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The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.
Brakedal, B, Dölle, C, Riemer, F, Ma, Y, Nido, GS, Skeie, GO, Craven, AR, Schwarzlmüller, T, Brekke, N, Diab, J, et al
Cell metabolism. 2022;34(3):396-407.e6
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Parkinson’s disease (PD) is a major cause of death and disability, and current treatments can provide partial symptomatic relief, mainly for motor symptoms but make no substantial impact on disease progression. A growing body of evidence supports that boosting cellular levels of nicotinamide adenine dinucleotide (NAD) may confer neuroprotective effects in both healthy aging and neurodegeneration. The primary aim of this study was to assess penetration and metabolic responses of the brain to nicotinamide riboside (NR) supplementation in patients with PD. This study is a double-blinded, randomised, placebo-controlled phase I study of NR in newly diagnosed PD patients, naïve to dopaminergic therapy. Participants (n=30) where randomly assigned (1:1) to one of the two groups: NR group or placebo group. Results show that: - oral NR therapy increases brain NAD levels and impacts cerebral metabolism in PD. - supplementation with NR may target multiple processes implicated in the pathophysiology of the disease by upregulating the expression of genes involved in mitochondrial respiration, oxidative damage response, lysosomal and proteasomal function and downregulating inflammatory cytokines in the central nervous system. Authors conclude that NR can be a potential neuroprotective agent against PD. However, further investigation in a larger trial is required to warrant these findings.
Abstract
We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson's disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels-measured by 31phosphorous magnetic resonance spectroscopy-and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials.
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The mitochondria-targeted antioxidant MitoQ, attenuates exercise-induced mitochondrial DNA damage.
Williamson, J, Hughes, CM, Cobley, JN, Davison, GW
Redox biology. 2020;36:101673
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Mitochondria have an established role in the life cycle of a cell, contributing to cellular networks aligned to metabolism, biosynthetic pathways, and apoptotic cell death. Exercise increases the univalent reduction of ground state molecular dioxygen to superoxide in skeletal muscle. The aim of this study was to determine whether (1) a bout of high-intensity intermittent exercise (HIIE) damaged mitochondrial (mt)DNA; and (2) Mitoquinone (MitoQ) [orally available mitochondrial-targeted coenzyme Q10] could prevent mtDNA damage. This study is a double-blind, randomized, placebo-controlled design. Twenty-four (n = 24) healthy, recreationally active males volunteered to take part in the study. The participants were allocated to two groups: MitoQ (n = 12) and placebo (n = 12), and subsequently took part in a two-phased supplementation trial. Results showed that: - exercise increased DNA damage in nucleus and mitochondria. In fact, HIIE damages mtDNA both systemically in lymphocytes and locally in muscle tissue, occurring in parallel with nuclear DNA damage. - chronic MitoQ supplementation offers a prophylactic effect. - MitoQ decreases exercise-induced DNA damage. Authors conclude that the notion that a protective effect of a mitochondria-targeted antioxidant is only unmasked by exercise, reinforces the value of interrogating multiple physiological states when appraising the efficacy of an antioxidant.
Abstract
High-intensity exercise damages mitochondrial DNA (mtDNA) in skeletal muscle. Whether MitoQ - a redox active mitochondrial targeted quinone - can reduce exercise-induced mtDNA damage is unknown. In a double-blind, randomized, placebo-controlled design, twenty-four healthy male participants consisting of two groups (placebo; n = 12, MitoQ; n = 12) performed an exercise trial of 4 x 4-min bouts at 90-95% of heart rate max. Participants completed an acute (20 mg MitoQ or placebo 1-h pre-exercise) and chronic (21 days of supplementation) phase. Blood and skeletal muscle were sampled immediately pre- and post-exercise and analysed for nuclear and mtDNA damage, lipid hydroperoxides, lipid soluble antioxidants, and the ascorbyl free radical. Exercise significantly increased nuclear and mtDNA damage across lymphocytes and muscle (P < 0.05), which was accompanied with changes in lipid hydroperoxides, ascorbyl free radical, and α-tocopherol (P < 0.05). Acute MitoQ treatment failed to impact any biomarker likely due to insufficient initial bioavailability. However, chronic MitoQ treatment attenuated nuclear (P < 0.05) and mtDNA damage in lymphocytes and muscle tissue (P < 0.05). Our work is the first to show a protective effect of chronic MitoQ supplementation on the mitochondrial and nuclear genomes in lymphocytes and human muscle tissue following exercise, which is important for genome stability.
