CRIS

Permanent URI for this communityhttps://investigadores.udd.cl/handle/123456789/1

Browse

Search Results

Now showing 1 - 10 of 16

Some of the metrics are blocked by your
consent settings
Gut Microbiota‐Derived Extracellular Vesicles Influence Alcohol Intake Preferences in Rats
(Wiley, 2025-03)
Macarena Díaz‐Ubilla
;
Aliosha I. Figueroa‐Valdés
;
Hugo E. Tobar
;
María Elena Quintanilla
;
Eugenio Díaz
<jats:title>ABSTRACT</jats:title><jats:p>Growing preclinical and clinical evidence suggests a link between gut microbiota dysbiosis and problematic alcohol consumption. Extracellular vesicles (EVs) are key mediators involved in bacteria‐to‐host communication. However, their potential role in mediating addictive behaviour remains unexplored. This study investigates the role of gut microbiota‐derived bacterial extracellular vesicles (bEVs) in driving high alcohol consumption. bEVs were isolated from the gut microbiota of a high alcohol‐drinking rat strain (UChB rats), either ethanol‐naïve or following chronic alcohol consumption and administered intraperitoneally or orally to alcohol‐rejecting male and female Wistar rats. Both types of UChB‐derived bEVs increased Wistar's voluntary alcohol consumption (three bottle choice test) up to 10‐fold (<jats:italic>p</jats:italic> < 0.0001), indicating that bEVs are able and sufficient to transmit drinking behaviour across different rat strains. Molecular analysis revealed that bEVs administration did not induce systemic or brain inflammation in the recipient animals, suggesting that the increased alcohol intake triggered by UChB‐derived bEVs operates through an inflammation‐independent mechanism. Furthermore, we demonstrate that the vagus nerve mediates the bEV‐induced increase in alcohol consumption, as bilateral vagotomy completely abolished the high drinking behaviour induced by both intraperitoneally injected and orally administered bEVs. Thus, this study identifies bEVs as a novel mechanism underlying gut microbiota‐induced high alcohol intake in a vagus nerve‐dependent manner.</jats:p>
7
Some of the metrics are blocked by your
consent settings
Morphine self-administration is inhibited by the antioxidant N‐acetylcysteine and the anti-inflammatory ibudilast; an effect enhanced by their co-administration
(2024)
María Elena Quintanilla
;
Paola Morales
;
Daniela Santapau
;
Javiera Gallardo
;
Rocío Rebolledo
<jats:sec id="sec001"> <jats:title>Background</jats:title> <jats:p>The treatment of opioid addiction mainly involves the medical administration of methadone or other opioids, aimed at gradually reducing dependence and, consequently, the need for illicit opioid procurement. Thus, initiating opioid maintenance therapy with a lower level of dependence would be advantageous. There is compelling evidence indicating that opioids induce brain oxidative stress and associated glial activation, resulting in the dysregulation of glutamatergic homeostasis, which perpetuates drug intake. The present study aimed to determine whether inhibiting oxidative stress and/or neuroinflammation reduces morphine self-administration in an animal model of opioid dependence.</jats:p> </jats:sec> <jats:sec id="sec002"> <jats:title>Methods</jats:title> <jats:p>Morphine dependence, assessed as voluntary morphine self-administration, was evaluated in Wistar-derived UChB rats. Following an extended period of morphine self-administration, animals were administered either the antioxidant N-acetylcysteine (NAC; 40 mg/kg/day), the anti-inflammatory ibudilast (7.5 mg/kg/day) or the combination of both agents. Oxidative stress and neuroinflammation were evaluated in the hippocampus, a region involved in drug recall that feeds into the nucleus accumbens, where the levels of the glutamate transporters GLT-1 and xCT were further assessed.</jats:p> </jats:sec> <jats:sec id="sec003"> <jats:title>Results</jats:title> <jats:p>Daily administration of either NAC or ibudilast led to a mild reduction in voluntary morphine intake, while the co-administration of both therapeutic agents resulted in a marked inhibition (-57%) of morphine self-administration. The administration of NAC or ibudilast markedly reduced both the oxidative stress induced by chronic morphine intake and the activation of microglia and astrocytes in the hippocampus. However, only the combined administration of NAC + ibudilast was able to restore the normal levels of the glutamate transporter GLT-1 in the nucleus accumbens.</jats:p> </jats:sec> <jats:sec id="sec004"> <jats:title>Conclusion</jats:title> <jats:p>Separate or joint administration of an antioxidant and anti-inflammatory agent reduced voluntary opioid intake, which could have translational value for the treatment of opioid use disorders, particularly in settings where the continued maintenance of oral opioids is a therapeutic option.</jats:p> </jats:sec>
1Scopus© Citations 3
Some of the metrics are blocked by your
consent settings
Chronic Voluntary Morphine Intake Is Associated with Changes in Brain Structures Involved in Drug Dependence in a Rat Model of Polydrug Use
(2023)
María Elena Quintanilla
;
Paola Morales
;
Daniela Santapau
;
Alba Ávila
;
Carolina Ponce
