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Naja haje envenomation is one of the leading causes of death due to snakebite. Antiserum therapy sometimes fails to provide enough protection against venom toxicity. In this study, we investigated the protective effects of melatonin against N. haje venom in rats. The animals were injected with venom (0.25mg/kg) and/or melatonin (10mg/kg) and compared with vehicle-treated rats. There was oxidative/nitrosative damage and apoptosis in the liver, heart, and kidneys of venom-injected rats. Melatonin counteracted the increased lipoperoxidation and nitric oxide, prevented decreased glutathione peroxidase and reductase activity, reduced the glutathione disulfide/glutathione (GSSG/GSH) ratio, and maintained the GSH pool. Furthermore, melatonin administration was associated with a reduction of apoptosis, which was increased in venom-injected rats. Overall, these results suggest that melatonin mitigates oxidative/nitrosative stress in venom-induced cardio-hepato-renal injury in rats. Our results suggest that melatonin treatment may ameliorate some of the effects of N. haje envenomation., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The aim of this study was to investigate whether different phases of training affect oxidative stress and antioxidant defences in professional cyclists. Ten professional cyclists, aged 21.8 ± 2.5 years, were enrolled in the study. They were classified into two groups of five athletes each one with similar nutritional intake excepting for the overload of vitamin C (1000 mg day(-1)) and E (400 mg day(-1)) supplementation in one of them. The cyclists of both groups performed the same exercise design, consisting of hard, tapering and recovery training periods. Total antioxidant capacity (TAC) of the diet, plasma oxygen radical absorption capacity (ORAC), lipid peroxidation (LPO), DNA damage (8-OHdG) and erythrocyte glutathione disulfide/glutathione ratio (GSSG:GSH(-1)) were measured. During the intense exercise trainings, the cyclists without vitamin supplements had the TAC of diet significantly lower than the supplemented group. Plasma ORAC, LPO and 8-OHdG were similar in both groups of athletes. Athletes with supplements had a basal LPO:ORAC(-1) ratio lower than that without supplements, but this ratio converged to the same level at the end of the training in both groups of cyclists. Both groups of cyclists showed similar changes in GSSG:GSH(-1) ratio and in GSSG and GSH levels along the study. The data suggest that well-trained athletes with suitable ultra-endurance training volume and intensity do not require antioxidant vitamin supplements to adapt their endogenous antioxidant defenses to exercise-induced ROS.

The present research was designed to evaluate the adaptive responses to oxidative stress and inflammation in handball players subjected to well-controlled training intervals over one-year of competition. Seven blood samples were collected over the season of the study, approximately one a month. Plasma lipid peroxidation, nitrite, cytokines (IL-1β, IL-6, INFγ and TNFα), and the glutathione cycle in erythrocytes, were measured. Exercise intensity, measured with the Borg's scale, increased significantly up to the middle of the competition season, coinciding with maximal creatine kinase and lactate dehydrogenase values, and then decreased at the end of the study. The inflammatory markers including nitrite, IL-1β, IL-6, and, to a lesser extent INFγ, increased early in the training season, and remained elevated until the end of the study. TNFα, however, remained low during the season. The oxidative stress response included a transient increase of the glutathione disulphide/glutathione ratio and glutathione reductase activity at the beginning of the study, returning to basal values somewhat later. Glutathione peroxidase also increased at the end of the training season, and lipid peroxidation levels remained low during the athletic season. These results suggest that well-trained athletes were best adapted to the oxidative response, although the beneficial effects of some of the inflammatory cytokines on skeletal muscle myogenesis and repair cannot be ruled out.

We assessed whether melatonin administration would prevent the hyperoxidative status that occurs in lung mitochondria with age. Mitochondria from lungs of male and female senescent prone mice at 5 and 10 months of age were studied. Age-dependent mitochondrial oxidative stress was evaluated by measuring the levels of lipid peroxidation and nitrite, glutathione/glutathione disulfide ratio, and glutathione peroxidase and reductase activities. Mitochondrial respiratory chain and oxidative phosphorylation capability were also measured. Age induces a significant oxidative/nitrosative status in lung mitochondria, which exhibited a significantly reduced activity of the respiratory chain and ATP production. These manifestations of age were more pronounced in males than in females. After 9 months of melatonin administration in the drinking water, the hyperoxidative status and functional deficiency of aged lung mitochondria were totally counteracted, and had increased ATP production. The beneficial effects of melatonin were generally similar in both mice genders. Thus, melatonin administration, as a single therapy, maintained fully functioning lung mitochondria during aging, a finding with important consequences in the pathophysiology of lung aging. In view of these data melatonin, the production of which decreases with age, should be considered a preventive therapy against the hyperoxidative status of the aged lungs, and its use may lead to the avoidance of respiratory complications in the elderly.

Objectives: To analyze whether the antioxidant melatonin could reduce the hyperoxidative status in the blood of patients with Duchenne's muscular dystrophy., Design and Methods: Ten patients aged 12.8±0.9 years were treated with melatonin (60mg at 21:00h plus 10mg at 09:00h) for 9 months, and erythrocyte markers of oxidative stress were determined at 3, 6, and 9 months of treatment. Healthy age- and sex-matched subjects served as controls., Results: Prior to treatment, the patients had higher glutathione disulfide/glutathione ratio and higher glutathione transferase and superoxide dismutase activities, and lower glutathione reductase activity than controls. After 3 months of melatonin treatment, the hyperoxidative status of these patients was counteracted, being reduced to the normal redox state between 3 and 9 months., Conclusion: These results, together with the reduction in the inflammatory process and in muscle injury recently reported in the same patients, support the efficacy of melatonin therapy in DMD patients., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objective: To correlate the clinical and hematological features of β-globin gene haplotypes with the oxidative stress status in pediatric patients with sickle cell disease (SCD)., Methods: A total of 95 patients with SCD and 40 healthy children were studied. The β-globin cluster, plasma lipid peroxidation (LPO) and plasma nitrite plus nitrate (NOx), and erythrocyte content of glutathione (GSH) and glutathione disulfide (GSSG), and glutathione peroxidase (GPx), reductase (GRd), and superoxide dismutase (SOD) activities were measured., Results: Plasma LPO (P < 0.001) and NOx (P < 0.05) were significantly higher in patients than in controls. In erythrocytes of patients with SCD, the activities of GRd (P < 0.001) and SOD (P < 0.05) were lower, and the GSSG/GSH ratio (P < 0.001) and GPx activity (P < 0.001) were higher than in controls. High LPO levels and low SOD plus GRd activities were associated with increased severity of clinical manifestations, which correspond mainly to patients with Bantu and Benin haplotypes. LPO levels were reduced in patients with high fetal hemoglobin (HbF) levels, whereas the NOx levels and GRd activity tended to increase in this group., Conclusion: Our results detected an important oxidative stress in patients with SCD and suggest that at least three redox markers, i.e., LPO, GRd, and SOD, were related with their clinical outcomes. Moreover, a relationship between high HbF and low LPO, and high HbF and high GRd activity and NOx levels were found., (© 2010 John Wiley & Sons A/S.)

