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Trabajo presentado en el VII Congreso Internacional de Investigación e Innovación en Enfermedades Neurodegenerativas (CiiiEN), celebrado en Valencia (España) del 17 al 20 de septiembre de 2019., Parkinson disease (PD) is the second most prevalent age-related neurodegenerative disorder after Alzheimer disease (1), resulting from degeneration of dopaminergic (DA) neurons in the ventral midbrain. To date, only symptomatic treatment is available; therefore, it is necessary to find new targets and treatments involved in the onset and progression of the disease. CCAAT/Enhancer Binding Protein ß (C/EBPß) is a transcription factor involved in numerous physiological as well as pathological conditions in the brain. Furthermore, C/EBPß depletion in in vitro and animal models of PD results in an amelioration of dopaminergic damage and glial activation (2), suggesting that this transcription factor could be a good therapeutic target for treatment of PD. Mitochondrial transcription factor A (TFAM) is a nuclear-encoded protein that is imported to this organelle and binds mitochondrial DNA (mtDNA) to regulate mitochondrial transcription initiation and mtDNA copy number. Furthermore, TFAM has a non-specific mtDNA binding activity that may have a structural role for genome packaging (3). It has been shown that TFAM has an important role in several neurodegenerative disorders (Reviewed in (4)) including PD. To date, there is no evidence about C/EBPß implication on mitochondrial activity. In this work, we demonstrate that C/EBPß regulates the expression of several mitochondrial genes and, more specifically TFAM transcription.

Data de publicació electrònica: 22-09-2017 Mixing alcohol with caffeinated energy drinks is a common practice, especially among young people. In humans, the research on this issue has mainly focused on the use of the mass-marketed energy drinks themselves, whereas in animal models, it has focused on the individual effects of their active ingredients (i.e. caffeine). Here, we have characterized how Red Bull®, one of the most consumed caffeinated energy drink worldwide, modulates operant alcohol self-administration in Wistar rats. We found that animals readily and steadily responded for Red Bull (mean: 90 responses, 30 minutes and fixed-ratio 1), which was accompanied by locomotor stimulating effects (26 percent increase). The higher the concentration of alcohol (3-20 percent), the higher the consumption of alcohol (g/kg) and associated blood alcohol levels (91.76 percent) in the mixed Red Bull-alcohol group (60 percent increase). Blood caffeine levels in the Red Bull group were 4.69 μg/ml and 1.31 μg/ml in the Red Bull-alcohol group after the 30-minute session. Because Red Bull also contains 11 percent sucrose, we examined the time course of blood glucose as well as insulin and corticosterone. The correlation between intake of Red Bull and blood glucose levels was higher at 90 minutes than 5 minutes after its consumption, and there was no relationship with blood insulin or blood corticosterone levels. Red Bull did not alter extinction and reacquisition of responding for alcohol nor did it affect relapse-like drinking. Overall, our results suggest that Red Bull might be a vulnerability factor to develop alcoholism given that it intensifies the consumption of higher concentrations of alcohol.

BACKGROUND AND PURPOSE: The opioid antagonist nalmefene (selincro®) was approved for alcohol-related disorders by the European Medicines Agency in 2013. However, there have been no studies regarding the effectiveness of nalmefene when alcohol is used in combination with cocaine. EXPERIMENTAL APPROACH: Using operant alcohol self-administration in Wistar rats and qRT-PCR, we evaluated (i) the dose-response curve for s.c. and p.o. nalmefene; (ii) the effects of nalmefene with increasing concentrations of alcohol; (iii) the efficacy of nalmefene on cocaine-potentiated alcohol responding; and (iv) the gene expression profiles of histone deacetylases (Hdac1-11) in peripheral blood in vivo and in the prefrontal cortex, heart, liver and kidney post mortem. KEY RESULTS: S.c. (0.01, 0.05, 0.1 mg·kg(-1) ) and p.o. (10, 20, 40 mg·kg(-1) ) nalmefene dose-dependently reduced alcohol-reinforced responding by up to 50.3%. This effect of nalmefene was not dependent on alcohol concentration (10, 15, 20%). Cocaine potentiated alcohol responding by approximately 40% and nalmefene (0.05 mg·kg(-1) ) reversed this effect of cocaine. Alcohol increased Hdac gene expression in blood and nalmefene prevented the increases in Hdacs 3, 8, 5, 7, 9, 6 and 10. In the other tissues, alcohol and nalmefene either did not alter the gene expression of Hdacs, as in the prefrontal cortex, or a tissue-Hdac-specific effect was observed. CONCLUSIONS AND IMPLICATIONS: Nalmefene might be effective as a treatment for alcohol-dependent patients who also use cocaine. Also, the expression of Hdacs in peripheral blood might be useful as a biomarker of alcohol use and drug response. This work was supported by The European Foundation for Alcohol Research (to J.A.L.M., F.R.d.F., R.M. and R.N.), the Fondo de Investigación Sanitaria (Red de Trastornos Adictivos, FEDER, RD12/0028/0015 to J.A.L.M., RD12/0028/001 to F.R.d.F., RD12/0028/023 to R.M., RD12/0028/0014 to R.N.) and Ministerio de Ciencia e Innovación (SAF2011-26818 to J.A.L.M.).

