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1.
Sci Rep ; 14(1): 16978, 2024 07 23.
Artículo en Inglés | MEDLINE | ID: mdl-39043899

RESUMEN

Methadone is a synthetic long-acting opioid that is increasingly used in the replacement therapy of opioid-addicted patients, including pregnant women. However, methadone therapy in this population poses challenges, as it induces cognitive and behavioral impairments in infants exposed to this opioid during prenatal development. In animal models, prenatal methadone exposure results in detrimental consequences to the central nervous system, such as: (i) increased neuronal apoptosis; (ii) disruption of oligodendrocyte maturation and increased apoptosis and (iii) increased microglia and astrocyte activation. However, it remains unclear whether these deleterious effects result from a direct effect of methadone on brain cells. Therefore, our goal was to uncover the impact of methadone on single brain cell types in vitro. Primary cultures of rat neurons, oligodendrocytes, microglia, and astrocytes were treated for three days with 10 µM methadone to emulate a chronic administration. Apoptotic neurons were identified by cleaved caspase-3 detection, and synaptic density was assessed by the juxtaposition of presynaptic and postsynaptic markers. Apoptosis of oligodendrocyte precursors was determined by cleaved caspase-3 detection. Oligodendrocyte myelination was assessed by immunofluorescence, while microglia and astrocyte proinflammatory activation were assessed by both immunofluorescence and RT-qPCR. Methadone treatment increased neuronal apoptosis and reduced synaptic density. Furthermore, it led to increased oligodendrocyte apoptosis and a reduction in the myelinating capacity of these cells, and promoted the proinflammatory activation of microglia and astrocytes. We showed that methadone, the most widely used drug in opioid replacement therapy for pregnant women with opioid addiction, directly impairs brain cells in vitro, highlighting the need for developing alternative therapies to address opioid addiction in this population.


Asunto(s)
Apoptosis , Astrocitos , Metadona , Microglía , Neuronas , Oligodendroglía , Metadona/farmacología , Animales , Ratas , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Apoptosis/efectos de los fármacos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Células Cultivadas , Femenino , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Embarazo , Analgésicos Opioides/farmacología , Ratas Sprague-Dawley
2.
Rev. ADM ; 81(2): 95-99, mar.-abr. 2024. ilus
Artículo en Español | LILACS | ID: biblio-1562186

RESUMEN

Introducción: la odontología es un campo indispensable para el ser humano, de no existir, se complica la prevención y atención de las patologías orales, resultando en estructuras dentales y bucales enfermas. La cantidad de pacientes diagnosticados con trastorno del espectro autista (TEA) que acuden a consulta odontológica va en aumento, lo cual genera ansiedad en el cirujano dentista al no contar con la capacitación adecuada para la atención de estos pacientes. Existen técnicas que ayudan al manejo correcto del comportamiento de los pacientes con trastorno del espectro autista como decir-mostrar-hacer, sedación consciente, TEACCH y desensibilización. Objetivo: explicar las técnicas para la atención de pacientes con trastorno del espectro autista durante la consulta odontológica. Conclusiones: aprender a tratar a los pacientes con trastorno del espectro autista es de suma importancia, ya que para ellos una simple consulta inicial podría convertirse en una experiencia traumática. Es necesario que todos los odontólogos conozcan las técnicas de manejo de conducta para que traten con profesionalidad a pacientes con trastorno del espectro autista debido al aumento de la prevalencia de personas diagnosticadas con este padecimiento (AU)


Introduction: dentistry is an indispensable field for the human being, if it did not exist, the prevention and care of oral pathologies would be complicated, resulting in diseased dental and oral structures. The number of patients diagnosed with autism spectrum disorder (ASD) who come to a dental office is increasing, which generates anxiety in the dentist surgeon because they do not have adequate training to care for these patients. There are techniques that help to correctly manage the behavior of patients with autism spectrum disorder such as tell-show-do, conscious sedation, TEACCH and desensitization. Objectives: explain the techniques for the care of patients with autism spectrum disorder during the dental consultation. Conclusions: learning to treat patients with autism spectrum disorder is extremely important, since for them a simple initial consultation could become a traumatic experience. It is necessary that all dentists know behavior management techniques so that they treat patients with autism spectrum disorder professionally due to the increase in the prevalence of people diagnosed with this condition (AU)


Asunto(s)
Ansiedad al Tratamiento Odontológico/terapia , Trastorno del Espectro Autista/psicología , Trastorno del Espectro Autista/terapia , Sedación Consciente/métodos , Desensibilización Psicológica/métodos
3.
CNS Neurosci Ther ; 30(4): e14517, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-37927136

RESUMEN

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.


