Biomedical subjects

Dario Acuña-Castroviejo

Publications and source records attributed to Dario Acuña-Castroviejo.

3 recordsLinked to original sources

PubMed2006

Inhibition of the cdk5/p25 fragment formation may explain the antiapoptotic effects of melatonin in an experimental model of Parkinson's disease.

In this study, the effects of melatonin on MPP+ -treated cerebellar granule neurons (CGNs) in culture were investigated. Results showed that MPP+ treatment significantly decreased cell viability and increased the apoptotic cell population at 24 and 48 hr. Calpain and caspase-3 activation was also determined, with results showing a strong increase in calpain (74%) and caspase 3 activity (70%), as measured by alpha-spectrin cleavage and fluorometric and colorimetric analysis, respectively. There are several studies suggesting that the activation of the cdk5/p35 pathway at its cleavage to cdk5/p25 may play a role in neuronal cell death in neurodegenerative diseases. Moreover, these studies indicate that this cleavage is mediated by calpains, and that MPP+ prompted an increase in cdk5 expression, as well as the cleavage of p35-p25, in a time-dependent manner. 1 mm Melatonin not only reduced the neurotoxic effects of MPP+ on cell viability, but also prevented apoptosis mediated by this Parkinsonian toxin in CGNs. 1 mm Melatonin reduced cdk5 expression, as well as the cleavage of p35-p25. These data indicate that melatonin possesses some neuro-protective properties against MPP+ -induced apoptosis. Moreover, these data suggest that the calpain/cdk5 signaling cascade has a potential role in the MPP+ -mediated apoptotic process in CGNs.

1-Methyl-4-phenylpyridinium↗

PubMed2004

Melatonin and mitochondrial function.

Melatonin is a natural occurring compound with well-known antioxidant properties. In the last decade a new effect of melatonin on mitochondrial homeostasis has been discovered and, although the exact molecular mechanism for this effect remains unknown, it may explain, at least in part, the protective properties found for the indoleamine in degenerative conditions such as aging as well as Parkinson's disease, Alzheimer's disease, epilepsy, sepsis and other injuries such as ischemia-reperfusion. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress, which may lead to a decrease in the activities of mitochondrial complexes and ATP production, and, as a consequence, a further increase in free radical generation. A vicious cycle thus results under these conditions of oxidative stress with the final consequence being cell death by necrosis or apoptosis. Melatonin is able of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival.

Animals↗

PubMed2003

Mitochondrial regulation by melatonin and its metabolites.

Our results show that melatonin and N-acetyl-5-methoxykynurenamine (aMK) physiologically regulate both the electron transport chain (ETC) and OXPHOS, increasing the electron transport and ATP synthesis by normal mitochondria. Melatonin also counteracts mitochondrial oxidative damage induced by t-butyl hydroperoxide, recovering glutathione levels and ATP production. However, the effects of melatonin not only depend of its antioxidant properties, since the indoleamine specifically interacts with complex I and IV of the ETC increasing their activity. Experiments in vivo showed that melatonin administration prevents sepsis-induced ETC damage decreasing the activity and expression of INOS and mtNOS, thus reducing intramitochondrial nitric oxide (NO) and peroxynitrite (ONOO-) levels. Consequently, mitochondrial ETC ad ATP production recovered to normal conditions. The presence of specific binding of melatonin in mitochondrial matrix led us to explore the genomic role of the indoleamine in these organelles. In vivo and in vitro experiments showed that administration of melatonin increased mtONA transcriptional activity of the subunits 1-3 of the complex IV. These effects correlated well with the effects of melatonin on complex IV activity. The data suggest a new rate for melatonin to regulate mitochondrial homeostasis. Due to the relationships between mitochondrial damage, aging and neurodegenerative diseases, the effects of melatonin here described further support its antiaging and neuroprotective properties.

Adenosine Triphosphate↗