Table 2.
Overview of studies assessing antioxidant intervention in mdx mice.
| Antioxidant | Author | Classification | Model | Age | Dose/Method of Delivery | Tissue Examined | Results |
|---|---|---|---|---|---|---|---|
| α-lipoic acid/L-carnitine | Hnia K. et al., 2007 [55] | Free radical scavenger | mdx mouse | 5 weeks old | 250 mg/kg α-lipoic acid/L-carnitine i.p injection for 14 days | Diaphragm | α-lipoic acid/L-carnitine decreased plasma CK levels and decreased muscle fibre central nucleation and fibre variance, antioxidant activity, lipid peroxidation, NF-kB and matrix metalloproteinase activity in mdx diaphragm. Β-dystroglycan expression was increased in mdx diaphragm following α-lipoic acid/L-carnitine. |
| Apocynin | Gonzalez D.R. et al., 2014 [24] | NADPH oxidase inhibitor | mdx cardiac myocytes | - | 100 µM apocynin in vitro | Isolated cardiac myocytes | Apocynin restored contractility in mdx cardiac myocytes and normalised the amplitude of evoked intracellular Ca2+ concentration transients and total SR Ca2+ content. The production of spontaneous diastolic Ca2+ release events was decreased and SR Ca2+ leakage was decreased, thus apocynin improved SR Ca2+ handling and contractility in mdx cardiac myocytes. |
| Ascorbic acid (vitamin C) | Tonon E. et al., 2012 [54] | Antioxidant | mdx mouse | 14 days old | Ascorbic acid 200 mg/kg via oral gavage daily for 14 days | Diaphragm | Ascorbic acid decreased plasma CK levels and diaphragm myonecrosis, inflammation, TNF-α and 4-HNE levels and Evans blue dye staining in mdx mice. |
| Cilostazol | Hermes Tde A.E. et al., 2016 [56] | PDE3 inhibitor | mdx mouse | 14 days old | Cilostazol 100 mg/kg/day for 14 days | Diaphragm | Cilostazol reduced plasma CK and diaphragm myonecrosis, inflammatory cell area and macrophage infiltration, NF-kB and TNF-α content, ROS production and oxidative stress in mdx mice. |
| Diacerhein | Mâncio R.D. et al., 2017 [57] | IL-1β inhibitor | mdx mouse | 14 days old | 20 mg/kg/day diacerhein via oral gavage for 14 days | Diaphragm | Diacerhin reduced plasma CK levels, diaphragm muscle fibre damage and central nucleation, inflammatory mediators, oxidative stress and lipid peroxidation in mdx mice. |
| EUK-134 | Kim J.H. and Lawler J.M. 2012 [53] | Superoxide dismutase mimetic | mdx mouse | 20 days old | 30 mg/kg/day EUK-134 i.p. injection for 8 days | Diaphragm | EUK-134 reduced 4-HNE, total hydroperoxides, positive staining of macrophages and T-cells, activation of NF-κB, p65 protein abundance and the number of centralised myonuclei and variability of fibre size in diaphragm muscle from mdx mice. Diaphragm contractile force was partially rescued following EUK-134 and increased citrate synthase activity in mdx mice. |
| Epigallocatechin-3-gallate (EGCG) | Nakae Y. et al., 2008 [58] | Green tea extract/antioxidant/Polyphenol | mdx mouse | From birth | 5 mg/kg EGCG s.c. injection 4 times per week for 8 weeks | Diaphragm | EGCG had no effect on body weight and no observable toxic effects in the liver and kidney. EGCG decreased plasma CK and decreased the number of lipofuscin granules, necrotic muscle fibres and connective tissue in mdx diaphragm and increased utrophin expression. EGCG did not affect diaphragm isometric force. |
| SNT-NC17/Idebenone | Buyse G.M. et al., 2009 [59] | Antioxidant | mdx mouse | 4 weeks old | 200 mg/kg SNT-MC17/idebenone for 9 months | Heart | SNT-NC17/Idebenone corrected cardiac diastolic dysfunction, improved contractile reserve and voluntary running and decreased cardiac inflammation and fibrosis in mdx mice. |
| L-arginine | Marques M.J. et al., 2010 [60] | Amino acid | mdx mouse | 6 months old | L-arginine in drinking water for 6 months | Heart | L-arginine had no effect on myocardial fibrosis but reduced the density of inflammatory cells in the mdx heart. |
| N-acetylcysteine (NAC) | Williams I.A. and Allen D.G. 2007 [19] | Glutathione precursor | mdx mouse | 3 weeks old | 1% NAC in drinking water for 6 weeks | Heart | NAC reduced DHE levels in mdx hearts, reduced abnormalities in mdx cardiomyocyte Ca2+ handling, returned mdx fractional shortening to WT values but did not affect Ca2+ sensitivity. NAC returned collagen type III and CD68 expression in mdx hearts to WT values. |
