Biomedical subjects

Josefa León

Publications and source records attributed to Josefa León.

23 records · Page 2Linked to original sources

PubMed2002

Inhibition of nNOS activity in rat brain by synthetic kynurenines: structure-activity dependence.

The overstimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is involved in excitotoxicity, a process participating in neurodegeneration that characterizes some neurological disorders and acute cerebral insults. In looking for compounds with neuroprotective properties, a series of kynurenine derivatives were synthesized, and their effects on both the NMDA and nNOS activity in rat striatum were evaluated. Two compounds, 15a (2-acetamido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid) and 15c (2-butyramido-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid), displayed more potent activities than the other synthetic compounds tested for the inhibition of NMDA excitability and nNOS activity. Two other compounds, 18a (2-acetamido-4-(3-methoxyphenyl)-4-oxobutyric acid) and 18c (2-butyramido-4-(3-methoxyphenyl)-4-oxobutyric acid), that have the same structure as 15a and 15c, except the amino group in R(1), showed different effects. Whereas compound 18a showed lower electrophysiological potency than compounds 15a and 15c in the inhibition of the NMDA-dependent excitability, compound 18c showed the opposite effect. Moreover, compounds 18a and 18c were unable to modify nNOS activity. The remaining kynurenines tested behave like compound 18a. These results suggest that a structure-related activity of these synthetic kynurenines and a N-H bond in a specific direction is necessary for some kynurenine analogues to inhibit nNOS activity.

Animals↗

PubMed2002

Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria.

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 10nM. 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 microM potassium cyanide. However, melatonin (up to 5mM) was unable to recover the activity of complex IV when it was completely blocked by 100 microM 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.

Adenosine Triphosphate↗

PubMed2002

Circadian rhythms of dopamine and dihydroxyphenyl acetic acid in the mouse striatum: effects of pinealectomy and of melatonin treatment.

The existence of dopamine (DA)-melatonin (aMT) relationships is well documented in several brain areas of the mammalian central nervous system such as the retina and hypothalamus or the nigrostriatal system. For instance, aMT tempers 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigrostriatal damage in C57BL/6 mice. In this mouse strain however, rhythmic production of aMT and its possible interaction with striatal DA is still unclear. In the present work we investigated circadian variations in pineal production of aMT and striatal DA levels in C57BL/6 mice. Effects of pinealectomy and aMT administration were also assessed. Intact, pinealectomized and pinealectomized + aMT-treated mice and their respective control groups were sacrificed at six different times during the 24-hour period. In control animals, aMT displayed a circadian rhythm with a narrow peak at midnight. The peak of aMT coincided with the nadir of the DA rhythm present in the striatum. Shortly after the decrease of DA levels, an increase in 3,4-dihydroxyphenylacetic acid (DOPAC), the main DA metabolite, was observed. The rhythmic changes of DA and DOPAC levels in the striatum were blunted by pinealectomy, whereas administration of aMT (0.1-10 mg/kg) during 6 days to pinealectomized mice restored the rhythms in a dose-dependent manner. Striatal levels of 3-methoxytyramine and homovanillic acid did not change during the 24-hour cycle. The serotonergic system, assessed by the determination of 5-hydroxytryptamine and 5-hydroxyindole-3-acetic acid concentration in striatum, did not show significant time-dependent changes in control animals and was not affected by pinealectomy or aMT treatment. These data substantiate the existence of a link between pineal function, melatonin secretion and DA circadian rhythm in the mouse striatum.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Melatonin, mitochondrial homeostasis and mitochondrial-related diseases.

The recently described 'hydrogen hypothesis' invokes metabolic symbiosis as the driving force for a symbiotic association between an anaerobic, strictly hydrogen-dependent organism (the host) and an eubacterium (the symbiont) that is able to respire, but which generates molecular hydrogen as an end product of anaerobic metabolism. The resulting proto-eukaryotic cell would have acquired the essentials of eukaryotic energy metabolism, evolving not only aerobic respiration, but also the cost of oxygen consumption, i.e., generation of reactive oxygen species (ROS) and oxidative damage. Mitochondria contain their own genome with a modified genetic code that is highly conserved among mammals. Control of gene expression suggests that transcription of certain mitochondrial genes may be regulated in response to the redox potential of the mitochondrial membrane. Mitochondria are involved in energy production and conservation, and they have an uncoupling mechanism to produce heat instead of ATP. Also, mitochondria are involved in programmed cell death. Increasing evidence suggests the participation of mitochondria in neurodegenerative and neuromuscular diseases involving alterations in both nuclear (nDNA) and mitochondrial (mtDNA) DNA. Melatonin is now known as a powerful antioxidant and increasing experimental evidence shows its beneficial effects against oxidative stress-induced macromolecular damage and diseases, including those in which mitochondrial function is affected. This review summarizes the data and mechanisms of action of melatonin in relation to mitochondrial pathologies.

Animals↗

PubMedDate not supplied

Synergistic effects of melatonin and deprenyl against MPTP-induced mitochondrial damage and DA depletion.

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.

3,4-Dihydroxyphenylacetic Acid↗