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1.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-33672922

RESUMEN

The identification of improved medical countermeasures against exposure to chemical warfare nerve agents (CWNAs), a class of organophosphorus compounds, is dependent on the choice of animal model used in preclinical studies. CWNAs bind to acetylcholinesterase and prevent the catalysis of acetylcholine, causing a plethora of peripheral and central physiologic manifestations, including seizure. Rodents are widely used to elucidate the effects of CWNA-induced seizure, albeit with a caveat: they express carboxylesterase activity in plasma. Carboxylesterase, an enzyme involved in the detoxification of some organophosphorus compounds, plays a scavenging role and decreases CWNA availability, thus exerting a protective effect. Furthermore, species-specific amino acid differences in acetylcholinesterase confound studies that use oximes or other compounds to restore its function after inhibition by CWNA. The creation of a human acetylcholinesterase knock-in/serum carboxylesterase knockout (C57BL/6-Ces1ctm1.1LocAChEtm1.1Loc/J; a.k.a KIKO) mouse may facilitate better modeling of CWNA toxicity in a small rodent species. The current studies characterize the effects of exposure to soman, a highly toxic CWNA, and evaluate the efficacy of anti-seizure drugs in this newly developed KIKO mouse model. Data demonstrate that a combination of midazolam and ketamine reduces seizure duration and severity, eliminates the development of spontaneous recurrent seizures, and protects certain brain regions from neuronal damage in a genetically modified model with human relevance to organophosphorus compound toxicity. This new animal model and the results of this study and future studies using it will enhance medical countermeasures development for both defense and homeland security purposes.


Asunto(s)
Acetilcolinesterasa/metabolismo , Carboxilesterasa/metabolismo , Modelos Animales de Enfermedad , Contramedidas Médicas , Soman/toxicidad , Acetilcolinesterasa/genética , Anestésicos/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Carboxilesterasa/genética , Sustancias para la Guerra Química/toxicidad , Humanos , Ketamina/farmacología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Midazolam/farmacología , Convulsiones/inducido químicamente , Convulsiones/fisiopatología , Convulsiones/prevención & control
2.
Aquat Toxicol ; 233: 105788, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33662878

RESUMEN

The gene expression response thought to underlie the negative apical effects resulting from estrogen exposure have been thoroughly described in fish. Although epigenetics are believed to play a critical role translating environmental exposures into the development of adverse apical effects, they remain poorly characterized in fish species. This study investigated alterations of DNA methylation of estrogen receptor alpha (esr1) in brain and liver tissues from 8 to 10 month old male fathead minnows (Pimephales promelas) after a 2d exposure to either 2.5 ng/L or 10 ng/L 17α-ethynylestradiol (EE2). Changes in the patterns of methylation were evaluated using targeted deep sequencing of bisulfite treated DNA in the 5' region of esr1. Methylation and gene expression were assessed at 2d of exposure and after a 7 and 14d depuration period. After 2d EE2 exposure, males exhibited significant demethylation in the 5' upstream region of esr1 in liver tissue, which was inversely correlated to gene expression. This methylation pattern reflected what was seen in females. No gene body methylation (GBM) was observed for liver of exposed males. Differential methylation was observed for a single upstream CpG site in the liver after the 14d depuration. A less pronounced methylation response was observed in the upstream region in brain tissue, however, several CpGs were necessarily excluded from the analysis. In contrast to the liver, a significant GBM response was observed across the entire gene body, which was sustained until at least 7d post-exposure. No differential expression was observed in the brain, limiting functional interpretation of methylation changes. The identification of EE2-dependent changes in methylation levels strongly suggests the importance of epigenetic mechanisms as a mediator of the organismal response to environmental exposures and the need for further characterization of the epigenome. Further, differential methylation following depuration indicates estrogenic effects persist well after the active exposure, which has implications for the risk posed by repeated exposures..


