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The coenzyme nicotinamide adenine dinucleotide (NADH) as biological antidepressive agent
Abstract
SUMMARY The coenzyme nicotinamide adenine dinucleotide (NADH) has been used in an open label trial as medication in 205 patients suffering from depression with various clinical symptoms. NADH was given orally, intramuscularly or intravenously. The duration of therapy ranged from 5 to 310 days. 93% of the patients exhibited a beneficial clinical effect. An improvement up to 44 with a mean value of 11,5 was observed.
... In one study, ACE was purified from ostrich lung and the in vitro effect of captopril inhibitor was investigated. The IC 50 and K i values for captopril were calculated as 36.5 and 16.6 nM, respectively [7]. In our previous study, the IC 50 and K i values of lisinopril, which showed an in vitro inhibition effect on the ACE enzyme purified from human plasma, were found to be 0.781 and 0.662 nM, respectively [8]. ...
... The IC 50 and K i values for captopril were calculated as 36.5 and 16.6 nM, respectively [7]. In our previous study, the IC 50 and K i values of lisinopril, which showed an in vitro inhibition effect on the ACE enzyme purified from human plasma, were found to be 0.781 and 0.662 nM, respectively [8]. The in vitro inhibition effect of captopril and lisinopril on the ACE enzyme purified from frog ovaries (Rana esculenta) was determined and IC 50 values were 68 ± 12.55 nM and 6.763 ± 0.66 nM, respectively [9]. ...
... In our previous study, the IC 50 and K i values of lisinopril, which showed an in vitro inhibition effect on the ACE enzyme purified from human plasma, were found to be 0.781 and 0.662 nM, respectively [8]. The in vitro inhibition effect of captopril and lisinopril on the ACE enzyme purified from frog ovaries (Rana esculenta) was determined and IC 50 values were 68 ± 12.55 nM and 6.763 ± 0.66 nM, respectively [9]. ...
Angiotensin-converting enzyme (ACE, EC 3.4.15.1) is a significant enzyme that regulates blood pressure. ACE inhibitors are often used in the treatment of hypertension. In this work, ACE was purified and characterized in one step with affinity chromatography from sheep kidneys. ACE was 10305-fold purified and specific activity was 19,075 EU/mg protein. The molecular weight and purity of ACE were found with SDS-PAGE and observed two bands at about 60 kDa and 70 kDa on the gel. The effects of reduced nicotinamide adenine dinucleotide (NADH), an antioxidant compound, on purified ACE activity were also researched. NADH on ACE activity showed an inhibition effect. The inhibition type of NADH was determined to be non-competitive inhibition by the Lineweaver–Burk chart and IC50 and Ki values for NADH were 244.33 and 175.08 µM, respectively. These results suggest that antioxidant substances might be efficient in preventing hypertension.
... Moreover, NADH serves as a cofactor for various enzyme reactions, further emphasizing the crucial role of NADH for numerous cell functions. Recent clinical studies have already demonstrated a positive effect of NADH treatment on patients suffering from Morbus Parkinson, chronic fatigue syndrome and depression (Birkmayer & Birkmayer, 1991; Birkmayer et al., 1993; Kuhn et al., 1996; Forsyth et al., 1999). In addition, changes in NADH levels seem to correspond with stimulation and inhibition of neuronal metabolism, respectively (Rex et al., 1999). ...
... Any direct effects of extracellular NADH on I K(ATP) could be excluded. Clinical studies have demonstrated a positive effect of NADH treatment on patients suffering from Morbus Parkinson, chronic fatigue syndrome and depression (Birkmayer & Birkmayer, 1991; Birkmayer et al., 1993; Kuhn et al., 1996; Forsyth et al., 1999). Vrecko et al. (1997) showed that NADH supplementation of PC12 cells leads to increased dopamine production being of interest for the treatment of Morbus Parkinson which is characterized by a dopamine deficit. ...
The aim of this study was to investigate the effect of nicotinamide-adenine dinucleotide (NADH) supplementation on the metabolic condition of isolated guinea-pig ventricular cardiomyocytes. The pinacidil-primed ATP-dependent potassium current IK(ATP) was used as an indicator of subsarcolemmal ATP concentration and intracellular adenine nucleotide contents were measured.
Membrane currents were studied using the patch-clamp technique in the whole-cell recording mode at 36–37°C. Adenine nucleotides were determined by HPLC.
Under physiological conditions (4.3 mM ATP in the pipette solution, ATPi) IK(ATP) did not contribute to basal electrical activity.
The ATP-dependent potassium (K(ATP)) channel opener pinacidil activated IK(ATP) dependent on [ATP]i showing a significantly more pronounced activation at lower (1 mM) [ATP]i.
Supplementation of cardiomyocytes with 300 μg ml−1 NADH (4–6 h) resulted in a significantly reduced IK(ATP) activation by pinacidil compared to control cells. The current density was 13.8±3.78 (n=6) versus 28.9±3.38 pA pF−1 (n=19; P<0.05).