Asunto(s)
Células Madre Mesenquimatosas , Dependencia de Morfina , Síndrome de Abstinencia a Sustancias , Humanos , Ratas , Animales , Morfina , Dependencia de Morfina/tratamiento farmacológico , Administración Intranasal , Enfermedades Neuroinflamatorias , Secretoma , Naloxona/farmacología , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Glutamatos , Antagonistas de Narcóticos/farmacología
4.
Am J Ophthalmol ; 260: 84-90, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38103875

RESUMEN

PURPOSE: To describe the ophthalmology primary practice emphasis area by underrepresented in medicine (URiM) status using the American Board of Ophthalmology (ABO) Diplomates database. DESIGN: Retrospective cohort study. METHODS: The study was based on a retrospective review of the ABO database from 1992 to 2020. The datapoints recorded included age at time of graduation and at time of certification, sex/gender, self-reported race/ethnicity, year of graduation and of certification, region of practice in the United States, and the self-reported primary practice emphasis area within ophthalmology. The URiM cohort included self-identified Black, Hispanic/Latinx, American Indian and Alaska Native, and Native Hawaiian and Other Pacific Islander individuals. Statistical analysis was conducted using Pearson χ2, Student t, and Fisher exact tests. RESULTS: A total of 575 (10.1%) ophthalmologists self-identified as URiM, vs 5132 (89.9%) as non-URiM. Diplomates who were URiM were more likely to be female and to be older at the time of ABO certification than those who were not URiM (P < .001). Over time, there was a steady decrease in the percentage of diplomates who were URiM (P < .001). There was a statistically significantly higher percentage of URiM ophthalmologists who reported glaucoma as their primary area of emphasis (P = .039) and non-URiM ophthalmologists who reported oncology, pathology, international, or genetics (P = .015), but no significant differences in the remaining subspecialties (P ≥ .123). CONCLUSIONS: There were modest differences in reported ophthalmology primary practice emphasis areas between URiM and non-URiM ABO diplomates. Despite efforts to increase diversity in ophthalmology, the percentage of graduating URiM ABO diplomates has decreased over the past 2 decades.


Asunto(s)
Oftalmólogos , Femenino , Humanos , Masculino , Certificación , Etnicidad , Estudios Retrospectivos , Estados Unidos , Grupos Raciales
5.
Int J Mol Sci ; 24(23)2023 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-38069404

RESUMEN

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.


Asunto(s)
Dependencia de Morfina , Trastornos Relacionados con Sustancias , Humanos , Ratas , Animales , Morfina/efectos adversos , Analgésicos Opioides/farmacología , Ratas Wistar , Naloxona/farmacología , Encéfalo , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Etanol/farmacología , Antagonistas de Narcóticos/farmacología
6.
Antioxidants (Basel) ; 12(9)2023 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-37760061

RESUMEN

High ethanol consumption triggers neuroinflammation, implicated in sustaining chronic alcohol use. This inflammation boosts glutamate, prompting dopamine release in reward centers, driving prolonged drinking and relapse. Fibrate drugs, activating peroxisome proliferator-activated receptor alpha (PPAR-α), counteract neuroinflammation in other contexts, prompting investigation into their impact on ethanol-induced inflammation. Here, we studied, in UChB drinker rats, whether the administration of fenofibrate in the withdrawal stage after chronic ethanol consumption reduces voluntary intake when alcohol is offered again to the animals (relapse-type drinking). Furthermore, we determined if fenofibrate was able to decrease ethanol-induced neuroinflammation and oxidative stress in the brain. Animals treated with fenofibrate decreased alcohol consumption by 80% during post-abstinence relapse. Furthermore, fenofibrate decreased the expression of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukins IL-1ß and IL-6, and of an oxidative stress-induced gene (heme oxygenase-1), in the hippocampus, nucleus accumbens, and prefrontal cortex. Animals treated with fenofibrate showed an increase M2-type microglia (with anti-inflammatory proprieties) and a decrease in phagocytic microglia in the hippocampus. A PPAR-α antagonist (GW6471) abrogated the effects of fenofibrate, indicating that they are dependent on PPAR-α activation. These findings highlight the potential of fenofibrate, an FDA-approved dyslipidemia medication, as a supplementary approach to alleviating relapse severity in individuals with alcohol use disorder (AUD) during withdrawal.

