NAD Abstracts 9

©

Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome
            (Castro-Marrero et al., 2015) Download
Chronic fatigue syndrome (CFS) is a chronic and extremely debilitating illness characterized by prolonged fatigue and multiple symptoms with unknown cause, diagnostic test, or universally effective treatment. Inflammation, oxidative stress, mitochondrial dysfunction, and CoQ10 deficiency have been well documented in CFS. We conducted an 8-week, randomized, double-blind placebo-controlled trial to evaluate the benefits of oral CoQ10 (200 mg/day) plus NADH (20 mg/day) supplementation on fatigue and biochemical parameters in 73 Spanish CFS patients. This study was registered in ClinicalTrials.gov (NCT02063126). A significant improvement of fatigue showing a reduction in fatigue impact scale total score (p<0.05) was reported in treated group versus placebo. In addition, a recovery of the biochemical parameters was also reported. NAD+/NADH (p<0.001), CoQ10 (p<0.05), ATP (p<0.05), and citrate synthase (p<0.05) were significantly higher, and lipoperoxides (p<0.05) were significantly lower in blood mononuclear cells of the treated group. These observations lead to the hypothesis that the oral CoQ10 plus NADH supplementation could confer potential therapeutic benefits on fatigue and biochemical parameters in CFS. Larger sample trials are warranted to confirm these findings.

Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial.
            (Castro-Marrero et al., 2016) Download
BACKGROUND & AIMS:  Chronic Fatigue Syndrome (CFS) is a complex condition, characterized by severe disabling fatigue with no known cause, no established diagnostic tests, and no universally effective treatment. Several studies have proposed symptomatic treatment with coenzyme Q10 (CoQ10) and nicotinamide adenine dinucleotide (NADH) supplementation. The primary endpoint was to assess the effect of CoQ10 plus NADH supplementation on age-predicted maximum heart rate (max HR) during a cycle ergometer test. Secondary measures included fatigue, pain and sleep. METHODS:  A proof-of-concept, 8-week, randomized, controlled, double-blind trial was conducted in 80 CFS patients assigned to receive either CoQ10 plus NADH supplementation or matching placebo twice daily. Maximum HR was evaluated at baseline and at end of the run-in period using an exercise test. Fatigue, pain and sleep were evaluated at baseline, and then reassessed at 4- and 8-weeks through self-reported questionnaires. RESULTS:  The CoQ10 plus NADH group showed a significant reduction in max HR during a cycle ergometer test at week 8 versus baseline (P = 0.022). Perception of fatigue also showed a decrease through all follow-up visits in active group versus placebo (P = 0.03). However, pain and sleep did not improve in the active group. Coenzyme Q10 plus NADH was generally safe and well tolerated. CONCLUSIONS:  Our results suggest that CoQ10 plus NADH supplementation for 8 weeks is safe and potentially effective in reducing max HR during a cycle ergometer test and also on fatigue in CFS. Further additional larger controlled trials are needed to confirm these findings. Clinical trial registrationThis trial was registered at clinicaltrials.gov as NCT02063126.

Treatment of Parkinson's disease with NADH.
            (Dizdar et al., 1994) Download
It has earlier been claimed that clinical improvement of patients with Parkinson's disease is obtained by treatment with NADH. This has to be verified by double-blind, clinical studies and measurement of biochemical effects of the treatment. In a double blind study five patients with clinically moderate Parkinson's disease were treated with NADH, 25 mg, given intravenously once a day for four days. Then they were given 25 mg NADH intramuscularly after 2 and 4 weeks. Disability scores were determined before each treatment and two weeks after the final injection. A control group (n = 4) with the same degree of Parkinson's disease obtained sodium chloride with the same schedule. According to the Unified Parkinson's Disease Rating Scale a tendency to clinical improvement was seen after the iv infusions in both treatment and placebo groups. However, the changes were not statistically significant, and no changes occurred during the following weeks. No changes were found neither in the study nor the control group regarding cerebrospinal fluid concentrations of dynorfin, metenkefalin, somatostatin, hydroxy-methoxy-phenylglycol, homovanillic acid and 5-hydroxyindole acetic acid. The results indicate that no great changes are obtained after short-term treatment of parkinsonian patients with NADH, neither clinically nor biochemically.