Equimolar amounts of the related compounds nicotinamide and NAD+ did not achieve a similar effect like NADH.
Measurement of adenine nucleotides by HPLC revealed a significant increase in intracellular ATP (NADH supplementation: 45.6±1.88 nmol mg−1 protein versus control: 35.4±2.57 nmol mg−1 protein, P<0.000005).
These data show that supplementation of guinea-pig ventricular cardiomyocytes with NADH results in a decreased activation of IK(ATP) by pinacidil compared to control myocytes, indicating a higher subsarcolemmal ATP concentration.
Analysis of intracellular adenine nucleotides by HPLC confirmed the significant increase in ATP.
British Journal of Pharmacology (2003) 139, 749–754. doi:10.1038/sj.bjp.0705300
... The effects of this sublingually absorbed NADH on anthropometric and metabolic profile were determined by different methods of biological assays (glucose, HbA1c and lipid) were performed by routine methods. Anthropometric parameters (BMI, fat mass, lean mass, body water), were measured by bioelectrical impedance kind Bodystat® 1500 MDD [10]. The software Statistical Package of Social Sciences (SPSS 17.0) was used for statistical analysis of the results [11]; ANOVA test was used for analysis of the comparison of the groups. ...
... NADH, as a cofactor, is involved in numerous enzymatic reactions of NAD + /NADH dependent dehydrogenases [37]. Some uncontrolled studies have found NADH benefits for patients suffering from Parkinson's disease, Alzheimer's disease, and depression [38][39][40]. Studies showed that NADH is needed for the regeneration of GSH after its oxidation; also supplementation of NADH may help restoring GSH to its active form. ...
... A preliminary clinical open-label study suggested that NADH may also be beneficial in major depression. NADH was found to be superior to placebo and effectively reduced depression symptoms (Birkmayer and Birkmayer, 1991). To our knowledge there are no data available on the activity of NADH in animal tests for antidepressive activity . ...
Nicotinamide adenine dinucleotide (NADH), a cosubstrate for energy transfer in the oxidative phosphorylation, has supposedly beneficial effects on central nervous system (CNS)-related diseases, e.g., shown in an open study with depressive patients. To our knowledge there are no data concerning the efficacy of NADH in animal tests. Acute effects of NADH and the precursor nicotinamide, compared to controls and the antidepressants desipramine and fluoxetine, were examined in the forced swim test (FST) in Wistar rats. NADH, but not nicotinamide, reduced immobility and increased swimming behaviour in the FST, with a minimum effective dose of 5 mg/kg. NADH-induced behavioural profile was similar to fluoxetine, but different from desipramine. Since NADH did not induce hyperlocomotion but even decreased motor activity in the open field test, the antidepressant-like effect cannot be attributed to an increase in motor activity. These data support an antidepressant potential of NADH.
... According to this theory, the major symptoms of depression arise from a deficiency in catecholamine neurotransmitters in the synaptic cleft. Although the postmortem studies on the brain concentration of tyrosine hydroxylase in depressed patients remain controversial, it has been reported that tyrosine hydroxylase levels are increased and that clinical depression is improved by treatment with nicotinamide adenine dinucleotide (Birkmayer & Birkmayer, 1991 ) or tetrahydrobiopterin (Thony et al., 2000), and that tyrosine hydroxylase gene expression is increased by electroconvulsive shock (Brady et al., 1994), a highly effective therapy for the treatment of major depression. Interestingly, the direct intravenous administration of tyrosine hydroxylase linked to protein transduction domain, an undecapeptide that is able to drive macromolecules across the blood– brain barrier, has antidepressant-like activity in both the forced swimming test and tail suspension test (Fu et al., 2006). ...
In the present study, we have coupled the chronic mild stress (CMS) protocol with Affymetrix microarray technology to screen the rat genome for gene changes in the frontal cortex. The aim of our work was to assess whether the CMS protocol could be a useful experimental model to provide insights into the molecular basis of depression. Under our experimental conditions, 59 transcripts changed by more than +/-1.5-fold between naïve and anhedonic rats and showed significantly altered expression levels (P < 0.05). Among these, 18 were upregulated (fold change range +1.509 to +3.161) and 41 were downregulated (fold change range -1.505 to -2.659). To confirm the data obtained with microarrays, we used real-time reverse transcription polymerase chain reaction (RT-PCR). The results confirmed the downregulation of Itga6, Camk2a, Plcb1, Cart, Gad1, Homer1 and Th and the upregulation of Egr2 and Ptgs2 observed in the DNA microarray analysis. Moreover, the fold change data of the nine validated transcripts from microarray analysis and real-time polymerase chain reaction showed a good correlation (r = 0.863, 7 d.f., P < 0.01; slope = 0.976). It is of great interest that prostaglandin-endoperoxide synthase 2, tyrosine hydroxylase, Cart, Homer1 and glutamate decarboxylase have already been implicated in affective disorders by different approaches in previous reports. In conclusion, our findings indicate that the CMS paradigm is a useful preclinical model with which to investigate the molecular basis of anhedonia and to help in the discovery of novel targets for antidepressant drugs.
