; Mechanical-metabolic impairment; Oxidative stress; Predictive pre-clinical tests; Resveratrol; Taurine; α-methyl prednisolone