Nicotinic acid supplementation: effects on niacin status, cytogenetic damage, and poly(ADP-ribosylation) in lymphocytes of smokers.
            (Hageman et al., 1998) Download
As a substrate for poly(ADP-ribose) polymerase (PARP; EC, 2.4.2.30), an enzyme that is activated by DNA strand breaks and is thought to facilitate efficient DNA repair, NAD+ and its precursor nicotinic acid (niacin) are involved in the cellular defense against DNA damage by genotoxic compounds. In this study, the effect of nicotinic acid supplementation on cytogenetic damage and poly(ADP-ribosylation) was evaluated in a human population that is continuously exposed to genotoxic agents, e.g., smokers. By use of a placebo-controlled intervention design, 21 healthy smokers received supplementary nicotinic acid at 0-100 mg/day for 14 weeks. An increased niacin status, as assessed from blood nicotinamide concentrations and lymphocyte NAD+ concentrations, was observed in groups supplemented with 50 and 100 mg/day. This effect was most pronounced in subjects with lower initial NAD+ levels. An increased niacin status did not result in decreased hypoxanthine guanine phosphoribosyltransferase variant frequencies and micronuclei induction in peripheral blood lymphocytes (PBLs). Sister chromatid exchanges in PBLs, however, were increased after supplementation with nicotinic acid. This increase was positively associated with the daily dose of nicotinic acid. No effects of nicotinic acid supplementation were found for ex vivo (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene-induced poly(ADP-ribosylation), although the small number of samples that could be analyzed (n = 12) does not allow firm conclusions. Because no evidence was found for a decrease in cigarette smoke-induced cytogenetic damage in PBLs of smokers after nicotinic acid supplementation of up to 100 mg/day, it is concluded that supplemental niacin does not contribute to a reduced genetic risk in healthy smokers.

Controlled evaluation of nicotinamide adenine dinucleotide in the treatment of chronic schizophrenic patients.
            (Kline et al., 1967) Download
In this double-blind placebo study, ten schizophrenic patients received nicotinamide adenine dinucleotide (NAD), known as diphosphopyridinenucleotide (DPN) for 20 days, while ten matched controls received placebo treatment during the same period. Many methods of patient evaluation were used; none revealed consistent differences between the treatment groups.

Parenteral application of NADH in Parkinson's disease: clinical improvement partially due to stimulation of endogenous levodopa biosynthesis.
            (Kuhn et al., 1996) Download
Exogenous application of levodopa is conventionally used to equalize the striatal dopamine deficit in idiopathic Parkinson's disease (PD). The stimulation of endogenous biosynthesis of levodopa via activation of tyrosine hydroxylase (TH) has been proposed as new therapeutic concept in PD. This may be achieved by exogenous supply with the reduced coenzyme nicotinamide adenine dinucleotide (NADH). Aim of this open prospective study was to investigate (1) the efficacy of a new developed, parenteral application form of NADH on Parkinsonian symptoms and (2) the influence of bioavailability of levodopa. 15 patients, suffering from idiopathic PD (11 male, 4 female, age: 61.40[mean] +/- 10.27[SD] range: 44-74 years, Hoehn and Yahr stage: 3.03 +/- 0.69, range 2-4) received intravenous infusions of NADH (10 mg a' 30 min) over a period of 7 days in addition to conventional Parkinsonian pharmacotherapy. Parkinsonian symptoms were scored before (day 1) and after NADH treatment (day 8). Levodopa plasma levels were estimated over a period of four hours on the day before and on the first day of NADH application by HPLC. Parkinsonian patients showed a significant response, evaluated by the Unified Parkinson's Disease Rating Scale Version 3.0 (p = 0.025; Wilcoxon test). Moreover application of NADH significantly increased bioavailability of plasma levodopa (AUC, p = 0.035; Cmax p = 0.025). In conclusion NADH in used galenic form may be a potent stimulator of endogenous levodopa biosynthesis with clinical benefit for Parkinsonian patients.