Duchenne muscular dystrophy (DMD), a lethal disorder characterized by dystrophin absence, courses with chronic inflammation, sarcolemmal damage, and skeletal muscle degeneration. Among the multiple pathogenic mechanisms proposed for DMD, oxidative stress and inflammation are directly involved in the dystrophic process. Unfortunately, there is no current treatment for DMD, and the inflammatory process is an important target for therapies. Based on the antioxidant and anti-inflammatory properties of melatonin, we investigated whether melatonin treatment may reduce the dystrophic process. Ten DMD patients aged 12.8 +/- 0.98 yr, were treated with melatonin (60 mg at 21:00 hr plus 10 mg at 09:00 hr), and plasma levels of lipid peroxidation (LPO), nitrites (NO(x)), interleukin (IL)-1beta, IL-2, IL-6, tumor necrosis factor-alpha, interferon-gamma, and plasma markers of muscle injury, were determined at 3, 6 and 9 months of treatment. Healthy age- and sex-matched subjects were used as controls. The results show a significant increase in LPO, NO(x), and cytokine levels in plasma of DMD patients compared with controls. Melatonin administration reduced these values to control levels at 3 months of treatment, decreasing further 9 months later. In parallel, melatonin also reduced plasma levels of creatine kinase (CK; 50%), lactate dehydrogenase (28%), aspartate aminotransferase (28%), alanine aminotransferase (20%), and myoglobin (13%). These findings strongly support the conclusion that melatonin administration significantly reduced the hyperoxidative and inflammatory process in DMD patients, reducing the muscle degenerative process.

Background: The antioxidant and anti-inflammatory hormone melatonin is secreted by saliva into the oral cavity, where it may protect the mucosal and gingival tissues from radical damage. To date, no studies have addressed the potential beneficial role of melatonin in the acute inflammatory response that follows oral surgical interventions, especially tooth extractions. The aim of this study was to determine whether tooth extraction induces changes in plasma oxidative stress levels, and whether melatonin treatment may counteract these changes., Methods: Maxillary and mandibular premolars and molars of 16 adult Beagle dogs were extracted under general anesthesia. Eight dogs were treated with 2 mg melatonin placed into the alveolar sockets, whereas the other eight dogs received only vehicle. Lipid peroxidation (LPO) and nitrite plus nitrate (NOx) levels were determined in plasma, whereas glutathione (GSH) and glutathione disulfide (GSSG) levels and glutathione peroxidase (GPx) and reductase (GRd) activities were measured in red blood cells before and 24 hours after tooth extraction., Results: Removal of the premolars and molars caused a significant rise in plasma LPO and NOx levels and in the erythrocyte GSSG/GSH ratio, whereas melatonin treatment restored the normal values of these parameters. Also, melatonin slightly increased erythrocyte GRd activity without changing GPx activity., Conclusion: For the first time to our knowledge, the results show that during the immediate postoperative period following tooth extraction, there is a significant increase of oxidative stress, which is counteracted by the administration of melatonin into the alveolar sockets.

Background: Oxidative stress constitutes the basis for many diseases and it may account for the severity of systemic and oral disease complications. The aim of this study was to assess whether saliva may be used to detect the body's oxidative stress level., Methods: Oxidative stress was determined in saliva from 14 diabetic patients and 10 heroin addicts; two different pathologic conditions related to free radical damage, and 21 healthy control subjects were included in the study. Glutathione peroxidase (GPx) and reductase (GRd) activities, and glutathione (GSH) and glutathione disulfide (GSSG) levels were analyzed in the saliva of all individuals. Other variables including salivary volume and the oral status were also analyzed., Results: Diabetic patients had GPx and GRd activities of 39.98 +/- 1.61 and 6.19 +/- 0.61 nmol/min/mg prot, respectively. These values were significantly higher (P < 0.001) than those obtained in control saliva (27.51 +/- 0.86 and 3.44 +/- 0.25 nmol/min/mg prot, respectively). Drug addicts showed significantly (P < 0.001) lower salivary GPx and GRd activities than controls. Both group of patients had significantly lower levels of GSH and higher of GSSG than controls (P < 0.001)., Conclusions: Changes in the antioxidant enzymes and glutathione levels in saliva from two different pathologic situations as those here studied suggest that this biologic fluid may be suitable for determining the prognosis and evolution of these diseases and its oral manifestations.

Objective(s): To study the changes in macrophage inducible nitric oxide synthase (iNOS) activity, plasma levels of nitrite, lipid peroxidation (LPO) and melatonin in human essential hypertension before and 6 months after 4 mg/day lacidipine treatment., Design: The study was carried out in a total of 25 subjects--11 healthy subjects and 14 hypertensive patients. Blood pressure and peripheral blood samples were taken before and after 6 months of lacidipine treatment (4 mg/day)., Methods: Systolic (SBP) and diastolic blood pressure (DBP), renal function, lipid and carbohydrate metabolism, renin, aldosterone and catecholamine levels were measured by routine methods. The activity of macrophage iNOS and plasma nitrite, LPO and melatonin levels were also measured., Conclusions: Besides reducing blood pressure, lacidipine treatment significantly decreased plasma LPO and macrophage iNOS activity, without changes in NO. Melatonin significantly increases in hypertensive patients, returning to control after lacidipine. Thus, lacidipine reduced blood pressure and free radicals, avoiding the oxidative damage to endothelium. It is suggested that administration of lacidipine plus melatonin may enhance the beneficial effects of each drug in essential hypertension.

