EZQUER, EDUARDO FERNANDO
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EZQUER, EDUARDO FERNANDO
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eezquer@udd.cl
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8614146900

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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 , Gabriel Riveras , Tirso Acuña , Mario Herrera-Marschitz , Yedy Israel , EZQUER, EDUARDO FERNANDO , Shao-Jun Tang

Background 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. Methods 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. Results 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. Conclusion 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.

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Intracerebral Stem Cell Administration Inhibits Relapse-like Alcohol Drinking in Rats

2016 , Yedy Israel , EZQUER, EDUARDO FERNANDO , María Elena Quintanilla , Paola Morales , EZQUER, EDUARDO MARCELO , Mario Herrera-Marschitz

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Acquisition, Maintenance and Relapse-Like Alcohol Drinking: Lessons from the UChB Rat Line

2017 , Yedy Israel , Eduardo Karahanian , EZQUER, EDUARDO FERNANDO , Paola Morales , EZQUER, EDUARDO MARCELO , Mario Rivera-Meza , Mario Herrera-Marschitz , María E. Quintanilla

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A Novel Morphine Drinking Model of Opioid Dependence in Rats

2022 , BERRIOS CARCAMO, PABLO ANDRES , Mauricio Quezada , Daniela Santapau , Paola Morales , OLIVARES, MARIA BELEN , Carolina Ponce , Alba Ávila , María Elena Quintanilla , EZQUER, EDUARDO MARCELO , DE GREGORIO CONCHA, CRISTIAN ALEJANDRO , Mario Herrera-Marschitz , Yedy Israel , EZQUER, EDUARDO FERNANDO

An animal model of voluntary oral morphine consumption would allow for a pre-clinical evaluation of new treatments aimed at reducing opioid intake in humans. However, the main limitation of oral morphine consumption in rodents is its bitter taste, which is strongly aversive. Taste aversion is often overcome by the use of adulterants, such as sweeteners, to conceal morphine taste or bitterants in the alternative bottle to equalize aversion. However, the adulterants’ presence is the cause for consumption choice and, upon removal, the preference for morphine is not preserved. Thus, current animal models are not suitable to study treatments aimed at reducing consumption elicited by morphine itself. Since taste preference is a learned behavior, just-weaned rats were trained to accept a bitter taste, adding the bitterant quinine to their drinking water for one week. The latter was followed by allowing the choice of quinine or morphine (0.15 mg/mL) solutions for two weeks. Then, quinine was removed, and the preference for morphine against water was evaluated. Using this paradigm, we show that rats highly preferred the consumption of morphine over water, reaching a voluntary morphine intake of 15 mg/kg/day. Morphine consumption led to significant analgesia and hyperlocomotion, and to a marked deprivation syndrome following the administration of the opioid antagonist naloxone. Voluntary morphine consumption was also shown to generate brain oxidative stress and neuroinflammation, signs associated with opioid dependence development. We present a robust two-bottle choice animal model of oral morphine self-administration for the evaluation of therapeutic interventions for the treatment of morphine dependence.

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Intragastric administration of short chain fatty acids greatly reduces voluntary ethanol intake in rats

2024 , María Elena Quintanilla , Daniela Santapau , Eugenio Diaz , Ignacio Valenzuela Martinez , Nicolas Medina , Glauben Landskron , Antonia Dominguez , Paola Morales , David Ramírez , Marcela Hermoso , Belén Olivares , Pablo Berríos-Cárcamo , EZQUER, EDUARDO MARCELO , Mario Herrera-Marschitz , Yedy Israel , EZQUER, EDUARDO FERNANDO

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Effect of human mesenchymal stem cell secretome administration on morphine self-administration and relapse in two animal models of opioid dependence

2022 , María Elena Quintanilla , Mauricio Quezada , Paola Morales , BERRIOS CARCAMO, PABLO ANDRES , Mario Herrera-Marschitz , EZQUER, EDUARDO MARCELO , Daniela Santapau , Israel Yacard, Yedy , EZQUER, EDUARDO FERNANDO