Zusammenfassung
Ziel dieser prospektiven randomisierten placebokontrollierten Doppelblindstudie war die Erhebung des Einflusses einer vierwöchigen NADH-Supplementation in Kombination mit einem Trainingsprogramm auf kognitive Fähigkeiten, Gesundheitszustand und auf die physische und physische Leistungsfähigkeit eines untrainierten Kollektivs. 27 statistisch vergleichbare gesunde Erwachsene nahmen vier Wochen lang an einem gezielten Trainingsprogramm teil und erhielten parallel entweder 10 mg NADH/Tag oder ein wirkstofffreies Placebopräparat. Die Sportintervention allein führte zu einer Verbesserung in sämtlichen getesteten Bereichen (motorische und kognitive Fähigkeiten, gesundheitsbezogene Lebensqualität). Die NADH-Supplementation resultierte in einer zusätzlichen Verbesserung des Gesamtgesundheitszustands sowie in einer 14,3%igen Steigerung der kognitiven Fähigkeiten im Vergleich zur Placebogruppe.
Scientific documentation confirms that nicotinamide adenine dinucleotide (NADH) improves mental and physical performance. Therefore, NADH (ENADA®) has been evaluated for the first time in the course of a non-interventional trial in the therapy of the climacteric syndrome. Overall, 49 women participated in the study: 14 in Switzerland (4 drop-outs), 35 in Austria (5 drop-outs). Inclusion criteria were: age 45-65 years, presence of hot flashes, FSH >20mlU/ml, no psychotropic or thyroid drugs. Over three months, women were assigned 10mg of NADH/ENADA® every morning. In addition, patients had to fill out a standardised questionnaire every day, which contained a 5-grade scale on relevant symptoms of menopause. Evaluation was carried out by means of the Friedman test. A significant improvement of the following symptoms was observed: intensity of hot flashes, mild depression and mood swings, restriction because of insomnia, loss of motivation and nervousness. No major changes could be observed regarding irritability and frequency of hot flashes. Administration of NADH as dietary supplement represents an interesting option for the treatment of the climacteric syndrome, aside of the established treatments with phytohormones and steroid hormones. Due to the favourable results and the fact that until present no studies on the matter have been conducted, it is highly desirable to carry out a placebo controlled clinical trial.
The effect of NADH on DMA repair was investigated on PC12 cells, damaged by doxorubicin. PC12 cells were incubated in medium without and with NADH before and after exposure to the DNA damaging agent doxorubicin. The changes of the cell proliferation genes (c-myc, c-erbB-2), the apoptosis inhibition gene bcl-2 and p53 (tumor suppressor gene), cell apoptosis gene (c-fos) and the proliferating cell nuclear antigen (PCNA) were investigated using a cytotoxicity assay and immunofluorescence flow cytometric analysis. Doxorubicin induced DNA damage in PC 12 cells by inhibiting the expression of the cell proliferation genes and by triggering apoptotic processes in the cells. This was shown by down regulating the expression of c-erb-2, c-myc, bcl-2 and upregulating the expression of PCNA and c-fos of the PC 12 cells. NADH did not only increase the resistance of PC 12 cells to the doxorubicin induced DNA damage but also repaired the damage partially. NADH promoted survival and differentiation by regulating the c-myc oncogene protein. Furthermore it supported the process of DNA repair by regulating the expression of p53 bcl-2 on the PC12 cells damaged by doxorubicin. NADH also down regulated expression of the cell apoptosis gene c-fos on the PC12 cells. The expression of c-erbB-2 oncogene protein and PCNA on the PC12 cells did not show a significant change in the group of cells incubated with NADH in comparison to the group incubated with medium alone. In addition, an abnormal proliferation effect of NADH on PC12 cells has not been observed in these experiments. For these results we conclude that NADH may be considered as a therapeutic adjunct for cancer patients to protect normal cells from the toxic effect of chemotherapeutic agents such as doxorubicin or cisplatin by stimulating the DNA repair system and by promoting normal cellular biosynthetic responses after chemotherapy.
Nicotinamide Adenine Dinucleotide (NADH) plays a primary role in the energy production in human cells. NADH is involved in cellular DNA repair. Chemotherapy for cancer often has severe side effects that limit its efficacy. The objective of this study was to elucidate molecular mechanisms of NADH in inhibiting apoptosis of human normal cells induced by chemotherapy drugs and identify NADH as a kind of chemotherapy protection factor. In cells treated with NADH and Cisplatin, no typical apoptotic morphological changes of cells were observed compared with cells treated with Cisplatin alone. Flow cytometry indicated the apoptotic rate of cells were as follows: 11.2%, 24.3%, 51.8% and 89.4%, when cells were treated with 10μM Cisplatin for 12h to 48h. In contrast with the group of Cisplatin, the apoptotic rate of cells in the group of NADH and Cisplatin decreased to 5.7%, 10.8%, 11.2% and 13.1%. Compared with Cisplatin treated cells, p53 mRNA expression decreased and Bcl-2 mRNA expression increased in the cells treated with NADH and Cisplatin. Caspase-3 activity raised quickly when cells were incubated with 1μm Cisplatin especially after 24h. However, if cells were cultured with NADH then with Cisplatin, Caspase-3 activity was kept in a low level. The alteration of Caspase-8 appeared to be similar to caspase-3. Our results showed NADH may inhibit human liver cells from apoptosis. These findings may raise the possibility of using NADH to reduce the side effects of chemotherapy for human cancer.