Etiological factors involved in myelodysplastic syndrome (MDS) include immunologic, oxidative stress and inflammatory factors, among others, and these are targets for microRNAs (miRNs). Here, we evaluated whether some miRNs may affect tumor development comparing untreated and 5-azacitidine (5-AZA) MDS-treated patients. Peripheral blood samples were collected from 20 controls and 24 MDS patients, and selected miRNs related to redox balance and inflammation (inflamma-miRs), including miR-18a, miR-21, miR-34a and miR-146a, were isolated and measured by quantitative real-time polymerase chain reaction (qRTPCR). A differential expression profile of miRNs was detected in untreated MDS patients and the 5-AZA group. Inflammation increases miRNs and, specifically, miR-18a, miR-21 and miR-34a were significantly overexpressed in untreated MDS, compared to controls. However, we did not observe any miRN profile alteration during the progression of the disease. On the other hand, 5-AZA treatment tends to restore miRN expression levels. Relating to prognostic risk factors, high-risk MDS groups (high Revised International Prognostic Scoring System (IPSS-R), high cytogenetic risk, high molecular risk (HMR) mutations) tended to be related with higher expression levels of miR-18a and miR-34a. Higher miRN expression is correlated with lower glutathione peroxidase activity, while they are related with a higher profile of pro-inflammatory cytokines (IL-2, IL-6, IL-8, TNF-α). Although our study was limited by the low number of MDS patients included, we identified miRN deregulation involved in MDS development that could regulate redox sensors and inflammatory responses. Finally, 5-AZA treatment is related with lower miRN expression levels in MDS patients. [ABSTRACT FROM AUTHOR]

Although ADHD is one of the most prevalent diseases during childhood, we still do not know its precise origin; oxidative/nitrosative stress and the hypothalamic–pituitary–adrenal axis are suggested contributors. Methylphenidate, among others, is the main drug used in ADHD patients, but its effects on relevant markers and structures remain unclear. This study, involving 59 patients diagnosed with ADHD according to DSM-5 criteria, aimed to assess changes in cortisol levels (using cortisol awakening response, CAR) and oxidative/nitrosative status with the treatment. Blood samples before and 3 months after treatment with methylphenidate were used to measure oxidative and inflammatory markers, as well as the endogenous antioxidant activity, while saliva samples tracked cortisol awakening response (CAR). The results showed a treatment-related improvement in the redox profile, with the reduction in advanced oxidation protein products (AOPP), lipid peroxidation (LPO), and nitrite plus nitrate (NOx) levels, and the increase in the enzymatic activities of glutathione reductase (GRd) and catalase (CAT). Moreover, the area under the curve (AUC) of CAR increased significantly, indicating increased reactivity of the HPA axis. These results support, for the first time, the involvement of the endogenous antioxidant system in the pathophysiology of ADHD. [ABSTRACT FROM AUTHOR]

Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risk of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like inflammation, oxidative stress, reduced mitochondrial capacity, and cell apoptosis contribute to this decline. Disruption of the circadian system with age may initiate these pathways in skeletal muscle, preceding the onset of sarcopenia. At present, there is no pharmacological treatment for sarcopenia, only resistance exercise and proper nutrition may delay its onset. Melatonin, derived from tryptophan, emerges as an exceptional candidate for treating sarcopenia due to its chronobiotic, antioxidant, and anti-inflammatory properties. Its impact on mitochondria and organelle, where it is synthesized and crucial in aging skeletal muscle, further highlights its potential. In this review, we discuss the influence of clock genes in muscular aging, with special reference to peripheral clock genes in the skeletal muscle, as well as their relationship with melatonin, which is proposed as a potential therapy against sarcopenia. [ABSTRACT FROM AUTHOR]

A common denominator of metabolic diseases, including type 2 diabetes Mellitus, dyslipidemia, and atherosclerosis, are elevated oxidative stress and chronic inflammation. These complex, multi-factorial diseases are caused by the detrimental interaction between the individual genetic background and multiple environmental stimuli. The cells, including the endothelial ones, acquire a preactivated phenotype and metabolic memory, exhibiting increased oxidative stress, inflammatory gene expression, endothelial vascular activation, and prothrombotic events, leading to vascular complications. There are different pathways involved in the pathogenesis of metabolic diseases, and increased knowledge suggests a role of the activation of the NF-kB pathway and NLRP3 inflammasome as key mediators of metabolic inflammation. Epigenetic-wide associated studies provide new insight into the role of microRNAs in the phenomenon of metabolic memory and the development consequences of vessel damage. In this review, we will focus on the microRNAs related to the control of anti-oxidative enzymes, as well as microRNAs related to the control of mitochondrial functions and inflammation. The objective is the search for new therapeutic targets to improve the functioning of mitochondria and reduce oxidative stress and inflammation, despite the acquired metabolic memory. [ABSTRACT FROM AUTHOR]

To determine whether IV melatonin therapy improves redox status and inflammatory responses in surgical patients with severe sepsis, a unicenter, phase II double‐blind, randomized, placebo‐controlled trial was carried out. The study included patients with severe sepsis marked by infectious systemic inflammatory response syndrome (SIRS), associated with organ dysfunction, hypoperfusion or hypotension requiring surgical intervention. IV melatonin at a daily dose of 60 mg, which was dissolved in 500 ml of 5% dextrose serum, was continuously administered to the patients for over 30 min starting on the day of the diagnoses during a 5‐day period. A total of 14 patients received a placebo treatment and 15 melatonin doses. Redox status decreased in melatonin‐treated patients during the 5 days of treatment as compared to the placebo‐treated patients. Procalcitonin performed better in the melatonin group, whose neutrophil to lymphocyte ratio was also significantly reduced, resulting in an improved evolution of the disease. Moreover, hospital stays decreased by 19.60% from 26.64 days for the placebo group to 21.42 days for the melatonin group. The placebo group recorded five mortalities, as compared to three for the melatonin group. IV melatonin administration improved the course of the disease in surgical patients with severe sepsis, with no side effects. Additional studies with higher doses of melatonin and a long duration of therapy need to be carried out to assess its clinical use. [ABSTRACT FROM AUTHOR]

Neural stem cells ( NSCs) are regarded as a promising therapeutic approach to protecting and restoring damaged neurons in neurodegenerative diseases ( NDs) such as Parkinson's disease and Alzheimer's disease ( PD and AD, respectively). However, new research suggests that NSC differentiation is required to make this strategy effective. Several studies have demonstrated that melatonin increases mature neuronal markers, which reflects NSC differentiation into neurons. Nevertheless, the possible involvement of mitochondria in the effects of melatonin during NSC differentiation has not yet been fully established. We therefore tested the impact of melatonin on NSC proliferation and differentiation in an attempt to determine whether these actions depend on modulating mitochondrial activity. We measured proliferation and differentiation markers, mitochondrial structural and functional parameters as well as oxidative stress indicators and also evaluated cell transplant engraftment. This enabled us to show that melatonin (25 μM) induces NSC differentiation into oligodendrocytes and neurons. These effects depend on increased mitochondrial mass/ DNA/complexes, mitochondrial respiration, and membrane potential as well as ATP synthesis in NSCs. It is also interesting to note that melatonin prevented oxidative stress caused by high levels of mitochondrial activity. Finally, we found that melatonin enriches NSC engraftment in the ND mouse model following transplantation. We concluded that a combined therapy involving transplantation of NSCs pretreated with pharmacological doses of melatonin could efficiently restore neuronal cell populations in PD and AD mouse models depending on mitochondrial activity promotion. [ABSTRACT FROM AUTHOR]