The opioid antagonist nalmefene (selincro®) was approved for alcohol-related disorders by the European Medicines Agency in 2013. However, there have been no studies regarding the effectiveness of nalmefene when alcohol is used in combination with cocaine.Using operant alcohol self-administration in Wistar rats and qRT-PCR, we evaluated (i) the dose-response curve for s.c. and p.o. nalmefene; (ii) the effects of nalmefene with increasing concentrations of alcohol; (iii) the efficacy of nalmefene on cocaine-potentiated alcohol responding; and (iv) the gene expression profiles of histone deacetylases (Hdac1-11) in peripheral blood in vivo and in the prefrontal cortex, heart, liver and kidney post mortem.S.c. (0.01, 0.05, 0.1 mg·kg(-1) ) and p.o. (10, 20, 40 mg·kg(-1) ) nalmefene dose-dependently reduced alcohol-reinforced responding by up to 50.3%. This effect of nalmefene was not dependent on alcohol concentration (10, 15, 20%). Cocaine potentiated alcohol responding by approximately 40% and nalmefene (0.05 mg·kg(-1) ) reversed this effect of cocaine. Alcohol increased Hdac gene expression in blood and nalmefene prevented the increases in Hdacs 3, 8, 5, 7, 9, 6 and 10. In the other tissues, alcohol and nalmefene either did not alter the gene expression of Hdacs, as in the prefrontal cortex, or a tissue-Hdac-specific effect was observed.Nalmefene might be effective as a treatment for alcohol-dependent patients who also use cocaine. Also, the expression of Hdacs in peripheral blood might be useful as a biomarker of alcohol use and drug response.

α-Synuclein (α-syn) protein and endocannabinoid CB1 receptors are primarily located in presynaptic terminals. An association between α-syn and CB1 receptors has recently been established in Parkinson's disease, but it is completely unknown whether there is an association between these two proteins in alcohol addiction. Therefore, we aimed to examine the α-syn mRNA transcript and protein expression levels in the prefrontal cortex, striatum, amygdala and hippocampus. These brain regions are the most frequently implicated in alcohol and other drug addiction. In these studies, we used C57BL/6 mice carrying a spontaneous deletion of the α-syn gene (C57BL/6(Snca-/-) ) and their respective controls (C57BL/6(Snca) (+/) (+) ). These animals were monitored for spontaneous alcohol consumption (3-10%) and their response to a hypnotic-sedative dose of alcohol (3 g kg(-1) ) was also assessed. Compared with the C57BL/6(Snca+/+) mice, we found that the C57BL/6(Snca-/-) mice exhibited a higher expression level of the CB1 mRNA transcript and CB1 receptor in the hippocampus and amygdala. Furthermore, C57BL/6(Snca-/-) mice showed an increase in alcohol consumption when offered a 10% alcohol solution. There was no significant difference in sleep time after the injection of 3 g/kg alcohol. These results are the first to reveal an association between α-syn and the CB1 receptor in the brain regions that are most frequently implicated in alcohol and other drug addictions.

Pio del Rio-Hortega was not only the discoverer of the microglia and oligodendroglia but also possibly the most prolific mentor of all Santiago Ramon y Cajal's disciples (Nobel awardee in Physiology or Medicine 1906 and considered as the father of modern Neuroscience). Among Río-Hortega's mentees, three exceptional women are frequently forgotten, chronologically: Pio's niece Asunción Amo del Río who worked with Río-Hortega at Madrid, Paris, and Oxford; the distinguished British neuropathologist Dorothy Russell who also worked with Don Pío at Oxford; and Amanda Pellegrino de Iraldi, the last mentee in his career. Our present work analyzes the figures of these three women who were in contact and collaborated with Don Pío del Río-Hortega, describing the influences received and the impact on their careers and the History of Neuroscience. The present work completes the contribution of women neuroscientists who worked with Cajal and his main disciples of the Spanish Neurological School both in Spain (previous work) and in other countries (present work).