<jats:p>Chronic opioid intake leads to several brain changes involved in the development of dependence, whereby an early hedonistic effect (liking) extends to the need to self-administer the drug (wanting), the latter being mostly a prefrontal–striatal function. The development of animal models for voluntary oral opioid intake represents an important tool for identifying the cellular and molecular alterations induced by chronic opioid use. Studies mainly in humans have shown that polydrug use and drug dependence are shared across various substances. We hypothesize that an animal bred for its alcohol preference would develop opioid dependence and further that this would be associated with the overt cortical abnormalities clinically described for opioid addicts. We show that Wistar-derived outbred UChB rats selected for their high alcohol preference additionally develop: (i) a preference for oral ingestion of morphine over water, resulting in morphine intake of 15 mg/kg/day; (ii) marked opioid dependence, as evidenced by the generation of strong withdrawal signs upon naloxone administration; (iii) prefrontal cortex alterations known to be associated with the loss of control over drug intake, namely, demyelination, axonal degeneration, and a reduction in glutamate transporter GLT-1 levels; and (iv) glial striatal neuroinflammation and brain oxidative stress, as previously reported for chronic alcohol and chronic nicotine use. These findings underline the relevance of polydrug animal models and their potential in the study of the wide spectrum of brain alterations induced by chronic morphine intake. This study should be valuable for future evaluations of therapeutic approaches for this devastating condition.</jats:p>
7Scopus© Citations 6
Some of the metrics are blocked by your
consent settings
Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell‐derived secretome in preclinical models of morphine dependence
(2023)
Mauricio Quezada
;
Carolina Ponce
;
Pablo Berríos‐Cárcamo
;
Daniela Santapau
;
Javiera Gallardo
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Morphine is an opiate commonly used in the treatment of moderate to severe pain. However, prolonged administration can lead to physical dependence and strong withdrawal symptoms upon cessation of morphine use. These symptoms can include anxiety, irritability, increased heart rate, and muscle cramps, which strongly promote morphine use relapse. The morphine‐induced increases in neuroinflammation, brain oxidative stress, and alteration of glutamate levels in the hippocampus and nucleus accumbens have been associated with morphine dependence and a higher severity of withdrawal symptoms. Due to its rich content in potent anti‐inflammatory and antioxidant factors, secretome derived from human mesenchymal stem cells (hMSCs) is proposed as a preclinical therapeutic tool for the treatment of this complex neurological condition associated with neuroinflammation and brain oxidative stress.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Two animal models of morphine dependence were used to evaluate the therapeutic efficacy of hMSC‐derived secretome in reducing morphine withdrawal signs. In the first model, rats were implanted subcutaneously with mini‐pumps which released morphine at a concentration of 10 mg/kg/day for seven days. Three days after pump implantation, animals were treated with a simultaneous intravenous and intranasal administration of hMSC‐derived secretome or vehicle, and withdrawal signs were precipitated on day seven by i.p. naloxone administration. In this model, brain alterations associated with withdrawal were also analyzed before withdrawal precipitation. In the second animal model, rats voluntarily consuming morphine for three weeks were intravenously and intranasally treated with hMSC‐derived secretome or vehicle, and withdrawal signs were induced by morphine deprivation.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In both animal models secretome administration induced a significant reduction of withdrawal signs, as shown by a reduction in a combined withdrawal score. Secretome administration also promoted a reduction in morphine‐induced neuroinflammation in the hippocampus and nucleus accumbens, while no changes were observed in extracellular glutamate levels in the nucleus accumbens.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Data presented from two animal models of morphine dependence suggest that administration of secretome derived from hMSCs reduces the development of opioid withdrawal signs, which correlates with a reduction in neuroinflammation in the hippocampus and nucleus accumbens.</jats:p></jats:sec>
Scopus© Citations 4 1
Some of the metrics are blocked by your
consent settings
Administration of N-acetylcysteine Plus Acetylsalicylic Acid Markedly Inhibits Nicotine Reinstatement Following Chronic Oral Nicotine Intake in Female Rats
(2021)
María Elena Quintanilla
;
Paola Morales
;
EZQUER, EDUARDO FERNANDO
;
Mario Herrera-Marschitz
;
EZQUER, EDUARDO MARCELO