7.
Clin Ophthalmol ; 17: 1967-1974, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37457873

RESUMEN

Purpose: To evaluate a novel sutureless glueless technique using a triple-layer dehydrated amniotic membrane (TLDAM) for pterygia excisions in surgical time, postoperative pain, epiphora, irritation, and FBS. Methods: Twenty eyes with pterygia underwent excision with mitomycin C. The conjunctival defect was closed with TLDAM placed on the dried scleral bed with the edges of the amniotic membrane tucked under the edges of the conjunctival defect. Surgical times were measured from injection of lidocaine to final placement of bandage contact lens. After a bandage contact lens was placed, the eye was patched until POD1. Patients graded self-administered questionnaires to rate pain, FBS, irritation, and epiphora on a scale of 1-5 (1-none; 5-severe) at POD1 and POW1. Results: Surgical times ranged from 6:55 to 12:00, with mean of 8:29. Compared with a previous study of sutureless glueless methodology, the difference in mean surgical time was 11.9 (p < 0.0001). Mean questionnaire scores were as follows: POD1 pain 1.8, FBS 2.3, irritation 1.0, and epiphora 2.6; POW1 pain 1.5, FBS 1.6, irritation 1.6, and epiphora 1.6. Compared to previous studies, this technique showed significantly improved pain at POD1 (p=0.0086, p<0.0001, p<0.0001, p<0.0001) and POW1 (p=0.0002, p=0.0016, p<0.0001). Significant improvement in irritation and FBS was noted at POD1 and POW1. See Table 1 for full analysis. Conclusion: The sutureless glueless technique using TLDAM is a safe and effective technique compared to current standard methods. There appears to be a significant benefit regarding surgical time and postoperative pain, irritation, epiphora, and FBS compared to previous studies.

8.
Life Sci ; 328: 121876, 2023 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-37348813

RESUMEN

AIMS: Alcohol relapse is a main limitation for the treatment of alcohol use disorders. Previous studies have shown that Alda-1, a pharmacological activator of ALDH2, inhibits both acquisition and chronic ethanol intake in rats; however, its effects on relapse-like ethanol intake are unknown. The aim of this study was to assess the effect of Alda-1 on post-deprivation and reaccess relapse-like ethanol intake in alcohol-preferring UChB rats. We also aimed to assess the possible mechanisms associated with the effects of Alda-1 by measuring the levels of glutamate transporter (GLT-1), oxidative stress and neuroinflammation markers in different regions of the mesocorticolimbic system. MAIN METHODS: In Experiment I, UChB female rats were exposed for 100 days to voluntary ethanol intake followed by 2-weeks of ethanol withdrawal and 1 week of ethanol reaccess. Alda-1 (25 mg/kg, intragastric, i.g) or vehicle was administered daily for 14 days during the withdrawal/re-access period. Experiment II was similar to Experiment I, but after the withdrawal period, ethanol re-access was not allowed, and Alda-1 was administered during the last week of withdrawal. At the end of both experiments, the levels of GLT-1, oxidative stress (GSH, MDA), and neuroinflammation markers (GFAP, Iba-1) were assessed in nucleus accumbens and/or hippocampus. KEY FINDINGS: The results showed that Alda-1 administration markedly blocked (90 %, p < 0.001) relapse-like ethanol intake in UChB rats. Alda-1 increased Iba-1 reactivity (microglial marker) in the NAc of ethanol-deprived rats. Alda-1 administration did not influence the levels of GLT-1, oxidative stress markers (MDA, GSH) or GFAP reactivity in the mesocorticolimbic system. SIGNIFICANCE: These preclinical findings support the use of activators of ALDH2, such as Alda-1, as a potential pharmacological strategy in the treatment of alcohol relapse.