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Introduction There is increasing interest in evaluating the potential health risks and biologic effects of exposure to extremely low-frequency magnetic fields (ELF-MF) and electromagnetic radiation (EMR), like those associated with personal computers, cellular phones, and environmental radiation ( e.g ., cellular towers, high-voltage power lines, radar). ELF-MF may generate free radicals in biological organisms, which leads to hyperoxidative status. Here, we investigated the potential efficacy of protective devices constructed with nonmetallic and metallic nanoparticles, which are conductors and semiconductors of electromagnetic energy. Methods In a before and after study, 20 healthy subjects who regularly used cellular phones and were exposed to typical environmental EMF were given one of three different (ELF-MF) protective devices. Blood samples were drawn at baseline and one month after using the devices to examine redox and inflammatory status. Results We found that, 30 days after using the devices, plasma levels of lipid peroxidation, nitrites, and interferon-γ decreased significantly. Furthermore, the disulfide glutathione/glutathione ratio decreased, which indicated reduced intracellular oxidative damage. These data suggested that continuous use of devices that contain nonmetallic and metallic nanoparticles could protect healthy subjects from EMF-induced oxidative/inflammatory damage. Conclusion Thus, for the first time, we have shown that the devices tested could be useful in counteracting the deleterious effects of EMF pollution by neutralizing harmful radiation before it reaches the body. [ABSTRACT FROM AUTHOR]

We determined the NF-ΚB- and NOD-like receptor (NLR)P3-dependent molecular mechanisms involved in sepsis and evaluated the role of retinoid-related orphan receptor (ROR)-α in melatonin's anti-inflammatory actions. Western blot, RT-PCR, ELISA, and spectrophotometric analysis revealed that NF-ΚB and NLRP3 closely interact, leading to proinflammatory and pro-oxidant status in heart tissue of septic C57BL/6J mice. Moreover, mitochondrial oxygen consumption was reduced by 80% in septic mice. In vivo and in vitro analysis showed that melatonin administration blunts NF-ΚB transcriptional activity through a sirtuin1-dependent NF-ΚB deacetylation in septic mice. Melatonin also decreased NF-ΚB-dependent proinflammatory response and restored redox balance and mitochondrial homeostasis, thus inhibiting the NLRP3 inflammasome. In an important finding, the inhibition of NF-ΚB by melatonin, but not that of NLRP3, was blunted in RORαsg/sg mice, indicating that functional RORα transcription factor is necessary for the initiation of the innate immune response against inflammation. Our results are evidence of the NF-ΚB/NLRP3 connection during sepsis and identify NLRP3 as a novel molecular target for melatonin. The multiple molecular targets of melatonin in this study explain its potent anti-inflammatory efficacy against systemic innate immune activation and herald a promising therapeutic application for melatonin in the treatment of sepsis. [ABSTRACT FROM AUTHOR]

Mucositis is a common and distressing side effect of chemotherapy or radiotherapy that has potentially severe consequences, and no treatment is available. The purpose of this study was to analyze the molecular pathways involved in the development of oral mucositis and to evaluate whether melatonin can prevent this pathology. The tongue of male Wistar rats was subjected to irradiation ( X-ray YXLON Y.Tu 320-D03 irradiator; the animals received a dose of 7.5 Gy/day for 5 days). Rats were treated with 45 mg/day melatonin or vehicle for 21 days postirradiation, either by local application into their mouths (melatonin gel) or by subcutaneous injection. A connection between reactive oxygen species, generating mitochondria and the NLRP3 ( NLR-related protein 3 nucleotide-binding domain leucine-rich repeat containing receptor-related protein 3) inflammasome, has been reported in mucositis. Here, we show that mitochondrial oxidative stress, bioenergetic impairment and subsequent NLRP3 inflammasome activation are involved in the development of oral mucositis after irradiation and that melatonin synthesized in the rat tongue is depleted after irradiation. The application of melatonin gel restores physiological melatonin levels in the tongue and prevents mucosal disruption and ulcer formation. Melatonin gel protects the mitochondria from radiation damage and blunts the NF- κB/ NLRP3 inflammasome signaling activation in the tongue. Our results suggest new molecular pathways involved in radiotherapy-induced mucositis that are inhibited by topical melatonin application, suggesting a potential preventive therapy for mucositis in patients with cancer. [ABSTRACT FROM AUTHOR]

While it is accepted that the high production of nitric oxide ( NO˙) by the inducible nitric oxide synthase ( iNOS) impairs cardiac mitochondrial function during sepsis, the role of neuronal nitric oxide synthase ( nNOS) may be protective. During sepsis, there is a significantly increase in the expression and activity of mitochondrial iNOS (i-mt NOS), which parallels the changes in cytosolic iNOS. The existence of a constitutive NOS form (c-mt NOS) in heart mitochondria has been also described, but its role in the heart failure during sepsis remains unclear. Herein, we analyzed the changes in mitochondrial oxidative stress and bioenergetics in wild-type and nNOS-deficient mice during sepsis, and the role of melatonin, a known antioxidant, in these changes. Sepsis was induced by cecal ligation and puncture, and heart mitochondria were analyzed for NOS expression and activity, nitrites, lipid peroxidation, glutathione and glutathione redox enzymes, oxidized proteins, and respiratory chain activity in vehicle- and melatonin-treated mice. Our data show that sepsis produced a similar induction of iNOS/i-mt NOS and comparable inhibition of the respiratory chain activity in wild-type and in nNOS-deficient mice. Sepsis also increased mitochondrial oxidative/nitrosative stress to a similar extent in both mice strains. Melatonin administration inhibited iNOS/i-mt NOS induction, restored mitochondrial homeostasis in septic mice, and preserved the activity of nNOS/c-mt NOS. The effects of melatonin were unrelated to the presence or the absence of nNOS. Our observations show a lack of effect of nNOS on heart bioenergetic impairment during sepsis and further support the beneficial actions of melatonin in sepsis. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction and oxidative/nitrosative stress are common features of senescence, and they explain some of the pathophysiological events during aging. In different animal models of aging, the existence of oxidative stress, inflammation, and mitochondrial dysfunction has been reported. There is no information, however, regarding the age when these symptoms begin and if they account for gender differences in aging. Here we analyzed oxidative/nitrosative stress markers and bioenergetics in the brain mitochondria of normal mice during the first 10 months of life, looking for early signs of senescence. Male and female mice were treated with vehicle or melatonin during the first 9 months of life, starting at weaning. Mice were sacrificed at 5 and 10 months of life, and pure brain mitochondria were prepared and assayed for respiratory chain activity, ATP production, and oxidative/nitrosative stress status. The results showed that the brain mitochondria from male mice have a better glutathione cycle than female mice, whereas female mice have higher electron transport chain activity and ATP production at 5 months old. Five months later, however, oxidative/nitrosative stress markers increased in both male and female mice, thus eliminating the differences between the genders. More importantly, these changes were prevented by chronic melatonin administration, which also restored the gender differences found in 5-month-old mice. Thus, melatonin administration as a single therapy can maintain the full function of the brain mitochondria during the early events of aging, a finding that has important consequences in the pathophysiology of brain senescence. [ABSTRACT FROM AUTHOR]