In order to investigate whether NADH can trigger proliferation activity of nerve cells and rescue nerve cells from apoptotic damage induced by cisplatin the changes of the cell proliferation genes (c-myc, c-erbB-2), apoptosis inhibition genes (bcl-2, P53), cell apoptosis gene (c-fos) and cyclin proteins (cyclin A1, B1, and D1) on PC12 cells damaged by cisplatin were analyzed by cycotoxicity test and flow cytometry analysis. The results show that after incubation with cisplatin for 12 hours, the apoptotic rate of PC12 cells is 82.4%. The cells were mainly arrested in the G1 phase and showed an higher expression of cyclin D1. The amount of P53, Bcl-2, c-erbB-2, c-myc, cylin A , cyclin B1 expressed on the PC12 cells damaged by cisplatin were found to be down-regulated to 52.2%, 60.8%, 21.9%, 90.7%, 40.9%, and 58.5% respectively. Flow cytometry analysis confirmed that after incubated with NADH for 48 hours, the amounts of P53, Bcl2 and cyclin B1 expressed on the cells damaged by cisplatin were significantly rescued and upregulated. The expression of p53 tumor suppressor protein was downregulated by 59.6% in comparison with the goup incubated with medium alone. However, the expression of c-myc and c-erbB-2 oncogene proteins on the PC12 cells did not show a significant increase in the group treated with NADH. It is suggested that NADH can not only promote survival and differentiation, but also rescue the PC12 cells from apoptotic damage by upregulation of P53 and Bcl-2 and downregulation of cyclinDI, c-fos expressed on the PC12 cells.____.
Drugs intended to increase wellness or quality of life (“lifestyle drugs“) have gained popularity and/or importance over recent years. Biogenic substances like nicotinamide adenine dinucleotide (NADH) are supposed to increase the physical and intellectual performance without side-effects. NADH is an energy-delivering co-substrate in the respiratory chain. Clinical studies showed positive effects of peripherally given NADH in Morbus Parkinson and major depression. NADH can be measured by its fluorescence. In this study a pulsed N2-laser combined with a fibre-optic probe and photomultipliers was used to induce and measure NADH fluorescence in the rat cortex. The aims of the study were to assess the suitability of the laser-induced spectroscopy for in vivo and on-line measurement of NADH in neuroscience and the assessment of the central availability of NADH after peripheral administration. NADH (50 mg/kg) but not the precursor nicotinamide caused a significant rise of the NADH fluorescence intensity indicating an increase of the NADH concentration in the rat cortex. In conclusion, the results suggest that NADH given orally or intraperitoneally increases the amounts of NADH in the brain. The results may thus help to explain the clinical effects reported.
A recently described novel compound, silica hydride, was used to investigate potential alternative hydrogen energy sources for use in industry, pharmacology and biochemistry. Acting as an anionic hydride, the silica hydride does not react violently with water and produces stable oxidation-reduction potential readings of greater than for extended periods providing capacity as an alternative for current transfer, hydrogen production and fuel cell applications in industrial arenas. In a biological venue, the silica hydride definitively reduces the pyridine NAD+ to the NADH form, indicating potential for use as a biochemical fuel cell. Subsequent analyses of the compound indicate no induced cytotoxicity as a result of the silica hydride and the increased NADH in a cell.
Es wurde in einer randomisierten, placebo-kontrollierten Doppelblindstudie im Cross-over-Design mit 14 männlichen Ausdauersportlern (20-50 Jahre, VO2max > 55 ml/min/kg) überprüft, ob unter intensivem Muskelstress und der oralen Gabe des zu prüfenden Nährstoffs (stabilisiertes NADH = ENADA®, Tagesdosierung 30 mg als 2x3 Tabletten) spezifische, gegen Placebo zu sichernde, als positiv zu bezeichnende Effekte auf den Energiestoffwechsel und die belastungsinduzierte muskuläre und systemische Begleitreaktion nachweisbar sind. Die Einnahme von Placebo bzw. Verum erfolgte über jeweils 4 Wochen (Interventionsphase 1), gefolgt von einer mindestens 6-wöchigen (maximal 8-wöchigen) Wash-out-Phase, in der die Wirkung der ersten Behandlung abklingen sollte, und einer zweiten Interventionsphase. Die Untersuchungen (Stufentest und Ausdauertest) fanden jeweils zu Beginn und nach 4-wöchiger Ernährungsintervention statt.