AbstractThe present study investigates the possible therapeutic effects of human mesenchymal stem cell-derived secretome on morphine dependence and relapse. This was studied in a new model of chronic voluntary morphine intake in Wistar rats which shows classic signs of morphine intoxication and a severe naloxone-induced withdrawal syndrome. A single intranasal-systemic administration of MSCs secretome fully inhibited (>95%; p < 0.001) voluntary morphine intake and reduced the post-deprivation relapse intake by 50% (p < 0.02). Since several studies suggest a significant genetic contribution to the chronic use of many addictive drugs, the effect of MSCs secretome on morphine self-administration was further studied in rats bred as high alcohol consumers (UChB rats). Sub-chronic intraperitoneal administration of morphine before access to increasing concentrations of morphine solutions and water were available to the animals, led UChB rats to prefer ingesting morphine solutions over water, attaining levels of oral morphine intake in the range of those in the Wistar model. Intranasally administered MSCs secretome to UChB rats dose-dependently inhibited morphine self-administration by 72% (p < 0.001); while a single intranasal dose of MSC-secretome administered during a morphine deprivation period imposed on chronic morphine consumer UChB rats inhibited re-access morphine relapse intake by 80 to 85% (p < 0.0001). Both in the Wistar and the UChB rat models, MSCs-secretome administration reversed the morphine-induced increases in brain oxidative stress and neuroinflammation, considered as key engines perpetuating drug relapse. Overall, present preclinical studies suggest that products secreted by human mesenchymal stem cells may be of value in the treatment of opioid addiction.

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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 , Yedy Israel

BackgroundNicotine 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.AimsThe present study assessed the effect of the coadministration of the antioxidant N-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.ResultsThe 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 N-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 N-acetylcysteine, while acetylsalicylic acid reversed the nicotine-induced downregulation of GLT-1 gene expression. The inhibitory effect of N-acetylcysteine on chronic nicotine intake was blocked by the administration of sulfasalazine, an inhibitor of the xCT transporter.ConclusionNicotine 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 N-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.

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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 , BERRIOS CARCAMO, PABLO ANDRES , OLIVARES, MARIA BELEN , Mario Herrera-Marschitz , EZQUER, EDUARDO MARCELO , Javiera Gallardo , Yedy Israel , EZQUER, EDUARDO FERNANDO

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.

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Intranasal Administration of Mesenchymal Stem Cell Secretome Reduces Hippocampal Oxidative Stress, Neuroinflammation and Cell Death, Improving the Behavioral Outcome Following Perinatal Asphyxia

2020 , Nancy Farfán , Jaime Carril , Martina Redel , Marta Zamorano , Maureen Araya , Estephania Monzón , Raúl Alvarado , Norton Contreras , Andrea Tapia-Bustos , María Elena Quintanilla , EZQUER, EDUARDO FERNANDO , José Luis Valdés , Yedy Israel , Mario Herrera-Marschitz , Paola Morales

Perinatal Asphyxia (PA) is a leading cause of motor and neuropsychiatric disability associated with sustained oxidative stress, neuroinflammation, and cell death, affecting brain development. Based on a rat model of global PA, we investigated the neuroprotective effect of intranasally administered secretome, derived from human adipose mesenchymal stem cells (MSC-S), preconditioned with either deferoxamine (an hypoxia-mimetic) or TNF-α+IFN-γ (pro-inflammatory cytokines). PA was generated by immersing fetus-containing uterine horns in a water bath at 37 °C for 21 min. Thereafter, 16 μL of MSC-S (containing 6 μg of protein derived from 2 × 105 preconditioned-MSC), or vehicle, were intranasally administered 2 h after birth to asphyxia-exposed and control rats, evaluated at postnatal day (P) 7. Alternatively, pups received a dose of either preconditioned MSC-S or vehicle, both at 2 h and P7, and were evaluated at P14, P30, and P60. The preconditioned MSC-S treatment (i) reversed asphyxia-induced oxidative stress in the hippocampus (oxidized/reduced glutathione); (ii) increased antioxidative Nuclear Erythroid 2-Related Factor 2 (NRF2) translocation; (iii) increased NQO1 antioxidant protein; (iv) reduced neuroinflammation (decreasing nuclearNF-κB/p65 levels and microglial reactivity); (v) decreased cleaved-caspase-3 cell-death; (vi) improved righting reflex, negative geotaxis, cliff aversion, locomotor activity, anxiety, motor coordination, and recognition memory. Overall, the study demonstrates that intranasal administration of preconditioned MSC-S is a novel therapeutic strategy that prevents the long-term effects of perinatal asphyxia.

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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 , Nancy Farfan-Troncoso , Marta Zamorano-Cataldo , Martina Redel-Villarroel , EZQUER, EDUARDO FERNANDO , Maria Elena Quintanilla , Yedy Israel , Paola Morales , Mario Herrera-Marschitz

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.

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