The aim of this review is to update the reader as to the association between physical exercise and melatonin, and to clarify how the melatonin rhythm may be affected by different types of exercise. Exercise may act as a zeitgeber, although the effects of exercise on the human circadian system are only now being explored. Depending on the time of the day, on the intensity of light, and on the proximity of the exercise to the onset or decline of the circadian production of melatonin, the consequence of exercise on the melatonin rhythm varies. Moreover, especially strenuous exercise per se induces an increased oxidative stress that in turn may affect melatonin levels in the peripheral circulation because indole is rapidly used to combat free radical damage. On the other hand, melatonin also may influence physical performance, and thus, there are mutually interactions between exercise and melatonin production which may be beneficial. [ABSTRACT FROM AUTHOR]

The effect of a chronic combined treatment with growth hormone (GH) plus melatonin (Mel) on different age-related processes in cytosolic and nuclear fractions of hearts from SAMP8 mice (2 and 10 months) has been investigated. The parameters studied have been messenger RNA expressions of IL-1, IL-10, NFkBp50, NFkBp52, TNFα, eNOS, iNOS, HO-1, HO-2, BAD, BAX, and Bcl2 and protein expressions of iNOS, eNOS, TNFα, IL-1, IL-10, NFkBp50, NFKbp52, and caspase activity (3 and 9). Our results supported the existence of a proapoptotic and oxidative status together with inflammatory processes in the heart of old mice, with increases of inflammatory cytokines, caspase activity, HO-1, BAX, NFkBp50, and NFkBp52 and decreases of eNOS and Bcl2. Also, we were able to observe the translocation of NFkB to nuclei. The combined treatment was able to partially reduce the incidence of these deleterious changes, showing differences with the separated treatments with GH and Mel as were investigated in previous articles from our group. [ABSTRACT FROM PUBLISHER]

Cycling competitions represent an important physical overload even for well-trained individuals. In six professional cyclists, we studied the adaptive oxidative and anti-inflammatory response to a 4-day road cycling competition and its relationship with melatonin, an antioxidant and anti-inflammatory stress hormone. Blood and urine samples were collected before and after the competition. Plasma lipid peroxidation, cytokines (interleukin-1β, interleukin-6, and tumour necrosis factor-α), creatine kinase and other metabolic markers, melatonin, erythrocyte glutathione, and glutathione peroxidase and reductase activities were measured. Urinary excretion of 6-sulphatoxymelatonin was analysed. Lipid peroxidation increased after the competition, but the erythrocyte glutathione pool remained unchanged. Changes in both glutathione peroxidase and reductase activities probably account for the recycling of glutathione after exercise. Interleukin-6 (216%) and tumour necrosis factor-α (159%) but not interleukin-1β increased after exercise. A parallel increase in plasma melatonin concentrations was detected, whereas metabolic markers, including creatine kinase, showed minor modifications. Thus, professional cyclists display an adaptative response to the physical overloads in the competitions for which they are trained. Consequently, they seem to be able to regulate efficiently the intracellular oxidative stress, and prevent an exaggerated pro-inflammatory cytokines induction. A modulator role of melatonin in these adaptive responses is also supported. [ABSTRACT FROM AUTHOR]

We tested whether chronic melatonin administration in the drinking water would reduce the brain mitochondrial impairment that accompanies aging. Brain mitochondria from male and female senescent prone (SAMP8) mice at 5 and 10 months of age were studied. Mitochondrial oxidative stress was determined by measuring the levels of lipid peroxidation and nitrite, glutathione/glutathione disulfide ratio, and glutathione peroxidase and glutathione reductase activities. Electron transport chain activity and oxidative phosphorylation capability of mitochondria were also determined by measuring the activity of the respiratory chain complexes and the ATP content. The results support a significant age-dependent mitochondrial dysfunction with a diminished efficiency of the electron transport chain and reduced ATP production, accompanied by an increased oxidative/nitrosative stress. Melatonin administration between 1 and 10 months of age completely prevented the mitochondrial impairment, maintaining or even increasing ATP production. There were no major age-dependent differences between males in females, although female mice seemed to be somewhat more sensitive to melatonin treatment than males. Thus, melatonin administration as a single therapy maintained fully functioning brain mitochondria during aging, a finding with important consequences in the pathophysiology of brain aging. [ABSTRACT FROM AUTHOR]

Abstract: We investigated whether chronic melatonin administration influences mitochondrial oxidative stress and life span in mice. Diaphragmatic mitochondria from female senescent prone (SAMP8) and senescent resistant (SAMR1) mice at 5 and 10 months of age were studied. Mitochondrial oxidative stress was determined by measuring the levels of lipid peroxidation, glutathione and glutathione disulfide, and glutathione peroxidase and reductase activities. Mitochondrial function was assessed by measuring the activity of the respiratory chain complexes and the ATP content. The results suggest that the age-dependent mitochondrial oxidative damage in the diaphragm of SAMP8 mice was accompanied by a reduction in the electron transport chain complex activities and in ATP levels. Furthermore, melatonin administration between 1 and 10 months of age normalized the redox and the bioenergetic status of the mitochondria and increased the ATP levels. Melatonin also increased both half-life and longevity, mainly in SAMP8 group. These results suggest an age-related increase in mitochondria vulnerability to oxidation in SAM mice at 10 months of age that was counteracted by melatonin therapy. The effects of melatonin on mitochondrial physiology probably underline the ability of the indoleamine to increase maximal life span in these animals. [Copyright &y& Elsevier]