| N-acetylcysteine (NAC) | de Senzi Moraes Pinto R. et al., 2013 [61] | Glutathione precursor | mdx mouse | 14 days old | 150 mg/kg NAC i.p. daily for 14 days | Diaphragm | NAC reduced plasma CK levels and reduced TNF-α and 4-HNE protein adduct levels, inflammation, Evans blue dye staining and myonecrosis in mdx diaphragm muscle. |
| Resveratrol | Kuno A. et al., 2013 [62] | SIRT1 activator | mdx mouse | 9 weeks old | 4 g/kg resveratrol enriched diet for 32 weeks | Heart | Resveratrol downregulated the pro-hypertrophic co-activator p300 protein level in the mdx heart thus inhibiting fibre hypertrophy. Resveratrol also suppressed cardiac fibrosis and preserved cardiac diastolic function in mdx hearts. |
| Pentoxifylline | Gosselin L.E. and Williams J.E. 2006 [63] | PDE inhibitor | mdx mouse | 4 weeks old | 16 mg/kg/day pentoxyifylline for 4 weeks | Diaphragm | Pentoxyifylline had no effect on mdx diaphragm force, hydroxyproline concentration, type I and III procollagen mRNA and TGF-β mRNA. |
| Pentoxifylline | Burdi R. et al., 2009 [64] | PDE inhibitor | mdx mouse | 4–5 weeks old | 50 mg/kg/day pentoxyifylline i.p. injection for 4–8 weeks | Diaphragm | Pentoxifylline modestly increased mdx diaphragm isometric tetanic force. |
| Pyrrolidine dithiocarbamate (PDTC) or ursodeoxycholic acid(UDCA) | Graham K.M. et al., 2010 [65] | NF-κB inhibitors | mdx mouse | 30 days old | 50 mg/kg/day PDTC i.p. injection for one month 40 mg/kg/day UDCA i.p. injection for one month |
Diaphragm | Neither PDTC or UDCA influenced collagen deposition or TGF-β1 expression in mdx diaphragm. |
| Quercetin | Hollinger K. et al., 2015 [66] | PGC-1α pathway activator | mdx mouse | 3 months old | 0.2% quercetin-enriched diet for 6 months | Diaphragm | Quercetin preserved diaphragm muscle fibres and reduced centralised nuclei, infiltrating immune cells, TNF-α gene expression and muscle fibrosis in mdx mice. Genes associated with oxidative metabolism were increased following quercetin. |
| Quercetin | Selsby J.T. et al., 2016 [67] | PGC-1α pathway activator | mdx mouse | 2 months old | 0.2% quercetin-enriched diet for 12 months | Diaphragm | Quercetin protected respiratory function in mdx mice during the first 4–6 months and declined thereafter. Mdx diaphragm muscle function and histology were not preserved following 12 months of quercetin treatment. |
| Quercetin | Ballmann C. et al., 2017 [68] | PGC-1α pathway activator | mdx mouse | 2 months old | 0.2% quercetin-enriched diet for 12 months | Heart | Quercetin decreased fibronectin, inflammation and indices of tissue damage while mitochondrial biogenesis and antioxidant enzymes were improved, and quercetin facilitated the assembly of the DAPC in mdx hearts. |
| Quercetin | Ballmann C. et al., 2015 [69] | PGC-1α pathway activator | mdx mouse | 3 weeks old 3 months old |
0.2% quercetin-enriched diet for 6 months | Heart | 3 weeks old: Quercetin increased cytochrome-c and superoxide dismutase 2 protein expression, increased utrophin and decreased matrix metalloproteinase 9 abundance in mdx heart. 3 months old: Quercetin decreased relative and absolute heart weights, damage indicators and TGFβ-1 in mdx heart. |
| Sildenafil | Percival J.M. et al., 2012 [70] | PDE-5 inhibitor | mdx mouse | 3 weeks old | 400 mg/L sildenafil citrate in drinking water for 14 weeks | Diaphragm | Sildenafil modestly increased diaphragm force generating capacity and reduced fibronectin, TNF-α, matrix metalloproteinase 13 and Evans blue dye staining in the mdx diaphragm. Fatigue resistance and TGF-β were unaffected. |
| Vitamin E | Mancio R.D. et al., 2017 [71] | Peroxyl radical scavenger | mdx mouse | 14 day old | 40 mg vitamin E/kg daily via oral gavage for 14 days | Diaphragm | Vitamin E reduced muscle fibre damage, oxidative stress and inflammation processes in mdx diaphragm. |
List of abbreviations: 4-HNE, 4-Hydroxynonenal; Ca2+, calcium; CD68, cluster of differentiation 68; CK, creatine kinase; DHE, dihydroethidium; EGCG, epigallocatechin-3-gallate; IL-1β, interleukin-1 beta; i.p., intra-peritoneal; MMP, matrix metalloproteinase; NAC, N-acetylcysteine; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; NFκB, nuclear factor lappa-light-chain-enhancer of activated B cells; PDE, phosphodiesterase; PDTC, pyrrolidine dithiocarbamate; PGC-1α, peroxisome proliferator activated receptor gamma co-activator 1 alpha; ROS, reactive oxygen species; SR, sarcoplasmic reticulum; s.c., sub-cutaneous; SIRT-1, sirtuin-1;TGF-β1, tumour growth factor beta 1; TNF-α, tumour necrosis factor alpha; UDCA, ursodeoxycholic acid.