Asunto(s)
Cyprinidae/metabolismo , Metilación de ADN/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Etinilestradiol/toxicidad , Expresión Génica/efectos de los fármacos , Contaminantes Químicos del Agua/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cyprinidae/genética , Estrógenos/metabolismo , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Vitelogeninas/metabolismo
3.
Life Sci ; 273: 119303, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33667518

RESUMEN

AIM: The current study aims to investigate the impact of paradoxical (REM) sleep deprivation and/or epileptic seizures on rat's cortical brain tissues. MAIN METHODS: Animals were divided into four groups; control, epileptic, REM sleep deprived and epileptic subjected to REM sleep deprivation. Electrocorticogram (ECoG) signals were recorded and quantitatively analyzed for each group. Concentrations of amino acid neurotransmitters; proinflammatory cytokines; and oxidative stress parameters; and acetylcholinesterase activity were determined in the cortex of the animals in different groups. KEY FINDINGS: Results showed significant variations in the spectral distribution of ECoG waves in the epilepsy model, 24- and 48-hours of REM sleep deprivation and their combined effects indicating a state of cortical hyperexcitability. Significant increases in NO and taurine and significant decrement in glutamine, GABA and glycine were determined. In REM sleep deprived rats significant elevation in glutamate, aspartate, glycine and taurine and a significant lowering in GABA were obtained. This was accompanied by significant reduction in AchE and IL-ß. In the cortical tissue of epileptic rats deprived from REM sleep significant increases in lipid peroxidation, TNF-α, IL-1ß, IL-6 and aspartate and a significant reduction in AchE were observed. SIGNIFICANCE: The present data indicate that REM sleep deprivation induces an increase in lipid peroxidation and storming in proinflammatory cytokines in the cortex of rat model of epilepsy during SRS. These changes are associated with a decreased seizure threshold as inferred from the increase in alpha and Beta waves and a decrease in Delta waves of ECoG.


Asunto(s)
Encéfalo/patología , Neurotransmisores/toxicidad , Estrés Oxidativo/efectos de los fármacos , Convulsiones/complicaciones , Privación de Sueño/complicaciones , Sueño REM/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Electrofisiología , Peroxidación de Lípido , Masculino , Ratas , Ratas Wistar
4.
Anticancer Res ; 41(3): 1445-1449, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788736

RESUMEN

BACKGROUND: Limited brain metastasis is treated definitively with stereotactic radiosurgery when surgical resection is not indicated. Although this has historically been performed in a single fraction, multi-fraction approaches such as fraction radiosurgery (FSRS) and staged radiosurgery (SSRS) have been recently examined as alternative approaches for larger lesions to permit better tumor control without increased toxicity. CASE REPORT: We present the case of a patient who developed symptomatic radionecrosis in two brain metastasis, 2.3 cm and 2.1 cm in size, which were treated with 18 Gy in one fraction, but no radionecrosis in a 3.3 cm lesion treated in two fractions of 15 Gy nor in two punctate lesions that were treated in one fraction of 20 Gy. Although she did not respond to steroids, she responded to bevacizumab symptomatically and on neuroimaging. CONCLUSION: Congruent with other recent studies, our report suggests that large brain metastasis should be considered for FSRS/SSRS.


Asunto(s)
Neoplasias Encefálicas/radioterapia , Encéfalo/efectos de la radiación , Fraccionamiento de la Dosis de Radiación , Radiocirugia/métodos , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Femenino , Humanos , Necrosis/radioterapia , Resultado del Tratamiento
5.
J Insect Sci ; 21(1)2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33560356