The antiproliferative and proapoptotic properties of melatonin in human colon cancer cells in culture were recently reported. To address the mechanisms involved in these actions, HT-29 human colon cancer cells were cultured in RPMI 1640 medium supplemented with fetal bovine serum at 37°C. Cell proliferation was assessed by the incorporation of [3H]-thymidine into DNA. Cyclic nucleotide levels, nitrite concentration, glutathione peroxidase and reductase activities, and glutathione levels were assessed after the incubation of these cells with the following drugs: melatonin membrane receptor agonists 2-iodo-melatonin, 2-iodo- N-butanoyl-5-methoxytryptamine, 5-methoxycarbonylamino- N-acetyltryptamine (GR-135,531), and the antagonists luzindole, 4-phenyl-2-propionamidotetralin, and prazosin; the melatonin nuclear receptor agonist CGP 52608, and four synthetic kynurenines analogs to melatonin 2-acetamide-4-(3-methoxyphenyl)-4-oxobutyric acid, 2-acetamide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid, 2-butyramide-4-(3-methoxyphenyl)-4-oxobutyric acid and 2-butyramide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid. The results show that the membrane receptors are not necessary for the antiproliferative effect of melatonin and the participation of the nuclear receptor in this effect is suggested. Moreover, the antioxidative and anti-inflammatory actions of melatonin, counteracting the oxidative status and reducing the production of nitric oxide by cultured HT-29 cells seem to be directly involved in the oncostatic properties of melatonin. Some of the synthetic kynurenines exert higher antiproliferative effects than melatonin. The results reinforce the clinical interest of melatonin due to the different mechanisms involved in its oncostatic role, and suggest a new synthetic pathway to obtain melatonin agonists with clinical applications to oncology. [ABSTRACT FROM AUTHOR]

The existence of an inducible mitochondrial nitric oxide synthase has been recently related to the nitrosative/oxidative damage and mitochondrial dysfunction that occurs during endotoxemia. Melatonin inhibits both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase activities, a finding related to the antiseptic properties of the indoleamine. Hence, we examined the changes in inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase expression and activity, bioenergetics and oxidative stress in heart mitochondria following cecal ligation and puncture-induced sepsis in wild-type (iNOS+/+) and inducible nitric oxide synthase-deficient (iNOS–/–) mice. We also evaluated whether melatonin reduces the expression of inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase, and whether this inhibition improves mitochondrial function in this experimental paradigm. The results show that cecal ligation and puncture induced an increase of inducible mitochondrial nitric oxide synthase in iNOS+/+ mice that was accompanied by oxidative stress, respiratory chain impairment, and reduced ATP production, although the ATPase activity remained unchanged. Real-time PCR analysis showed that induction of inducible nitric oxide synthase during sepsis was related to the increase of inducible mitochondrial nitric oxide synthase activity, as both inducible nitric oxide synthase and inducible mitochondrial nitric oxide synthase were absent in iNOS–/– mice. The induction of inducible mitochondrial nitric oxide synthase was associated with mitochondrial dysfunction, because heart mitochondria from iNOS–/– mice were unaffected during sepsis. Melatonin treatment blunted sepsis-induced inducible nitric oxide synthase/inducible mitochondrial nitric oxide synthase isoforms, prevented the impairment of mitochondrial homeostasis under sepsis, and restored ATP production. These properties of melatonin should be considered in clinical sepsis. [ABSTRACT FROM AUTHOR]

Heart mitochondria from female senescence-accelerated (SAMP8) and senescence-resistant (SAMR1) mice of 5 or 10 months of age, were studied. Mitochondrial oxidative stress was determined by measuring the levels of lipid peroxidation, glutathione and glutathione disulfide and glutathione peroxidase and reductase activities. Mitochondrial function was assessed by measuring the activity of the respiratory chain complexes and ATP content. The results show that the age-dependent mitochondrial oxidative damage in the heart of SAMP8 mice was accompanied by a reduction in the electron transport chain complex activities and in ATP levels. Chronic melatonin administration between 1 and 10 months of age normalized the redox and the bioenergetic status of the mitochondria and increased ATP levels. The results support the presence of significant mitochondrial oxidative stress in SAM mice at 10 months of age, and they suggest a beneficial effect of chronic pharmacological intervention with melatonin, which reduces the deteriorative and functional oxidative changes in cardiac mitochondria with age. [ABSTRACT FROM AUTHOR]

Abstract: Senescence amplifies the sensitivity to endotoxemia, which correlates with increased nitric oxide (NO) levels and mortality. Melatonin displays antioxidant and anti-inflammatory effects, but its levels decrease with age. Lipopolysaccharide (LPS) (10mg/kg) was injected to 3- and 18-month-old rats 6h before they were killed, and melatonin (60mg/kg) was injected before and/or after LPS. Inducible nitric oxide synthase (iNOS) expression and activity, nitrite content, lipoperoxidation (LPO) levels, and serum markers of liver, renal, and metabolic dysfunction, were measured in liver and lung of these animals. An age-dependent increase in iNOS activity, NO content, and LPO levels was observed, and these changes were augmented further by LPS. Melatonin decreased the expression and activity of iNOS, reducing NO and LPO levels to basal values in both septic LPS-treated groups. Liver, kidney, and metabolic dysfunctions were also significantly higher in aged that in young rats and further increased by LPS. Melatonin treatment counteracted these alterations in young and aged septic rats. Melatonin reduced LPS-dependent iNOS expression and multiorgan failure in a similar extent in young and aged rats. Because aged rats showed higher organ and metabolic impairment than young animals in response to LPS, the results also suggest an increased efficacy of the anti-septic properties of melatonin in the aged animals. [Copyright &y& Elsevier]

Abstract: Sepsis provokes an induction of inducible nitric oxide synthase (iNOS) and melatonin down-regulates its expression and activity. Looking for an inducible mtNOS isoform, we induced sepsis by cecal ligation and puncture in both normal and iNOS knockout mice and studied the changes in mtNOS activity. We also studied the effects of mtNOS induction in mitochondrial function, and the role of melatonin against induced mtNOS and mitochondrial dysfunction. The activity of mtNOS and nitrite levels significantly increased after sepsis in iNOS+/+ mice. These animals showed a significant inhibition of the respiratory chain activity and an increase in mitochondrial oxidative stress, reflected in the disulfide/glutathione ratio, glutathione redox cycling enzymes activity and lipid peroxidation levels. Interestingly, mtNOS activity remained unchanged in iNOS−/− septic mice, and mitochondria of these animals were unaffected by sepsis. Melatonin administration to iNOS+/+ mice counteracted mtNOS induction and respiratory chain failure, restoring the redox status. The results support the existence of an inducible mtNOS that is likely coded by the same gene as iNOS. The results also suggest that sepsis-induced mtNOS is responsible for the increase of mitochondrial impairment due to oxidative stress in sepsis, perhaps due to the high production of NOin treatment prevents mitochondrial failure at the same extend as the lack of iNOS gene. [Copyright &y& Elsevier]

