Thumbnail Image
Project Title
The Oxidative stress-neuroinflammation Synergy: Role in the perpetuation of alcohol intake and therapeutic avenues
Partner Organisations
Internal ID
1180042
Principal Investigator
ISRAEL JACARD, YEDY
Start Date
18 April 2018
Investigators

Filters

Reset filters

Settings
Now showing 1 - 10 of 11
No Thumbnail Available
Publication

Intranasal mesenchymal stem cell secretome administration markedly inhibits alcohol and nicotine self-administration and blocks relapse-intake: mechanism and translational options

2019 , María Elena Quintanilla , EZQUER, EDUARDO FERNANDO , Paola Morales , Daniela Santapau , BERRIOS CARCAMO, PABLO ANDRES , Mario Herrera-Marschitz , EZQUER, EDUARDO MARCELO , Yedy Israel

View
No Thumbnail Available
Publication

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.

View
No Thumbnail Available
Publication

N-Acetylcysteine and Acetylsalicylic Acid Inhibit Alcohol Consumption by Different Mechanisms: Combined Protection

2020 , María Elena Quintanilla , EZQUER, EDUARDO FERNANDO , Paola Morales , EZQUER, EDUARDO MARCELO , OLIVARES, MARIA BELEN , Mario Herrera-Marschitz , Daniela Santapau , Yedy Israel

View
No Thumbnail Available
Publication

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.

View
No Thumbnail Available
Publication

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 , BERRIOS CARCAMO, PABLO ANDRES , EZQUER, EDUARDO MARCELO , OLIVARES, MARIA BELEN , Mario Herrera‐Marschitz

View
No Thumbnail Available
Publication

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

2020 , BERRIOS CARCAMO, PABLO ANDRES , Mauricio Quezada , María Elena Quintanilla , Paola Morales , EZQUER, EDUARDO MARCELO , Mario Herrera-Marschitz , Yedy Israel , EZQUER, EDUARDO FERNANDO

Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system Xc− activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse.

View
No Thumbnail Available
Publication

Commonality of Ethanol and Nicotine Reinforcement and Relapse in Wistar-Derived UChB Rats: Inhibition by N-Acetylcysteine

2018 , Maria Elena Quintanilla , Paola Morales , EZQUER, EDUARDO FERNANDO , EZQUER, EDUARDO MARCELO , Mario Herrera-Marschitz , Yedy Israel

View
No Thumbnail Available
Publication

Gene and cell therapy on the acquisition and relapse-like binge drinking in a model of alcoholism: translational options

2019 , Yedy Israel , Quintanilla, María Elena , Paola Ezquer , Mario Morales , Eduardo Rivera-Meza , Marcelo Karahanian , EZQUER, EDUARDO FERNANDO

View
No Thumbnail Available
Publication

Innate gut microbiota predisposes to high alcohol consumption

2021 , EZQUER, EDUARDO FERNANDO , Maria Elena Quintanilla , Francisco Moya‐Flores , Paola Morales , MUNITA SEPULVEDA, JOSE MANUEL , OLIVARES, MARIA BELEN , Glauben Landskron , Marcela A. Hermoso , EZQUER, EDUARDO MARCELO , Mario Herrera‐Marschitz , Yedy Israel

View
No Thumbnail Available
Publication

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.

View