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Additional Effects of Nutritional Antioxidant Supplementation on Peripheral Muscle during Pulmonary Rehabilitation in COPD Patients: A Randomized Controlled Trial.
Gouzi, F, Maury, J, Héraud, N, Molinari, N, Bertet, H, Ayoub, B, Blaquière, M, Bughin, F, De Rigal, P, Poulain, M, et al
Oxidative medicine and cellular longevity. 2019;2019:5496346
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Chronic obstructive pulmonary disease (COPD) is systematically associated with comorbidities. Muscle atrophy and weakness are therefore targets of exercise training interventions in pulmonary rehabilitation (PR). The aim of the study was to test the effects of oral antioxidant supplementation with vitamins and trace elements (i.e. vitamins C and E, zinc and selenium) versus placebo on muscle endurance (primary outcome) and muscle strength, oxidative stress, inflammation, and PR outcomes (secondary outcomes). The study is a randomized double-blind controlled trial during PR. COPD patients (aged between 40 and 78 years) were randomly assigned to the PR antioxidant group or to the PR placebo group. Results indicate that nutritional antioxidant supplementation (vitamins C and E, zinc, and selenium) failed to further improve the patients’ quadriceps endurance. However, results also demonstrate that additional improvements of three secondary outcomes and a trend toward increased muscle type I fiber proportion with supplementation versus placebo during PR. Authors conclude that efficient antioxidant supplementation results in greater improvement in muscle function when compared to placebo in combination with exercise training.
Abstract
BACKGROUND Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD) is not fully reversed by exercise training. Antioxidants are critical for muscle homeostasis and adaptation to training. However, COPD patients experience antioxidant deficits that worsen after training and might impact their muscle response to training. Nutritional antioxidant supplementation in combination with pulmonary rehabilitation (PR) would further improve muscle function, oxidative stress, and PR outcomes in COPD patients. METHODS Sixty-four COPD patients admitted to inpatient PR were randomized to receive 28 days of oral antioxidant supplementation targeting the previously observed deficits (PR antioxidant group; α-tocopherol: 30 mg/day, ascorbate: 180 mg/day, zinc gluconate: 15 mg/day, selenomethionine: 50 μg/day) or placebo (PR placebo group). PR consisted of 24 sessions of moderate-intensity exercise training. Changes in muscle endurance (primary outcome), oxidative stress, and PR outcomes were assessed. RESULTS Eighty-one percent of the patients (FEV1 = 58.9 ± 20.0%pred) showed at least one nutritional antioxidant deficit. Training improved muscle endurance in the PR placebo group (+37.4 ± 45.1%, p < 0.001), without additional increase in the PR antioxidant group (-6.6 ± 11.3%; p = 0.56). Nevertheless, supplementation increased the α-tocopherol/γ-tocopherol ratio and selenium (+58 ± 20%, p < 0.001, and +16 ± 5%, p < 0.01, respectively), muscle strength (+11 ± 3%, p < 0.001), and serum total proteins (+7 ± 2%, p < 0.001), and it tended to increase the type I fiber proportion (+32 ± 17%, p = 0.07). The prevalence of muscle weakness decreased in the PR antioxidant group only, from 30.0 to 10.7% (p < 0.05). CONCLUSIONS While the primary outcome was not significantly improved, COPD patients demonstrate significant improvements of secondary outcomes (muscle strength and other training-refractory outcomes), suggesting a potential "add-on" effect of the nutritional antioxidant supplementation (vitamins C and E, zinc, and selenium) during PR. This trial is registered with NCT01942889.