Die Einnahme des NADH-Präparates führte bei Ausdauersportlern zu keiner unerwünschten Nebenwirkung oder Beeinflussung der Sicherheits- und Routineparameter. Es konnten folgende tendenziell signifikante (p<0.1) und signifikante Veränderungen (p<0.05) durch NADH-Supplementation festgestellt werden:
Im metabolisch-energetischen Bereich kam es zu einer Reduzierung der körpergewicht-bezogenen O2-Aufnahme an der aeroben Schwelle im Stufentest, einer Verschiebung der gefitteten Kurven des CO2/O2-Scattergramms zu kleineren Sauerstoffaufnahmewerten, einer Reduzierung des Blut-Laktatspiegel bei Ausdauerarbeit, einer Reduzierung der Blut-Pyruvat-Konzentration im Stufentest und einer Erhöhung der freien Fettsäuren im Plasma unter Nüchtern-Ruhe-Bedingungen.
Im Bereich der systemischen Stressindikatoren und Routineparameter konnte eine Reduzierung der Plasma-Cortisol-Konzentration jedoch vor Belastung im Stufentest festgestellt werden und bei Ausdauerarbeit eine Reduzierung der Serum-Kreatin-kinase-Aktivität, der Serum-Kaliumkonzentration, der Serum-Kreatininkonzentration und der Blut-Leukozytenanzahl.
Die Richtung der beschriebenen Ergebnisse lässt eine Beeinflussung der zellulären Energiebereitstellung durch die gewählte Substitution vermuten, jedoch sind zur Sicherung der Ergebnisse weitere konfirmatorische Studien notwendig.
A gradual increase in blood pressure (BP), often attaining hypertensive levels, is common during aging--"age-related hypertension." Therefore, means to prevent or ameliorate this elevated BP safely are important. Although oral B-nicotinamide adenine dinucleotide (NADH), a natural coenzyme, is used principally to treat various neurologic disorders, we wished to investigate whether this agent had the same potential to lower BP and benefit the cardiovascular system as does coenzyme Q10, a similar-type agent. As a first approximation, spontaneously hypertensive rats (SHR) were used to determine effects of oral NADH. In a blinded, placebo-controlled study, ten rats received placebo; and ten, NADH for ten weeks. Systolic BP was measured by tail plethysmography. Blood was collected terminally, and chemistries were performed by routine methodologies. Thiobarbituric acid reactive species (TBARS) (an estimate of lipid peroxidation/free radical formation) was measured in renal and hepatic tissues. The following was noted: water and food intake were comparable, and the steady weight gain of young SHR were similar in the placebo and NADH groups. Although systolic BP did not differ between the two groups over the first month, it decreased and stayed markedly lower for the remainder of study in SHR receiving oral NADH. At the end of 60 days, SBP in NADH-treated SHR was 184 mm Hg +/- 2.8 (SEM) compared to 201 mm Hg +/- 2.1 (SEM) in control SHR (p < 0.001). No significant differences were seen in blood levels of glucose, insulin, triglyceride, and HDL levels but NADH intake lowered total cholesterol (p < 0.002) and LDL (p < 0.02). Renal TBARS were also significantly lower in SHR receiving NADH (P < 0.001). Accordingly, supplementation with the natural coenzyme NADH theoretically could prove to be useful in preventing age-related increases in BP and, thus, various cardiovascular maladies.
Chronic fatigue syndrome (CFS) is a disorder of unknown etiology, consisting of prolonged, debilitating fatigue, and a multitude of symptoms including neurocognitive dysfunction, flu-like symptoms, myalgia, weakness, arthralgia, low-grade fever, sore throat, headache, sleep disturbances, and swelling and tenderness of lymph nodes. No effective treatment for CFS is known.
The purpose of the study was to evaluate the efficacy of the reduced form of nicotinamide adenine dinucleotide (NADH) i.e., ENADA the stabilized oral absorbable form, in a randomized, double-blind, placebo-controlled crossover study in patients with CFS. Nicotinamide adenine dinucleotide is known to trigger energy production through ATP generation which may form the basis of its potential effects.
Twenty-six eligible patients who fulfilled the Center for Disease Control and Prevention criteria for CFS completed the study. Medical history, physical examination, laboratory studies, and questionnaire were obtained at baseline, 4, 8, and 12 weeks. Subjects were randomly assigned to receive either 10 mg of NADH or placebo for a 4-week period. Following a 4-week washout period, subjects were crossed to the alternate regimen for a final 4-week period.
No severe adverse effects were observed related to the study drug. Within this cohort of 26 patients, 8 of 26 (31%) responded favorably to NADH in contrast to 2 of 26 (8%) to placebo. Based upon these encouraging results we have decided to conduct an open-label study in a larger cohort of patients.
Collectively, the results of this pilot study indicate that NADH may be a valuable adjunctive therapy in the management of the chronic fatigue syndrome and suggest that further clinical trials be performed to establish its efficacy in this clinically perplexing disorder.