Asunto(s)
Alcoholismo , Etanol , Ratas , Femenino , Animales , Alcoholismo/tratamiento farmacológico , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Enfermedades Neuroinflamatorias , Aldehído Deshidrogenasa Mitocondrial , Enfermedad Crónica , Sistema de Transporte de Aminoácidos X-AG , Recurrencia
9.
Int J Vitam Nutr Res ; 93(6): 498-506, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35965421

RESUMEN

Background: The aim of this study was to evaluate the effect of propolis or metformin versus placebo on glycemic control in pharmacological treatment-naïve patients with type 2 diabetes mellitus (T2DM). Methods: A double-blind, randomized, placebo-controlled in parallel groups clinical trial was performed in 36 pharmacological treatment-naïve patients with T2DM. They received propolis (300 mg), metformin (850 mg), or placebo twice daily before breakfast and dinner for 12 weeks. At the beginning and end of the study, fasting plasma glucose (FPG), 2-h postload glucose (2-h PG) during a 75-g oral glucose tolerance test, glycated hemoglobin A1c (A1C) and a metabolic profile were measured. Areas under the curve (AUC) of glucose and insulin, total insulin secretion (insulinogenic index), the first phase of insulin secretion (Stumvoll index), and insulin sensitivity (Matsuda index) were calculated. Statistical analyses: Kruskal-Wallis, Mann-Whitney U and Wilcoxon tests. Results: The propolis and metformin groups exhibited significant reductions in FPG (p=0.009 and p=0.001, respectively), 2-h PG (p=0.034 and p=0.001, respectively) levels, AUC of insulin, Stumvoll index, and an increment in the Matsuda index. The comparison of the changes from baseline to the end showed significant differences between placebo and propolis in FPG (p=0.004) and A1C (p=0.049) levels, while between placebo and metformin were in FPG (p=0.002), 2-h PG (p=0.004) and A1C (p=0.007) levels. Conclusions: The administration of propolis and metformin compared to placebo reduced FPG and A1C levels; in addition, metformin decreased 2-h PG, AUC of glucose and insulin, high-density lipoprotein cholesterol, and increased the insulin sensitivity.


Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Metformina , Própolis , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metformina/uso terapéutico , Metformina/farmacología , Própolis/uso terapéutico , Hemoglobina Glucada , Glucemia/metabolismo , Insulina/metabolismo , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/farmacología , Método Doble Ciego
10.
Transl Psychiatry ; 12(1): 462, 2022 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-36333316

RESUMEN

The 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.


Asunto(s)
Células Madre Mesenquimatosas , Trastornos Relacionados con Opioides , Síndrome de Abstinencia a Sustancias , Humanos , Animales , Ratas , Morfina/farmacología , Ratas Wistar , Secretoma , Etanol , Recurrencia , Enfermedad Crónica , Modelos Animales , Agua
11.
Drug Alcohol Depend ; 236: 109466, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35489181

RESUMEN

RATIONALE: Gut microbiota communicates information to the brain. Some animals are born with a gut microbiota that predisposes to high alcohol consumption, and transplantation of fecal material from alcoholics to mice increases animal preference for ethanol. Alcohol-use-disorders are chronic conditions where relapse is the hallmark. A predictive animal model of relapse is the "alcohol deprivation effect" where ethanol re-access is allowed following chronic alcohol intake and a long alcohol deprivation. The present study evaluates the effect of gut microbiota modification on relapse, as an adjunct to N-acetylcysteine + Acetylsalicylic acid administration, which inhibits the alcohol-induced hyper-glutamatergic condition. METHODS: Rats bred as heavy alcohol consumers (UChB) were allowed ethanol intake for one month, were deprived of alcohol for two-weeks and subsequently offered re-access to ethanol. Prior to ethanol re-access animals received orally either (i) vehicle-control, (ii) Lactobacillus-rhamnosus-GG after antibiotic treatment (LGG); (iii) N-acetylcysteine+Acetylsalicylic acid (NAC/ASA) or (iv) both treatments: LGG+ (NAC/ASA). RESULTS: Marked binge drinking (1.75 g ethanol/kg in 60 min) and blood alcohol levels exceeding 80 mg/dl were observed in the control group upon ethanol-re-access. Lactobacillus-GG or (NAC+ASA) treatments inhibited alcohol intake by 66-80%. The combination of both treatments virtually suppressed (inhibition of 90%) the re-access binge-like drinking, showing additive effects. Treatment with NAC+ASA increased the levels of glutamate transporters xCT and GLT-1 in nucleus accumbens, while Lactobacillus-GG administration increased those of the dopamine transporter (DAT). CONCLUSIONS: The administration of a well-accepted probiotic may be of value as an adjunct in the treatment of alcohol-use-disorders.


