Antonio Molina-Carballo

Melatonin treatment normalizes plasma pro‐inflammatory cytokines and nitrosative/oxidative stress in patients suffering from Duchenne muscular dystrophy

Abstract:  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 (NOx), interleukin (IL)‐1β, IL‐2, IL‐6, tumor necrosis factor‐α, interferon‐γ, 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, NOx, 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.

Melatonin's role as an anticonvulsant and neuronal protector: Experimental and clinical evidence

The pineal gland classically has been considered as a vestigial and mystic organ. In the last decades, and with the incorporation of new methodologic procedures, it could be proved that it also has physiologic actions that vary depending on the level of the phylogenetic scale. Its best-known secretion, melatonin, has been related to many different actions, such as sleep promotion, control of biologic rhythms, hormonal inhibition, and an inhibiting action on central nervous system regulation mechanisms. In animal experimentation, there are papers even accepting an anticonvulsant effect. In humans, evidence is reduced to few experiences. In addition to this clinical experience, there is other evidence that clearly relates melatonin to convulsive phenomena. This relationship must be mediated by the following mechanisms attributed to melatonin: altered brain GABAergic neurotransmission, its known interaction with benzodiazepinic brain receptors, through tryptophan metabolite activity (kynurenine, kynurenic acid), or even by its efficacy as a free-radical scavenger. (J Child Neurol 1998;13:501-509).

Day-night variations in melatonin secretion by the pineal gland during febrile and epileptic convulsions in children

The pineal gland is a complex neuroendocrine organ with pronounced effects on central nervous system activity. Because previous studies in animals and humans have suggested an anticonvulsant role for the pineal hormone melatonin, we studied the day-night variations in plasma melatonin in normal children and children with febrile or epileptic convulsions. We found significant changes in day-night melatonin levels during convulsions, consistent with the hypothesis that melatonin has an inhibitory function on central nervous system activity.

Melatonin concentration in the umbilical artery and vein in human preterm and term neonates and neonates with acute fetal distress

Abstract: In order to assess the existence of a rhythmic secretion of melatonin (aMT) in newborns and whether this rhythm is affected by neonatal stress, we studied 112 newborns classified in three groups: normal babies delivered at term, preterm infants born before the 38th week, and babies with fetal distress. Melatonin was measured by RIA in the umbilical artery and vein at the time of birth. Melatonin levels in umbilical arterial and venous blood showed a diurnal rhythm in all groups. Melatonin levels in umbilical cord artery and vein were closely related. Nocturnal melatonin levels were increased in newborns with acute fetal distress in comparison with normal term and preterm neonates. These results suggest that (1) a rhythm of aMT secretion exists in newborns, although it cannot be determined whether this rhythm is of maternal or fetal origin and (2) neonatal stress (acute fetal distress) increases aMT production during the night in comparison with normal term and preterm neonates.

Melatonin treatment counteracts the hyperoxidative status in erythrocytes of patients suffering from Duchenne muscular dystrophy.

OBJECTIVES To analyze whether the antioxidant melatonin could reduce the hyperoxidative status in the blood of patients with Duchennes 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.

Melatonin Levels during the First Week of Life and Their Relation with the Antioxidant Response in the Perinatal Period

Aim: Melatonin is a potent free radical scavenger and an indirect antioxidant. Knowledge about the behavior of melatonin secretion in the early neonatal period, which may relate to its properties at a vital stage during very high antioxidant demands, is limited. Patients and Methods: We studied 35 newborns admitted to the Neonatal Unit with respiratory distress syndrome (RDS) and with no signs of sepsis, severe anemia, hemodynamic compromise or malformation. The gestational age of the newborns was 26–40 weeks (mean value 32.5 weeks) and the weight at birth was 870–4,400 g (mean value 1,800 g). They were classified into two groups: ≤1,500 g or >1,500 g birthweight. In all cases, at 09:00 h on their 1st, 3rd and 7th days of life, serum melatonin was measured by RIA. The clinical history was recorded and treatment and follow-up were performed according to established neonatology practice, and the resultant data recorded. Informed consent from the parents or guardians was obtained in accordance with the Declaration of Helsinki. Statistical analysis was carried out using ANOVA-II (factor I: day of sample; factor II: birthweight). Results: There were significant increases in melatonin levels with increasing birthweight (p = 0.017), but no changes by day of sample. Although in both study groups melatonin levels increased during the first few days this was not statistically significant. Conclusions: In newborns of low birthweight, we report high melatonin concentrations in the morning and during the first week of life. These increase with maturation, and at full-term were similar to nocturnal levels during the acrophase of pineal gland secretion in toddlers and schoolage children, when pineal gland secretion is maximal and takes place reflecting environmental variations. In the early neonatal period these high levels of melatonin seem to derive from extrapineal sources, which mature to provide antioxidant protection in accordance with other elements of the antioxidant network to compensate for the high levels of oxidative stress that are present in the perinatal period.