We investigated the antiproliferative effects of extracellular nicotinamide adenine dinucleotide against human malignant CaCo-2 (colon carcinoma), Hep-2 (laryngeal carcinoma), MCF-7 (breast carcinoma), CaSki (cervix carcinoma) cell lines, as well as against murine fibrosarcoma and normal human embryonal fibroblast (HEF). NADH was very potent in the growth inhibition of murine fibrosarcoma and human Hep-2 cells, regardless of the dose applied. During the observed period (4 or 5 days) only one dose of NADH was sufficient in reducing the growth rate for up to 92%. It had no effect on the growth of other cell lines tested. The identification of DNA-fragmentation and p53 and Ki-67 genes expression suggest that the mechanism of NADH action is different from disregulation of genes considered as check-points in cell cycle.
Recently, therapy with nicotinamide adenine dinucleotide (NADH) revealed positive effects on neurodegenerative disorders associated with inflammation of the CNS, such as Parkinson's disease or Alzheimer's disease. Pathophysiologically, focal CNS inflammation seems to be accompanied by an unbalanced cytokine production, pointing to an involvement of the immune system. Therefore, the aim of our study was to investigate whether NADH could influence cytokine release of peripheral blood leukocytes (PBLs) with special reference to interleukin-6 (IL-6).
PBLs from 18 healthy donors were incubated in vitro with different concentrations of NADH to generate dose-response curves. As a control, mitogen-treated cells and unstimulated cells were included.
In PBLs from the 18 healthy donors, NADH significantly stimulated the dose-dependent release of IL-6, ranging from 6.25 to 400 microg/ml, compared to medium-treated cells (p < 0.001). An amount of 1,000 pg/ml IL-6 was induced by NADH concentrations ranging from 3.1 to >25 microg/ml.
It is concluded that NADH possesses cytokine-modulating effects on peripheral blood cells. The biological relevance of these data is discussed in the context of the recent use of NADH for the treatment of several neurodegenerative disorders.
Among many important physiological functions played by NADH (the reduced form of beta-nicotinamide adenine dinucleotide) its antioxidative properties are remarkable. Acting directly as an antioxidant, NADH can effectively protect the cell and its membrane from destruction by free radicals. NADH can be stabilized as a suspension in hydrophobic ointments prepared in a way that prevents contact with atmosphere containing oxygen and water. We present the first report of NADH as a treatment for some inflammatory dermatoses. It was found that topical application of 1% NADH diluted in Vaseline ointment can be very effective in the treatment of rosacea and contact dermatitis. Since no adverse effects were observed, therapy with NADH can be viewed as a potential alternative to other established treatments.
This study was designed to evaluate the effect of stabilized oral reduced nicotinamide adenine dinucleotide (NADH) on cognitive functioning in patients with Alzheimer's disease (AD). NADH is a coenzyme that plays a key role in cellular energy production and stimulates dopamine production. In previous trials NADH has been shown to improve cognitive functioning in patients with Parkinson's disease, depression and AD. The present trial was a randomized, placebo-controlled, matched-pairs, double-blind, 6-month clinical study. Patients with probable AD (n = 26) were randomized to receive either stabilized oral NADH (10 mg/day) or placebo. Twelve pairs of subjects were matched for age and baseline total score on the Mattis Dementia Rating Scale (MDRS) and the Mini Mental State Examination. After 6 months of treatment, subjects treated with NADH showed no evidence of progressive cognitive deterioration and had significantly higher total scores on the MDRS compared with subjects treated with placebo (p < 0.05). Analysis of MDRS subscales revealed significantly better performance by NADH subjects on measures of verbal fluency (p = 0.019), visual-constructional ability (p = 0.038) and a trend (p = 0.08) to better performance on a measure of abstract verbal reasoning. There were no differences between groups in measures of attention, memory, or in clinician ratings of dementia severity (Clinical Dementia Rating). Consistent with earlier studies, the present findings support NADH as a treatment for AD.
The objective of the study was to determine both the toxicity of the stabilized orally absorbable form of nicotinamide adenine dinucleotide (NADH) (ENADA) and the maximum tolerated intravenous dose (MTD) of betaNADH (the reduced form of NADH) in beagle dogs. The administration of the stabilized orally absorbable form of NADH to beagle dogs at dose levels of 20, 100, and 150 mg/kg for 14 days elicited no signs of a toxicological effect. A transitory change in stool formation was observed with the intermediate and high dose in males. There were also apparent increases in adrenal, heart, kidney, liver, brain, and thyroid weights, particularly in males, but none of these changes were considered to be toxicologically significant. In addition, four dogs (two of each sex) received intravenous infusions of 100 mg NADH/kg/day for 4 days, followed by 200 mg NADH/kg/day for 3 days, followed by 500 mg NADH/kg/day for 4 days, and 1000 mg NADH/kg/day on the final day. At the end of the MTD phase, the control animals that had received saline solution in the MTD phase were used to evaluate the potential toxicity of the established MTD. These animals received 500 mg NADH/kg/day for 14 days (fixed dose phase). There were no deaths. At dose levels between 100 and 1000 mg/kg/day, effects on the cardiovascular system and also some evidence of an effect on the central nervous system and on the adrenals were observed. At doses of 500 mg/kg/day and above, food consumption and body weight were reduced. On the basis of the observed changes, the maximum intravenous dose of NADH tolerated by beagle dogs was considered to be 500 mg/kg/day. There were no gross histological findings indicative of toxicity in the organs of tissues examined. Based on these findings, the stabilized orally absorbable form of NADH (ENADA) can be regarded as safe.