Asunto(s)
Trastornos Relacionados con Alcohol , Alcoholismo , Microbiota , Acetilcisteína/farmacología , Acetilcisteína/uso terapéutico , Consumo de Bebidas Alcohólicas , Alcoholismo/tratamiento farmacológico , Animales , Aspirina , Enfermedad Crónica , Etanol , Humanos , Ratones , Ratas , Recurrencia
12.
Int J Mol Sci ; 23(7)2022 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-35409269

RESUMEN

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.


Asunto(s)
Dependencia de Morfina , Trastornos Relacionados con Opioides , Animales , Modelos Animales de Enfermedad , Morfina/farmacología , Trastornos Relacionados con Opioides/tratamiento farmacológico , Quinina/farmacología , Quinina/uso terapéutico , Ratas , Gusto , Agua
13.
Addict Biol ; 27(2): e13140, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35229957

RESUMEN

Previous studies showed that vagotomy markedly inhibits alcohol self-administration. Present studies hypothesised that vagotomy significantly adds to the inhibition of alcohol relapse induced by drugs that reduce the alcohol-induced hyperglutamatergic state (e.g., N-acetylcysteine + acetylsalicylic acid). The alcohol relapse paradigm tested gauges the elevated alcohol intake observed in animals that had consumed ethanol chronically, were subjected to a prolonged alcohol deprivation and are subsequently allowed ethanol re-access. Ethanol-drinker rats (UChB) were exposed to 10% and 20% ethanol and water concurrently for 4 months, were alcohol deprived for 14 days and were thereafter allowed re-access to the ethanol solutions. An initial binge-like drinking episode is observed upon ethanol re-access, followed by a protracted elevated ethanol intake that exceeds the predeprivation intake baseline. Prior to ethanol re-access, animals were (i) administered N-acetylcysteine (40 mg/kg/day) + acetylsalicylic acid (15 mg/kg/day), (ii) were bilaterally vagotomised, (iii) were exposed to both treatments or (iv) received no treatments. The initial binge-like relapse intake and a protracted elevated ethanol intake observed after repeated ethanol deprivations/re-access cycles were inhibited by 50%-70% by the administration of N-acetylcysteine + acetylsalicylic acid and by 40%-70% by vagotomy, while the combined vagotomy plus N-acetylcysteine + acetylsalicylic acid treatment inhibited both the initial binge-like intake and the protracted ethanol intake by >95% (p < 0.001), disclosing a dual mechanism of ethanol relapse and subsequent inhibition beyond that induced by either treatment alone. Future exploration into the mechanism by which vagal activity contributes to ethanol relapse may have translational promise.


Asunto(s)
Consumo de Bebidas Alcohólicas , Etanol , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Animales , Enfermedad Crónica , Etanol/farmacología , Ratas , Recurrencia , Autoadministración
14.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806988

RESUMEN

The effect of perinatal asphyxia (PA) on oligodendrocyte (OL), neuroinflammation, and cell viability was evaluated in telencephalon of rats at postnatal day (P)1, 7, and 14, a period characterized by a spur of neuronal networking, evaluating the effect of mesenchymal stem cell (MSCs)-treatment. The issue was investigated with a rat model of global PA, mimicking a clinical risk occurring under labor. PA was induced by immersing fetus-containing uterine horns into a water bath for 21 min (AS), using sibling-caesarean-delivered fetuses (CS) as controls. Two hours after delivery, AS and CS neonates were injected with either 5 µL of vehicle (10% plasma) or 5 × 104 MSCs into the lateral ventricle. Samples were assayed for myelin-basic protein (MBP) levels; Olig-1/Olig-2 transcriptional factors; Gglial phenotype; neuroinflammation, and delayed cell death. The main effects were observed at P7, including: (i) A decrease of MBP-immunoreactivity in external capsule, corpus callosum, cingulum, but not in fimbriae of hippocampus; (ii) an increase of Olig-1-mRNA levels; (iii) an increase of IL-6-mRNA, but not in protein levels; (iv) an increase in cell death, including OLs; and (v) MSCs treatment prevented the effect of PA on myelination, OLs number, and cell death. The present findings show that PA induces regional- and developmental-dependent changes on myelination and OLs maturation. Neonatal MSCs treatment improves survival of mature OLs and myelination in telencephalic white matter.