RESUMEN

Honey bees are important pollinators of wild plants and crops. MicroRNAs (miRNAs) are endogenous regulators of gene expression. In this study, we initially determined that the lethal concentration 50 (LC50) of dinotefuran was 0.773 mg/l. Then, the expression profiles and differentially expressed miRNAs (DE miRNAs) in honey bee brains after 1, 5, and 10 d of treatment with the lethal concentration 10 (LC10) of dinotefuran were explored via deep small-RNA sequencing and bioinformatics. In total, 2, 23, and 27 DE miRNAs were identified after persistent exposure to the LC10 of dinotefuran for 1, 5, and 10 d, respectively. Some abundant miRNAs, such as ame-miR-375-3p, ame-miR-281-5p, ame-miR-3786-3p, ame-miR-10-5p, and ame-miR-6037-3p, were extremely significantly differentially expressed. Enrichment analysis suggested that the candidate target genes of the DE miRNAs are involved in the regulation of biological processes, cellular processes, and behaviors. These results expand our understanding of the regulatory roles of miRNAs in honey bee Apis mellifera (Hymenopptera: Apidae) responses to neonicotinoid insecticides and facilitate further studies on the functions of miRNAs in honey bees.


Asunto(s)
Abejas/efectos de los fármacos , Encéfalo/metabolismo , Guanidinas/toxicidad , Insecticidas/toxicidad , MicroARNs/genética , Neonicotinoides/toxicidad , Nitrocompuestos/toxicidad , Transcriptoma , Animales , Abejas/genética , Abejas/metabolismo , Encéfalo/efectos de los fármacos , MicroARNs/metabolismo
6.
Am J Public Health ; 111(4): 687-695, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33600256

RESUMEN

Robust data from longitudinal birth cohort studies and experimental studies of perinatally exposed animals indicate that exposure to ortho-phthalates can impair brain development and increase risks for learning, attention, and behavioral disorders in childhood. This growing body of evidence, along with known adverse effects on male reproductive tract development, calls for immediate action.Exposures are ubiquitous; the majority of people are exposed to multiple ortho-phthalates simultaneously. We thus recommend that a class approach be used in assessing health impacts as has been done with other chemical classes. We propose critically needed policy reforms to eliminate ortho-phthalates from products that lead to exposure of pregnant women, women of reproductive age, infants, and children. Specific attention should be focused on reducing exposures among socially vulnerable populations such as communities of color, who frequently experience higher exposures.Ortho-phthalates are used in a vast array of products and elimination will thus necessitate a multipronged regulatory approach at federal and state levels. The fact that manufacturers and retailers have already voluntarily removed ortho-phthalates from a wide range of products indicates that this goal is feasible.


Asunto(s)
Encéfalo/efectos de los fármacos , Exposición a Riesgos Ambientales/efectos adversos , Ácidos Ftálicos , Formulación de Políticas , Efectos Tardíos de la Exposición Prenatal , Reproducción/efectos de los fármacos , Animales , Niño , Desarrollo Infantil/efectos de los fármacos , Femenino , Regulación Gubernamental , Humanos , Lactante , Estudios Longitudinales , Masculino , Ácidos Ftálicos/efectos adversos , Ácidos Ftálicos/toxicidad , Embarazo
7.
Ecotoxicol Environ Saf ; 212: 111999, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33550078

RESUMEN

Tramadol is a widely used analgesic with additional antidepressant and anxiolytic effects. This compound has been reported in continental waters reaching concentrations of µg/L as a consequence of its inefficient removal in sewage treatment plants and increasing use over time. In this study, European chubs (Squalius cephalus) were exposed to 1 µg/L of tramadol in water for 42 days with a subsequent 14 days of depuration. Our results revealed that chubs exposed to this analgesic underwent changes in their behaviour as compared to the control group. The behavioural outcome was also influenced by the individual concentration of tramadol in brain tissue. In particular, experimental fish presented anxiolytic-like effects, characterized by less bold and less social individuals. Exposed animals were less frequently out of the shelter and moved a shorter distance, indicating that they explored the new environment less during the boldness test. In the novel object recognition experiment, although they distinguished the new item, they examined it less and displayed a reduced activity. Shoal cohesion was disrupted as observed in an increased distance between individuals. After the depuration phase, this alteration remained whereas the boldness effect disappeared. Moreover, the degree of behavioural changes was correlated with the concentration of the substance in brain. According to our findings, chronic presence of tramadol in the environment can impact the fitness of exposed aquatic fauna by altering evolutionary crucial behaviours.