<jats:sec><jats:title>Background</jats:title><jats:p>Nicotine is the major addictive component of cigarette smoke and the prime culprit of the failure to quit smoking. Common elements perpetuating the use of addictive drugs are (i) cues associated with the setting in which drug was used and (ii) relapse/reinstatement mediated by an increased glutamatergic tone (iii) associated with drug-induced neuroinflammation and oxidative stress.</jats:p></jats:sec><jats:sec><jats:title>Aims</jats:title><jats:p>The present study assessed the effect of the coadministration of the antioxidant <jats:italic>N</jats:italic>-acetylcysteine (NAC) plus the anti-inflammatory acetylsalicylic acid (ASA) on oral nicotine reinstatement intake following a post-deprivation re-access in female rats that had chronically and voluntarily consumed a nicotine solution orally. The nicotine-induced oxidative stress and neuroinflammation in the hippocampus and its effects on the glutamate transporters GLT-1 and XCT mRNA levels in prefrontal cortex were also analyzed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The oral coadministration of NAC (40 mg/kg/day) and ASA (15 mg/kg/day) inhibited by 85% of the oral nicotine reinstatement intake compared to control (vehicle), showing an additive effect of both drugs. Acetylsalicylic acid and <jats:italic>N</jats:italic>-acetylcysteine normalized hippocampal oxidative stress and blunted the hippocampal neuroinflammation observed upon oral nicotine reinstatement. Nicotine downregulated GLT-1 and xCT gene expression in the prefrontal cortex, an effect reversed by <jats:italic>N</jats:italic>-acetylcysteine, while acetylsalicylic acid reversed the nicotine-induced downregulation of GLT-1 gene expression. The inhibitory effect of <jats:italic>N</jats:italic>-acetylcysteine on chronic nicotine intake was blocked by the administration of sulfasalazine, an inhibitor of the xCT transporter.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Nicotine reinstatement, following post-deprivation of chronic oral nicotine intake, downregulates the mRNA levels of GLT-1 and xCT transporters, an effect reversed by the coadministration of <jats:italic>N</jats:italic>-acetylcysteine and acetylsalicylic acid, leading to a marked inhibition of nicotine intake. The combination of these drugs may constitute a valuable adjunct in the treatment of nicotine-dependent behaviors.</jats:p></jats:sec>
2Scopus© Citations 8
Some of the metrics are blocked by your
consent settings
Innate gut microbiota predisposes to high alcohol consumption
(2021)
EZQUER, EDUARDO FERNANDO
;
Maria Elena Quintanilla
;
Francisco Moya‐Flores
;
Paola Morales
;
MUNITA SEPULVEDA, JOSE MANUEL
Scopus© Citations 34 5
Some of the metrics are blocked by your
consent settings
Aspirin and N‐acetylcysteine co‐administration markedly inhibit chronic ethanol intake and block relapse binge drinking: Role of neuroinflammation‐oxidative stress self‐perpetuation
(2019)
Yedy Israel
;
María Elena Quintanilla
;
EZQUER, EDUARDO FERNANDO
;
Paola Morales
;
Daniela Santapau
Scopus© Citations 34 2
Some of the metrics are blocked by your
consent settings
A dual mechanism fully blocks ethanol relapse: Role of vagal innervation
(2022)
María Elena Quintanilla
;
EZQUER, EDUARDO FERNANDO
;
Paola Morales
;
Daniela Santapau
;
EZQUER, EDUARDO MARCELO
3
Some of the metrics are blocked by your
consent settings
A dual treatment blocks alcohol binge-drinking relapse: Microbiota as a new player
(2022)
EZQUER, EDUARDO FERNANDO
;
María Elena Quintanilla
;
Paola Morales
;
Daniela Santapau
;
MUNITA SEPULVEDA, JOSE MANUEL
Scopus© Citations 22 2
Some of the metrics are blocked by your
consent settings
Sustained Energy Deficit Following Perinatal Asphyxia: A Shift towards the Fructose-2,6-bisphosphatase (TIGAR)-Dependent Pentose Phosphate Pathway and Postnatal Development
(2021)
Carolyne Lespay-Rebolledo
;
Andrea Tapia-Bustos
;
Ronald Perez-Lobos
;
Valentina Vio
;
Emmanuel Casanova-Ortiz
<jats:p>Labor and delivery entail a complex and sequential metabolic and physiologic cascade, culminating in most circumstances in successful childbirth, although delivery can be a risky episode if oxygen supply is interrupted, resulting in perinatal asphyxia (PA). PA causes an energy failure, leading to cell dysfunction and death if re-oxygenation is not promptly restored. PA is associated with long-term effects, challenging the ability of the brain to cope with stressors occurring along with life. We review here relevant targets responsible for metabolic cascades linked to neurodevelopmental impairments, that we have identified with a model of global PA in rats. Severe PA induces a sustained effect on redox homeostasis, increasing oxidative stress, decreasing metabolic and tissue antioxidant capacity in vulnerable brain regions, which remains weeks after the insult. Catalase activity is decreased in mesencephalon and hippocampus from PA-exposed (AS), compared to control neonates (CS), in parallel with increased cleaved caspase-3 levels, associated with decreased glutathione reductase and glutathione peroxidase activity, a shift towards the TIGAR-dependent pentose phosphate pathway, and delayed calpain-dependent cell death. The brain damage continues long after the re-oxygenation period, extending for weeks after PA, affecting neurons and glial cells, including myelination in grey and white matter. The resulting vulnerability was investigated with organotypic cultures built from AS and CS rat newborns, showing that substantia nigra TH-dopamine-positive cells from AS were more vulnerable to 1 mM of H2O2 than those from CS animals. Several therapeutic strategies are discussed, including hypothermia; N-acetylcysteine; memantine; nicotinamide, and intranasally administered mesenchymal stem cell secretomes, promising clinical translation.</jats:p>
1Scopus© Citations 5

CRIS

Browse

Filters

Settings

Sort By

Results per page

Search Results