Asunto(s)
Asfixia/metabolismo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Vaina de Mielina/metabolismo , Animales , Animales Recién Nacidos , Puntaje de Apgar , Asfixia/etiología , Biomarcadores , Encéfalo/metabolismo , Encéfalo/patología , Diferenciación Celular , Supervivencia Celular , Citocinas/genética , Citocinas/metabolismo , Expresión Génica , Hipocampo/metabolismo , Hipocampo/patología , Inmunohistoquímica , Mediadores de Inflamación , Células Madre Mesenquimatosas/citología , Vaina de Mielina/patología , Neuroglía/inmunología , Neuroglía/metabolismo , Oligodendroglía/metabolismo , ARN Mensajero , Ratas
15.
Addict Biol ; 26(4): e13018, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33508889

RESUMEN

Gut microbiota is known to be transferred from the mother to their offspring. This study determines whether the innate microbiota of rats selectively bred for generations as high alcohol drinkers play a role in their alcohol intake. Wistar-derived high-drinker UChB rats (intake 10-g ethanol/kg/day) administered nonabsorbable oral antibiotics before allowing access to alcohol, reducing their voluntary ethanol intake by 70%, an inhibition that remained after the antibiotic administration was discontinued. Oral administration of Lactobacillus rhamnosus Gorbach-Goldin (GG) induced the synthesis of FGF21, a vagal ß-Klotho receptor agonist, and partially re-invoked a mechanism that reduces alcohol intake. The vagus nerve constitutes the main axis transferring gut microbiota information to the brain ("microbiota-gut-brain" axis). Bilateral vagotomy inhibited rat alcohol intake by 75%. Neither antibiotic treatment nor vagotomy affected total fluid intake. A microbiota-mediated marked inflammatory environment was observed in the gut of ethanol-naïve high-drinker rats, as gene expression of proinflammatory cytokines (TNF-α; IL-6; IL-1ß) was significantly reduced by nonabsorbable antibiotic administration. Gut cytokines are known to activate the vagus nerve, while vagal activation induces pro-rewarding effects in nucleus accumbens. Both alcoholics and alcohol-preferring rats share a marked preference for sweet tastes-likely an evolutionary trait to seek sweet fermented fruits. Saccharin intake by UChB rats was inhibited by 75%-85% by vagotomy or oral antibiotic administration, despite saccharin-induced polydipsia. Overall, data indicate that the mechanisms that normally curtail heavy drinking are inhibited in alcohol-preferring animals and inform a gut microbiota origin. Whether it applies to other mammals and humans merits further investigation.


Asunto(s)
Alcoholismo/metabolismo , Microbioma Gastrointestinal/fisiología , Animales , Etanol/administración & dosificación , Genotipo , Masculino , Ratas , Ratas Wistar , Sacarina/administración & dosificación , Autoadministración
16.
Antioxidants (Basel) ; 11(1)2021 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-35052577

RESUMEN

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.