Asunto(s)
Conducta Animal/efectos de los fármacos , Cyprinidae/fisiología , Tramadol/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Agua Dulce/química , Tramadol/metabolismo , Contaminantes Químicos del Agua/metabolismo
8.
Int J Nanomedicine ; 16: 775-788, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33574665

RESUMEN

Background: Intracerebral hemorrhage (ICH) is a common neurological crisis leading to high mortality and morbidity. Oxidative stress-induced secondary injury plays a critical role in neurological deterioration. Previously, we synthesized a porous Se@SiO2 nanocomposite and identified their therapeutic role in osteonecrosis of the femoral head. Whether this nanocomposite is neuroprotective remains to be elucidated. Methods: A porous Se@SiO2 nanocomposite was synthesized, and its biosafety was determined using a CCK-8 assay. The neuroprotective effect was evaluated by TUNEL staining, and intracellular ROS were detected with a DCFH-DA probe in SH-SY5Y cells exposed to hemin. Furthermore, the effect of the nanocomposite on cell apoptosis, brain edema and blood-brain barrier permeability were evaluated in a collagenase-induced ICH mouse model. The potential mechanism was also explored. Results: The results demonstrated that Se@SiO2 treatment significantly improved neurological function, increased glutathione peroxidase activity and downregulated malonaldehyde levels. The proportion of apoptotic cells, brain edema and blood-brain barrier permeability were reduced significantly in ICH mice treated with Se@SiO2 compared to vehicle-treated mice. In vitro, Se@SiO2 protected SH-SY5Y cells from hemin-induced apoptosis by preventing intracellular reactive oxygen species accumulation. Conclusion: These results suggested that the porous Se@SiO2 nanocomposite exerted neuroprotection by suppressing oxidative stress. Se@SiO2 may be a potential candidate for the clinical treatment of ICH and oxidative stress-related brain injuries.


Asunto(s)
Encéfalo/patología , Hemorragia Cerebral/patología , Nanocompuestos/química , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Selenio/farmacología , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Biomarcadores/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/patología , Encéfalo/efectos de los fármacos , Edema Encefálico/complicaciones , Edema Encefálico/tratamiento farmacológico , Línea Celular Tumoral , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/tratamiento farmacológico , Citoprotección/efectos de los fármacos , Modelos Animales de Enfermedad , Hemina/toxicidad , Humanos , Masculino , Malondialdehído/metabolismo , Ratones Endogámicos C57BL , Nanocompuestos/toxicidad , Nanocompuestos/ultraestructura , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/farmacología , Selenio/uso terapéutico , Dióxido de Silicio/farmacología , Pruebas de Toxicidad
9.
Br J Anaesth ; 126(4): 845-853, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33549320

RESUMEN

BACKGROUND: Non-human primates are commonly used in neuroimaging research for which general anaesthesia or sedation is typically required for data acquisition. In this analysis, the cumulative effects of exposure to ketamine, Telazol® (tiletamine and zolazepam), and the inhaled anaesthetic isoflurane on early brain development were evaluated in two independent cohorts of typically developing rhesus macaques. METHODS: Diffusion MRI scans were analysed from 43 rhesus macaques (20 females and 23 males) at either 12 or 18 months of age from two separate primate colonies. RESULTS: Significant, widespread reductions in fractional anisotropy with corresponding increased axial, mean, and radial diffusivity were observed across the brain as a result of repeated anaesthesia exposures. These effects were dose dependent and remained after accounting for age and sex at time of exposure in a generalised linear model. Decreases of up to 40% in fractional anisotropy were detected in some brain regions. CONCLUSIONS: Multiple exposures to commonly used anaesthetics were associated with marked changes in white matter microstructure. This study is amongst the first to examine clinically relevant anaesthesia exposures on the developing primate brain. It will be important to examine if, or to what degree, the maturing brain can recover from these white matter changes.