Rosacea is a chronic facial dermatosis with a progressive course, which is characterized by the presence of erythema, papules, pustules, telangiectasias and sebaceous gland hyperplasia. However, the aetiology is still unknown; genetic predisposition, gastrointestinal disorders (Helicobacter pylori), infestations with Demodex folliculorum and environmental stimuli are considered to be involved in the inflammatory process. A metabolite of nicotinamide, 1-methylnicotinamide (MNA(+)), has anti-inflammatory properties, and this is the first study to test the effectiveness of this agent in treating rosacea. In total, 34 patients with rosacea were treated with a gel containing 0.25% MNA(+) as a chloride salt, twice daily for 4 weeks, after which improvement was observed in 26/34 cases. The improvement was good in 9/34 and moderate in 17/34, but no clinical effect was noted in seven subjects. In only one case was skin irritation given as the reason for treatment withdrawal. These results indicate that MNA(+) might be a useful agent for treating rosacea.
Tyrosine hydroxylase (tyrosine 3-monooxygenase, EC 1.14.16.2, TH) is the rate-limiting enzyme in the biosynthesis of catecholamine neurotransmitters, dopamine (DA), noradrenaline (NE), and adrenaline, in the neurons. The regulated activity of TH is thought to play a critical role in modulating the functional activity of catecholaminergic neuronal systems in the brain. It is well known that the catecholaminergic neuronal systems are associated with depression. Here we showed that TH, delivered by protein transduction domain (PTD), passed through the blood-brain barrier and entered the neurons. Systemic TH treatment improved the behavioral despair in the forced swim test (FST) and the tail suspension test (TST), the two models widely used to screen the potential anti-depressant efficacy. The results indicated a novel and potential therapeutic use of TH in the depression disorder.
The aim of this study was to assess the effects of nicotinamide adenine dinucleotide hydride (NADH) on maximal oxygen uptake (VO2max), maximal anaerobic running time, and mental performance. Eight men were exposed to a supplement treatment (30 mg NADH as ENACHI tablets per day) and to a placebo treatment, each of 4 weeks' duration, in a balanced, double-blind, and cross-over design. The two treatments were separated by a 14-week wash-out period. The results indicated that VO2max, maximal anaerobic running time, and the ability to concentrate were similar in the NADH and placebo conditions. There were also no differences in blood lactate, creatine kinase, reaction time or feelings of fatigue between the treatments. A counter-movement jump performed at rest and 2 min after the aerobic test differed significantly (P <or= 0.05) between the treatment conditions and was higher in the NADH group. In conclusion, the NADH supplementation for 4 weeks had no effects on VO2max, maximal anaerobic running time or mental performance.
The coenzyme Nicotinamide adenine dinucleotide (NADH) has been used as medication in 415 Parkinsonian patients in an open label trial. In 85% of the patients a beneficial clinical effect was observed: 31,5% of the patients showed a very good (30-50%) improvement of disability, 53.5% a moderate (10-30%) improvement. In a certain percentage of the patients in which the HVA level was determined, the improvement in disability is parallel by an increase in the urinary HVA concentration indicating a higher dopamine turnover. Statistical analysis of the improvement in correlation with the disability prior to treatment, the duration of the disease and the age of the patients revealed the following results: all these 3 parameters have a significant although weak influence on the improvement. The disability before the treatment has a positive regression coefficient (t value <0,01). The duration of the disease has a negative regression coefficient (<0,01) and so has the age a negative regression coefficient (t value < 0,05). In other words younger patients and patients with a shorter duration of disease have a better chance to gain a marked improvement than older patients and patients with longer duration of the disease.