17.
Addict Biol ; 26(1): e12853, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-31733014

RESUMEN

Chronic alcohol intake leads to neuroinflammation and cell injury, proposed to result in alterations that perpetuate alcohol intake and cued relapse. Studies show that brain oxidative stress is consistently associated with alcohol-induced neuroinflammation, and literature implies that oxidative stress and neuroinflammation perpetuate each other. In line with a self-perpetuating mechanism, it is hypothesized that inhibition of either oxidative stress or neuroinflammation could reduce chronic alcohol intake and relapse. The present study conducted on alcohol-preferring rats shows that chronic ethanol intake was inhibited by 50% to 55% by the oral administration of low doses of either the antioxidant N-acetylcysteine (40 mg/kg/d) or the anti-inflammatory aspirin (ASA; 15 mg/kg/d), while the co-administration of both dugs led to a 70% to 75% (P < .001) inhibition of chronic alcohol intake. Following chronic alcohol intake, a prolonged alcohol deprivation, and subsequent alcohol re-access, relapse drinking resulted in blood alcohol levels of 95 to 100 mg/dL in 60 minutes, which were reduced by 60% by either N-acetylcysteine or aspirin and by 85% by the co-administration of both drugs (blood alcohol: 10 to 15 mg/dL; P < .001). Alcohol intake either on the chronic phase or following deprivation and re-access led to a 50% reduction of cortical glutamate transporter GLT-1 levels, while aspirin administration fully returned GLT-1 to normal levels. N-acetylcysteine administration did not alter GLT-1 levels, while N-acetylcysteine may activate the cystine/glutamate transport xCT, presynaptically inhibiting relapse. Overall, the study suggests that a neuroinflammation/oxidative stress self-perpetuation cycle maintains chronic alcohol intake and relapse drinking. The co-administration of anti-inflammatory and antioxidant agents may have translational value in alcohol-use disorders.


Asunto(s)
Acetilcisteína/uso terapéutico , Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Aspirina/uso terapéutico , Consumo Excesivo de Bebidas Alcohólicas/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Alcoholismo/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Enfermedad Crónica , Etanol/administración & dosificación , Transportador 2 de Aminoácidos Excitadores , Femenino , Ratas , Recurrencia , Autoadministración
18.
J Control Release ; 331: 443-459, 2021 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-33220325

RESUMEN

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS). Interferon (IFN)-ß constitutes one of the first-line therapies to treat MS, but has limited efficacy due to the injectable systemic administration, short half-life, and limited CNS access. To address these limitations, we developed IFN-ß-loaded chitosan/sulfobutylether-ß-cyclodextrin nanoparticles (IFN-ß-NPs) for delivery of IFN-ß into the CNS via the intranasal (i.n.) route. The nanoparticles (NPs) (≈200 nm, polydispersity ≈0.1, and zeta potential ≈20 mV) were prepared by mixing two aqueous solutions and associated human or murine IFN-ß with high efficiency (90%). Functional in vitro assays showed that IFN-ß-NPs were safe and that IFN-ß was steadily released while retaining biological activity. Biodistribution analysis showed an early and high fluorescence in the brain after nasal administration of fluorescent probe-loaded NPs. Remarkably, mice developing experimental autoimmune encephalomyelitis (EAE), an experimental model of MS, exhibited a significant improvement of clinical symptoms in response to intranasal IFN-ß-NPs (inIFN-ß-NPs), whereas a similar dose of intranasal or systemic free IFN-ß had no effect. Importantly, inIFN-ß-NPs treatment was equally effective despite a reduction of 78% in the total amount of weekly administered IFN-ß. Spinal cords obtained from inIFN-ß-NPs-treated EAE mice showed fewer inflammatory foci and demyelination, lower expression of antigen-presenting and costimulatory proteins on CD11b+ cells, and lower astrocyte and microglia activation than control mice. Therefore, IFN-ß treatment at tested doses was effective in promoting clinical recovery and control of neuroinflammation in EAE only when associated with NPs. Overall, inIFN-ß-NPs represent a potential, effective, non-invasive, and low-cost therapy for MS.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Nanopartículas , Administración Intranasal , Animales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Interferón beta/metabolismo , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/tratamiento farmacológico , Distribución Tisular
19.
Int J Mol Sci ; 21(20)2020 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-33096871

RESUMEN

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.


Asunto(s)
Asfixia Neonatal/terapia , Hipocampo/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Fármacos Neuroprotectores/farmacología , Administración Intranasal , Animales , Puntaje de Apgar , Asfixia Neonatal/patología , Conducta Animal , Muerte Celular/efectos de los fármacos , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Inflamación/patología , Inflamación/terapia , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Embarazo , Ratas Wistar
20.
Antioxidants (Basel) ; 9(9)2020 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-32899889

RESUMEN

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.

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