Asunto(s)
Anestesia General/efectos adversos , Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Sustancia Blanca/efectos de los fármacos , Sustancia Blanca/diagnóstico por imagen , Animales , Animales Recién Nacidos , Encéfalo/metabolismo , Imagen de Difusión Tensora/tendencias , Femenino , Macaca mulatta , Masculino
10.
Aquat Toxicol ; 231: 105734, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33385846

RESUMEN

Several studies have suggested eugenol as a suitable anaesthetic for fish. However, it has also been regarded as a toxic and aversive substance to several aquatic organisms, including fish. This study sought to assess the eugenol-induced behavioural alterations and its seizurogenic potential to fish. Moreover, a distinctive methodology for an in vivo evaluation of the brain activity was also presented. Prior to the evaluation of eugenol-induced responses, fish were exposed to pentylenetetrazole (PTZ), to characterize any seizure-like patterns. Antagonizing responses to PTZ were assessed in fish receiving diazepam (BDZ) and subsequently exposed to PTZ. Tambaqui fish juveniles, Colossoma macropomum (15.8 ± 2.8 g) were used as models and assayed as follows: (i) fish exposed to PTZ (15 mM) and (ii) fish receiving a dose of BDZ (10 mg Kg-1) and later exposed to PTZ (15 mM) (BDZ-PTZ group). Thereafter, fish were evaluated throughout (iii) eugenol exposure at 65 µL L-1 (ethanolic solution) and recovery. Control fish and a vehicle control group (ethanol at 585 µL L-1) were also established. PTZ baths elicited body immobilization preceded by hyperactivity in a stereotyped seizure-like behaviour with increased EEG wave amplitude and frequency. PTZ effects in the brain were attenuated by a pre-administration of BDZ. Upon eugenol exposure, tambaqui had an intense neuronal excitability, showing a clonus-like seizure behaviour, also corroborated by the EEG patterns, which were consistent with a seizure-like response. Responses of eugenol-exposed fish resembled those of the PZT-exposed animals, with epileptiform discharges. EMG was in line with the EEG modulation, showing increased tracing oscillations and higher mean amplitudes in PTZ-exposed fish whereas in BDZ-PTZ group muscle contraction was less frequent and powerful. Fish exposed to eugenol showed initially some muscle activity followed by a loss of muscle tonus over time. In summary, our results showed that upon eugenol exposure, although a time-dependent body immobilization was attained, fish presented an intense neuronal excitability comparable to that evoked by PTZ. Eugenol failed to promote depression of the CNS and therefore may be not suitable to be used for general anaesthesia of C. macropomum. As eugenol could be implicated in seizurogenesis and be potentially toxic to the fish brain, protocols suggesting the broad use of eugenol for short-term anaesthesia or euthanasia of fish should be carefully revised, as it raises important concerns in terms of ethics and fish welfare.


Asunto(s)
Characiformes/fisiología , Eugenol/toxicidad , Inmovilización , Neuronas/patología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Electrodos , Electroencefalografía , Electromiografía , Fenómenos Electrofisiológicos , Masculino , Músculos/efectos de los fármacos , Neuronas/efectos de los fármacos , Pentilenotetrazol/toxicidad , Contaminantes Químicos del Agua/toxicidad
11.
Ecotoxicol Environ Saf ; 209: 111820, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33385678