The behavioural and biological effects L-dopa administration in combination with DL-α-methyl-dopa-hydrazine (MK 485) were evaluated in depressed patients. MK 485 (750-1000 mg. daily) and L-dopa (300-1500 mg. daily) were administered on a non-random double-blind basis to nine depressed hospital inpatients with alternating drug and placebo periods in each patient. Three of the patients treated with the drug combination evidenced clearcut improvement, two of them relapsing when placebo was substituted; six showed no change. Those who improved were predominantly retarded. Cerebrospinal-fluid homovanilic-acid (H.V.A.) levels increased modestly (compared with the profound increase observed in patients on L-dopa alone) with no change in 5-hydroxyindole-acetic acid (5-H.I.A.A.). Plasma-dopa levels in two patients receiving 1 g. of L-dopa were equivalent to levels observed in these same patients receiving 100 mg. of L-dopa plus MK 485. The incidence of gastrointestinal side-effects was significantly lower than in patients receiving L-dopa alone. Preliminary experience suggests that α-methyl-dopa-hydrazine is a safe drug capable of inhibiting the peripheral decarboxylation of administered L-dopa. Consequent reduction in the incidence of peripherally based side-effects may allow more rapid attainment of therapeutic levels, and a potentiation of the effects of L-dopa on the central nervous system.
Akinetic crises are one of the problems arising in patients with Parkinson's disease in particular after long term treatment with levo-dihydroxyphenylalanine (L-DOPA). They are characterized by severe disability to move. Increasing dosages of L-DOPA and decarboxylase or monoaminooxidase inhibitors do not improve these symptoms. Intravenously applied iron in the form of a ferri-ferro-complex exhibits a considerable benefit for all patients treated so far. They regained a remarkable mobility. Their disability score dropped from up to 90 percent down to 30 percent. The effect is dosage-dependent, and withdrawal of iron will lead again to akinetic crises.
Some inconsistencies in the biogenic amine hypothesis of depression have arisen from clinical studies with L-dopa and L-tryptophan, the metabolic precursors of the amines. The evidence obtained from the studies of changes in cellular amine levels in depressed patients reported here suggests that the interactions between catecholamines and indoleamines, and possibly other "false transmitter" amines, need to be considered in reevaluating the role of biogenic amines in the affective disorders.
An accumulation of norepinephrin, serotonin and dopamin exists in the brainstem. A decrease of biogenic amines in the brains of Parkinson's cases has been demonstrated. A substitution by the precursor L-DOPA produces an increase of dopamin in the brain and a decrease of serotonin. The high level of dopamin improves the akinesia and the depletion of serotonin causes a toxic delir. A substitution by l-tryptophan restores the balance and the Dopa-psychosis disappears.
The role of the indoleamines in the affective disorders is reviewed. There is increasing evidence of abnormal indoleamine metabolism in depression and mania. In depression the urinary excretion of tryptamine and the cerebrospinal fluid concentration of 5-hydroxy-indoleacetic acid is considerably reduced. Brain levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid are lower in the brains of suicides than in those of subjects who died by other means. In mania, C.S.F. levels of 5-HIAA were also found be to low. In neither mania nor depression did the lumbar C.S.F. 5-HIAA levels change after clinical recovery. These changes in indoleamine metabolism may play a role in the aetiology of depression, since tryptophan, the amino acid precursor of the indoleamines, administered with or without a monoamine-oxidase inhibitor has a therapeutic action in depressed patients.
Total biopterin concentrations in the post-mortem human brain (caudate nucleus) and in the urine of controls and parkinsonian patients were measured by a newly developed radioimmunoassay. There was good correlation between the total biopterin level and tyrosine hydroxylase activity in the human brain. Biopterin concentrations in the caudate nucleus were greatly reduced in parkinsonian patients. In contrast, the reduction of urinary biopterin in parkinsonian patients was slight and not statistically significant, as compared with normal controls.
- W Birkmayer
- P Riederer
Birkmayer W., Riederer P. (1987): Psychopathology, Vol.1 9, Suppl.l.
Die Bedeutung der serotonergen Raphe-Kortex-Projektion for die Beeinflussung der 13-adrenergen Neurotransmission durch Antidepressiva
- I Brocke
- E Sofic
- P Riederer
- E Gabriel
- K Jellinger
- W Danielcyk
BrOcke I, Sofic E., Riederer P., Gabriel E., Jellinger K., Danielcyk W. (1984): Die
Bedeutung der serotonergen Raphe-Kortex-Projektion for die Beeinflussung der
13-adrenergen Neurotransmission durch Antidepressiva. Neuropsychiatr Clin 3: 249-255.
Changes in 5-hydroxy-tryptophan metabolism in depression
- A Coppen
- D M Shaw
- A Mallerson
Coppen A., Shaw D.M., Mallerson A. (1965): Changes in 5-hydroxy-tryptophan
metabolism in depression. Brit S Psychiat 111, 105.
- P Riederer
Riederer P (1988).: In: Biologische Psych iatri e-Synops is 86/87 (Beckmann H., Laux G., eds.),
Springer Verlag, Heidelberg 54-59.
Excretion of 3-methoxy-4-hydroxy-mandelic-acid (VIVIA) in depressed patients treated with antidepressants drugs
- J J Schildkraut
- G L Klerman
- R Hammond
- D G Freud
Schildkraut J.J., Klerman G.L., Hammond R., Freud D.G. (1964): Excretion of
3-methoxy-4-hydroxy-mandelic-acid (VIVIA) in depressed patients treated with antidepressants drugs.
J Psychiatr Res 2, 257-266.