Influence of the antioxidant content of saliva on dental caries in an at-risk community

Objective This study aims to evaluate the relationship between the total antioxidant capacity of saliva and the presence of dental caries in deciduous and permanent teeth, in a group of Saharan children.Methods The dental examination was carried out in accordance with the recommendations of the World Health Organization (WHO). The total antioxidant capacity of the saliva was determined by colorimetry.Results The total antioxidant capacity (TAC) of the saliva of patients with caries in deciduous teeth was 2.89 1/IC50 greater than among those without. We observed a statistically significant linear regression between the number of deciduous teeth affected by caries and the total antioxidant capacity of the saliva: y = 0.24 + 0.53 × TAC saliva (t = 2.93; p = 0.004) (95% CI of b: 0.018-0.088).Conclusions Our results show that the amount of caries in deciduous teeth is in direct proportion to the observed TAC of saliva, and that the presence of caries in deciduous teeth is associated with caries in permanent teeth.

Methylphenidate effects on blood serotonin and melatonin levels may help to synchronise biological rhythms in children with ADHD

UNLABELLED The neuroendocrine mediators that may contribute to ADHD (Attention deficit and hyperactivity disorder), serotonin and melatonin, are both thought to regulate circadian rhythms, neurological function and stress response. The objective of this study was to determine the effect of the chronic administration of prolonged release methylphenidate (PRMPH) on daily variations in blood serotonin and melatonin and on the excretion of 6-sulphatoxy-melatonin. A total of 179 children (136 males, 42 females) between the ages of 5 and 14 (9.70 ± 2.55) years were enrolled in a controlled quasi-experimental open clinical study. Of the sample, there were 136 Children with ADHD (based on DSM-IV-TR criteria), who were further grouped into subtypes, and the 42 siblings of the participants who did not ADHD patients. Blood samples were taken at 20:00 and 09:00; urine was collected between 21:00 and 09:00. In the ADHD group, the study protocol was repeated after 4.61 ± 2.3 months of treatment. Measurements included melatonin and serotonin by RIA and urine 6-S-aMT by ELISA. Factorial analyses were conducted by STATA 12.0. RESULTS ADHD patients showed reduced morning serotonin with a daily profile that was different than the control group due to the predominance of nocturnal concentrations. PRMPH did not result in any significant changes. Melatonin and its daily profile did not differ between controls and the ADHD group with a diurnal rhythm showing higher morning levels that disappear after PRMPH administration. Melatonin was higher in children with predominantly hyperactive-impulsive/conduct disorder subtype. PRMPH resulted in a decrease in 6-S-aMT excretion for both ADHD subtypes. CONCLUSION Chronic treatment with prolonged release methylphenidate induces subtle changes in the daily fluctuations and concentrations of both serotonin and melatonin. Improvement in Childrens Depression Inventory (CDI) scores was not related to a morning increase in serotonin.

5‐Methoxytryptophol and melatonin in children: Differences due to age and sex

Abstract: It seems clear that the pineal hormone, melatonin (N‐acetyl‐5‐methoxytryptamine), is involved in the reproductive behavior of several animal species including humans. Moreover, several data also support a role for 5‐methoxytryptophol (ML), another pineal hormone, in the control of sexual processes. To test the role of ML in human reproductive axis, 128 healthy children, 68 boys and 60 girls, were studied. Each of these groups was divided in three age subgroups of 6, 11, and 14 years. A single blood sample (0900 hours) was obtained from each subject to determine melatonin, ML, FSH, LH, estradiol (girls), and testoterone (boys) by RIA. Statistical analysis of the data included ANOVA‐II (factor I: age, factor II: sex) and an analysis of covariance with age as covariate. A similar plasma melatonin concentration, with a significant decrease between 6 and 11 years, was found in boys and girls. Melatonin concentrations correlate well with initiation of the pubertal development in these children, although no sex differences were found. Concentrations of ML are approximately 50% of those of melatonin. In contrast to melatonin, ML levels show significant age and sex differences. Plasma ML concentration significantly increased in boys (P < 0.001) and decreased in girls (P < 0.001) after 8 years of age. These results support the hypothesis that, besides melatonin, other pineal compounds such as ML may be involved in the maturation process in humans. The pineal indole ML may also be used as a marker of the different chronobiology in the pubertal development in boys and girls.

Relationships between methoxyindole and kynurenine pathway metabolites in plasma and urine in children suffering from febrile and epileptic seizures

The methoxyindole pathway metabolite, melatonin (aMT), and the kynurenine pathway metabolites, kynurenic acid (KYNA), xanturenic acid (XA) and 3‐hydroxyantranilic acid (3HANA) are anticonvulsants, whereas the kynurenine pathway metabolites, l‐kynurenine (KYN) and 3‐hydroxykynurenine (3HK), are proconvulsants. It is thought that alterations in the concentrations of these compounds may be responsible for the excitotoxic aspect of human seizures. The aim of this study was to determine whether alterations in tryptophan metabolism might be related to the occurrence and type (febrile or non‐febrile) of seizures in children.