Mitochondrial nitric oxide synthase (mtNOS) produces nitric oxide (NO) to modulate mitochondrial respiration. Besides a constitutive mtNOS isoform it was recently suggested that mitochondria express an inducible isoform of the enzyme during sepsis. Thus, the mitochondrial respiratory inhibition and energy failure underlying skeletal muscle contractility failure observed in sepsis may reflect the high levels of NO produced by inducible mtNOS. The fact that mtNOS is induced during sepsis suggests its relation to inducible nitric oxide synthase (iNOS). Thus, we examined the changes in mtNOS activity and mitochondrial function in skeletal muscle of wild-type (iNOS+/+) and iNOS knockout (iNOS−/−) mice after sepsis. We also studied the effects of melatonin administration on mitochondrial damage in this experimental paradigm. After sepsis, iNOS+/+ but no iNOS−/− mice showed an increase in mtNOS activity and NO production and a reduction in electron transport chain activity. These changes were accompanied by a pronounced oxidative stress reflected in changes in lipid peroxidation levels, oxidized glutathione/reduced glutathione ratio, and glutathione peroxidase and reductase activities. Melatonin treatment counteracted both the changes in mtNOS activity and rises in oxidative stress; the indole also restored mitochondrial respiratory chain in septic iNOS+/+ mice. Mitochondria from iNOS−/− mice were unaffected by either sepsis or melatonin treatment. The data suggest that inducible mtNOS, which is coded by the same gene as that for iNOS, is responsible for mitochondrial dysfunction during sepsis. The results also suggest the use of melatonin for the protection against mtNOS-mediated mitochondrial failure. [ABSTRACT FROM AUTHOR]

Previous studies showed a synergistic effect of melatonin and deprenyl against dopamine (DA) autoxidation in vitro. Since oxidative stress is implicated in Parkinson’s disease (PD), we explored the effects of melatonin plus deprenyl administration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in C57/Bl6 mice. Melatonin, but not deprenyl prevents the inhibition of mitochondrial complex I and the oxidative damage in nigrostriatal neurons induced by MPTP. With the dose used deprenyl recovers 50% DA levels and tyrosine hydroxylase activity depressed by the neurotoxin, normalizing locomotor activity of mice. Melatonin, which was unable to counteract MPTP-induced DA depletion and inhibition of tyrosine hydroxylase activity, potentiates the effect of deprenyl on catecholamine turnover and mice ambulatory activity. These results suggest a dissociation of complex I inhibition from DA depletion in this model of Parkinson’s disease. The data also support that a combination of melatonin, which improves mitochondrial electron transport chain and reduces oxidative damage, and deprenyl, which promotes the specific function of the rescued neurons, i.e. DA turnover, may be a promising strategy for the treatment of PD. [Copyright &y& Elsevier]

When exposed to hostile environments such as radiation, physical injuries, chemicals, pollution, and microorganisms, the skin requires protective chemical molecules and pathways. Melatonin, a highly conserved ancient molecule, plays a crucial role in the maintenance of skin. As human skin has functional melatonin receptors and also acts as a complete system that is capable of producing and regulating melatonin synthesis, melatonin is a promising candidate for its maintenance and protection. Below, we review the studies of new metabolic pathways involved in the protective functions of melatonin in dermal cells. We also discuss the advantages of the topical use of melatonin for therapeutic purposes and skin protection. In our view, endogenous intracutaneous melatonin production, together with topically-applied exogenous melatonin and its metabolites, represent two of the most potent defense systems against external damage to the skin. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma present a high mortality rate. Melatonin has been shown to have oncostatic effects in different types of cancers. However, inconsistent results have been reported for in vivo applications. Consequently, an alternative administration route is needed to improve bioavailability and establish the optimal dosage of melatonin for cancer treatment. On the other hand, the use of patient-derived tumor models has transformed the field of drug research because they reflect the heterogeneity of patient tumor tissues. In the present study, we explore mechanisms for increasing melatonin bioavailability in tumors and investigate its potential as an adjuvant to improve the therapeutic efficacy of cisplatin in the setting of both xenotransplanted cell lines and primary human HNSCC. We analyzed the effect of two different formulations of melatonin administered subcutaneously or intratumorally in Cal-27 and SCC-9 xenografts and in patient-derived xenografts. Melatonin effects on tumor mitochondrial metabolism was also evaluated as well as melatonin actions on tumor cell migration. In contrast to the results obtained with the subcutaneous melatonin, intratumoral injection of melatonin drastically inhibited tumor progression in HNSCC-derived xenografts, as well as in patient-derived xenografts. Interestingly, intratumoral injection of melatonin potentiated CDDP effects, decreasing Cal-27 tumor growth. We demonstrated that melatonin increases ROS production and apoptosis in tumors, targeting mitochondria. Melatonin also reduces migration capacities and metastasis markers. These results illustrate the great clinical potential of intratumoral melatonin treatment and encourage a future clinical trial in cancer patients to establish a proper clinical melatonin treatment. [Display omitted] • High concentrations of melatonin completely abolish tumor growth. • Melatonin synergized the effects of cisplatin. • Intratumoral melatonin also reduces tumor formation in patient-derived models. • Melatonin induces changes in tumor mitochondrial morphology and distribution. [ABSTRACT FROM AUTHOR]