The behavioral effects of nicotinamide adenine dinucleotide in chronic schizophrenia.
            (Meltzer et al., 1969) Download
Two grams of NAD were administered orally to ten chronic schizophrenic patients for twenty-one days. Five of the patients were also receiving thioridazine. There was no gross clinical improvement noted in any of the patients despite the fact that related experiments suggested that the NAD was absorbed. In those patients who were not also receiving phenothiazines there was a distinct tendency towards increased hostility, aggressiveness and irritability beginning one week after the initiation of NAD treatment and lasting for nearly two weeks after the NAD was discontinued.

Sleep, psychological and clinical changes during alcohol withdrawal in NAD-treated alcoholics.
            (Smith et al., 1971) Download
In a 12-day double-blind experiment, indigent hospitalized volunteers experiencing acohol withdrawal received orally 3 g NAD daily or placebo. No significant differences occurred.

Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing.
            (Zhou et al., 2016) Download
BACKGROUND AND PURPOSE:  Ageing is an important risk factor of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD(+) ), a ubiquitous coenzyme, links ageing with NAFLD. EXPERIMENTAL APPROACH:  Hepatic concentrations of NAD(+) , protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD(+) biosynthesis, were compared in middle-aged and aged mice or patients. The influences of NAD(+) decline on the steatosis and steatohepatitis were evaluated in wild-type and H247A dominant-negative, enzymically-inactive NAMPT transgenic mice (DN-NAMPT) given normal or high-fat diet (HFD). KEY RESULTS:  Hepatic NAD(+) level decreased in aged mice and humans. NAMPT-controlled NAD(+) salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle-age DN-NAMPT mice displayed systemic NAD(+) reduction and had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver. All these NAFLD phenotypes, especially release of pro-inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α-SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD(+) precursor, completely corrected these NAFLD phenotypes induced by NAD(+) deficiency alone or HFD, whereas adenovirus-mediated SIRT1 overexpression only partially rescued these phenotypes. CONCLUSIONS AND IMPLICATIONS:  These results provide the first evidence that ageing-associated NAD(+) deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD(+) substrates may be a promising therapeutic strategy to prevent and treat NAFLD.

 


References

Castro-Marrero, J, et al. (2015), ‘Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome’, Antioxid Redox Signal, 22 (8), 679-85. PubMed: 25386668
Castro-Marrero, J, et al. (2016), ‘Effect of coenzyme Q10 plus nicotinamide adenine dinucleotide supplementation on maximum heart rate after exercise testing in chronic fatigue syndrome - A randomized, controlled, double-blind trial.’, Clin Nutr, 35 (4), 826-34. PubMed: 26212172
Dizdar, N, B Kågedal, and B Lindvall (1994), ‘Treatment of Parkinson’s disease with NADH.’, Acta Neurol Scand, 90 (5), 345-47. PubMed: 7887134
Hageman, GJ, et al. (1998), ‘Nicotinic acid supplementation: effects on niacin status, cytogenetic damage, and poly(ADP-ribosylation) in lymphocytes of smokers.’, Nutr Cancer, 32 (2), 113-20. PubMed: 9919621
Kline, NS, et al. (1967), ‘Controlled evaluation of nicotinamide adenine dinucleotide in the treatment of chronic schizophrenic patients.’, Br J Psychiatry, 113 (500), 731-42. PubMed: 4292729
Kuhn, W, et al. (1996), ‘Parenteral application of NADH in Parkinson’s disease: clinical improvement partially due to stimulation of endogenous levodopa biosynthesis.’, J Neural Transm (Vienna), 103 (10), 1187-93. PubMed: 9013405
Meltzer, H, R Shader, and L Grinspoon (1969), ‘The behavioral effects of nicotinamide adenine dinucleotide in chronic schizophrenia.’, Psychopharmacologia, 15 (2), 144-52. PubMed: 4310848
Smith, JW, LC Johnson, and JA Burdick (1971), ‘Sleep, psychological and clinical changes during alcohol withdrawal in NAD-treated alcoholics.’, Q J Stud Alcohol, 32 (4), 982-94. PubMed: 4332864
Zhou, CC, et al. (2016), ‘Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing.’, Br J Pharmacol, 173 (15), 2352-68. PubMed: 27174364