Aging is associated with an increase in oxidative stress and inflammation. The aging lung is particularly affected since it is continuously exposed to environmental oxidants while antioxidant machinery weakens with age. Melatonin, a free radical scavenger, counteracts inflammation and apoptosis in healthy cells from several tissues. Its effects on the aging lung are, however, not yet fully understood. This study aimed to investigate the effect of chronic administration of melatonin on the expression of inflammation markers (TNF-α, IL-1β, NFκB2, HO-1) and apoptosis parameters (BAD, BAX, AIF) in the lung tissue of male senescence-accelerated prone mice (SAMP8). In addition, RNA oxidative damage, as the formation of 8-hydroxyguanosine (8-OHG), was also evaluated. Young and old animals, aged 2 and 10 months respectively, were divided into 4 groups: untreated young, untreated old, old mice treated with 1 mg/kg/day melatonin, and old animals treated with 10 mg/kg/day melatonin. Untreated young and old male senescence accelerated resistant mice (SAMR1) were used as controls. After 30 days of treatment, animals were sacrificed. Lungs were collected and immediately frozen in liquid nitrogen. mRNA and protein expressions were measured by RT-PCR and Western blotting, respectively. Levels of 8-OHG were quantified by ELISA. Mean values were analyzed using ANOVA. Old nontreated SAMP8 animals showed increased (p < 0.05) mRNA and protein levels of TNF-α, IL-1β, NFκB2, and HO-1 compared to young mice and SAMR1 mice. Melatonin treatment with either dose reversed the aging-derived inflammation (p < 0.05). BAD, BAX and AIF expressions also rose with aging, the effect being counteracted with melatonin (p < 0.05). Aging also caused a significant elevation (p < 0.05) in SAMP8 8-OHG values. This increase was not observed in animals treated with melatonin (p < 0.05). In conclusion, melatonin treatment was able to modulate the inflammatory and apoptosis status of the aging lungs, exerting a protective effect on age-induced damage. [ABSTRACT FROM AUTHOR]

Aims Previous data showed that melatonin maintains liver mitochondrial homeostasis during sepsis, but neither the mechanisms underlying mitochondrial dysfunction nor the target of melatonin are known. Main methods Here, we analyzed mitochondrial respiration in isolated mouse liver mitochondria with different substrate combinations (glutamate/malate, glutamate/malate/sucinate or succinate/rotenone) to identify mitochondrial defects and melatonin targets during sepsis. Other bioenergetic parameters including a + a 3 , b , and c + c 1 content, mitochondrial mass, and mitochondrial supercomplexes formation were analyzed. Mitochondrial function was assessed during experimental sepsis induced by cecal ligation and puncture (CLP) in livers of 3 mo. C57BL/6 mice at early and late phases of sepsis, i.e., at 8 and 24 h after sepsis induction. Key findings Septic mice showed mitochondrial injury with a decrease in state 3, respiratory control rate, mitochondrial mass, and cytochrome b and c + c 1 content, which was prevented by melatonin treatment. Mitochondrial dysfunction in sepsis was mainly linked to complex I damage, because complex II was far less impaired. These mitochondria preserved the respiratory supramolecular organization, maintaining their electron transport system capacity. Significance This work strengthens the use of substrate combinations to identify specific respiratory defects and selective melatonin actions in septic mitochondria. Targeting mitochondrial complex I should be a main therapeutical approach in the treatment of sepsis, whereas the use of melatonin should be considered in the therapy of clinical sepsis. [ABSTRACT FROM AUTHOR]

Abstract: Coenzyme Q10 (CoQ10) deficiency (MIM 607426) causes a mitochondrial syndrome with variability in the clinical presentations. Patients with CoQ10 deficiency show inconsistent responses to oral ubiquinone-10 supplementation, with the highest percentage of unsuccessful results in patients with neurological symptoms (encephalopathy, cerebellar ataxia or multisystemic disease). Failure in the ubiquinone-10 treatment may be the result of its poor absorption and bioavailability, which may be improved by using different pharmacological formulations. In a mouse model (Coq9X/X ) of mitochondrial encephalopathy due to CoQ deficiency, we have evaluated oral supplementation with water-soluble formulations of reduced (ubiquinol-10) and oxidized (ubiquinone-10) forms of CoQ10. Our results show that CoQ10 was increased in all tissues after supplementation with ubiquinone-10 or ubiquinol-10, with the tissue levels of CoQ10 with ubiquinol-10 being higher than with ubiquinone-10. Moreover, only ubiquinol-10 was able to increase the levels of CoQ10 in mitochondria from cerebrum of Coq9X/X mice. Consequently, ubiquinol-10 was more efficient than ubiquinone-10 in increasing the animal body weight and CoQ-dependent respiratory chain complex activities, and reducing the vacuolization, astrogliosis and oxidative damage in diencephalon, septum–striatum and, to a lesser extent, in brainstem. These results suggest that water-soluble formulations of ubiquinol-10 may improve the efficacy of CoQ10 therapy in primary and secondary CoQ10 deficiencies, other mitochondrial diseases and neurodegenerative diseases. [Copyright &y& Elsevier]

Abstract: Mitochondrial complex I inhibition is thought to underlie the neurodegenerative process in Parkinson''s disease (PD). Moreover, an overproduction of nitric oxide due to both cytosolic (iNOS) and mitochondrial (i-mtNOS) inducible nitric oxide synthases causes free radicals generation and oxidative/nitrosative stress, contributing to mitochondrial dysfunction and neuronal cell death. Looking for active molecules against mitochondrial dysfunction and inflammatory response in PD, we show here the effects of four synthetic kynurenines in the MPTP model of PD in mice. After MPTP administration, mitochondria from substantia nigra and, in a lesser extent, from striatum showed a significant increase in i-mtNOS activity, nitric oxide production, oxidative stress, and complex I inhibition. The four kynurenines assayed counteracted the effects of MPTP, reducing iNOS/i-mtNOS activity, and restoring the activity of the complex I. Consequently, the cytosolic and mitochondrial oxidative/nitrosative stress returned to control values. The results suggest that the kynurenines here reported represent a family of synthetic compounds with neuroprotective properties against PD, and that they can serve as templates for the design of new drugs able to target the mitochondria. [Copyright &y& Elsevier]

We recently showed that melatonin counteracted mitochondrial oxidative stress and increased the activity of the mitochondrial oxidative phosphorylation (OXPHOS) enzymes both in vivo and in vitro. To further clarify these effects, we studied here the activity of OXPHOS enzymes and the synthesis of ATP in rat liver and brain mitochondria in vitro. In sub-mitochondrial particles, melatonin increases the activity of the complexes I and IV dose-dependently, the effect being significant between 1 and 10 nM. Blue native-PAGE followed by histochemical analysis of the OXPHOS enzymes further showed the melatonin-induced increase of complex I activity. Titration studies show that melatonin counteracts the partial inhibition of complex IV induced by 5 μM potassium cyanide. However, melatonin (up to 5 mM) was unable to recover the activity of complex IV when it was completely blocked by 100 μM cyanide. These data suggest that the indoleamine could stimulate the activity of the non-inhibited part of the complex IV. Melatonin also increases the production of ATP in control mitochondria and counteracts the cyanide-induced inhibition of ATP synthesis. These results provide new hormonal mechanism regulating mitochondrial homeostasis and may explain, at least in part, the anti-aging and neuroprotective properties of melatonin. [Copyright &y& Elsevier]