RESUMEN

The objective of this study was to investigate the influence of deltamethrin (DLM)on brain function and to find whether DLM-induced neurotoxicity is prevented by the treatment with cinnamon oil. Four groups of ten Wistar albino male rats each were used. Group I (control) received saline only. Group II received cinnamon oil alone at 0.5 mg/kg B.W. intraperitonally, whereas Group III received orally DLM alone at 6 mg/kg B.W. Groups IV was treated with cinnamon oil plus DLM for 21 days to induce neurotoxicity. Rat behaviour, brain acetylcholine esterase (AChE), serotonin, oxidative stress profile were assessed. Serum sampling for the assessment of corticosterone concentration was also carried out. Finally, we demonstrate the gene expression of CYP1A1 and iNOS and the histological picture of the brain. Considering the behaviour assessment, DLM administration alone caused neurobehavioral deficits manifested by anxiety-like behavior which represented ina marked decrease in the sleeping frequency and duration, and marked increase the digging frequency and a wake non-active behavior duration. Moreover, the open field result showed a significant decrease in central square entries and duration. The neurochemical analysis revealed that DLM significantly suppressed AChE activity and elevated serotonin and corticosterone concentrations. Furthermore, results revealed thatthe brain reduced glutathione (GSH) content, superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration were significantly altered in DLM treated rats. Neurochemical disturbances were confirmed by histopathological changes in the brain. Furthermore, DLM up-regulates the mRNA expression of brain CYP1A1 and iNOS. Co-treatment with cinnamon oil exhibited significant improvement in behavioural performance and the brain antioxidant capacities with an increase in AChE activity and diminished the concentration of serotonin, serum corticosterone and MDA. Cinnamon oil treatment resulted in down-regulation of CYP1A1 and iNOS and improve the histologically picture. In conclusion, cinnamon oil ameliorated DLM-induced neurotoxicity through preventing oxidative stress-induced genotoxicity and apoptosis of brain in rats.


Asunto(s)
Cinnamomum zeylanicum , Citocromo P-450 CYP1A1/metabolismo , Insecticidas/toxicidad , Neurotransmisores/farmacología , Nitrilos/toxicidad , Aceites Volátiles/farmacología , Piretrinas/toxicidad , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Encéfalo/efectos de los fármacos , Glutatión/metabolismo , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar
12.
J Insect Sci ; 21(1)2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33400795

RESUMEN

Honey bees are important pollinators of wild plants and crops. MicroRNAs (miRNAs) are endogenous regulators of gene expression. In this study, we initially determined that the lethal concentration 50 (LC50) of dinotefuran was 0.773 mg/l. Then, the expression profiles and differentially expressed miRNAs (DE miRNAs) in honey bee brains after 1, 5, and 10 d of treatment with the lethal concentration 10 (LC10) of dinotefuran were explored via deep small-RNA sequencing and bioinformatics. In total, 2, 23, and 27 DE miRNAs were identified after persistent exposure to the LC10 of dinotefuran for 1, 5, and 10 d, respectively. Some abundant miRNAs, such as ame-miR-375-3p, ame-miR-281-5p, ame-miR-3786-3p, ame-miR-10-5p, and ame-miR-6037-3p, were extremely significantly differentially expressed. Enrichment analysis suggested that the candidate target genes of the DE miRNAs are involved in the regulation of biological processes, cellular processes, and behaviors. These results expand our understanding of the regulatory roles of miRNAs in honey bee Apis mellifera (Hymenopptera: Apidae) responses to neonicotinoid insecticides and facilitate further studies on the functions of miRNAs in honey bees.


Asunto(s)
Encéfalo/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Guanidinas/toxicidad , Insecticidas/toxicidad , MicroARNs/metabolismo , Neonicotinoides/toxicidad , Nitrocompuestos/toxicidad , Animales , Abejas , Encéfalo/metabolismo
13.
Br J Anaesth ; 126(2): 445-457, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33461725

RESUMEN

Electroencephalographic (EEG) activity is used to monitor the neurophysiology of the brain, which is a target organ of general anaesthesia. Besides its use in evaluating hypnotic states, neurophysiologic reactions to noxious stimulation can also be observed in the EEG. Recognising and understanding these responses could help optimise intraoperative analgesic management. This review describes three types of changes in the EEG induced by noxious stimulation when the patient is under general anaesthesia: (1) beta arousal, (2) (paradoxical) delta arousal, and (3) alpha dropout. Beta arousal is an increase in EEG power in the beta-frequency band (12-25 Hz) in response to noxious stimulation, especially at lower doses of anaesthesia drugs in the absence of opioids. It is usually indicative of a cortical depolarisation and increased cortical activity. At higher concentrations of anaesthetic drug, and with insufficient opioids, delta arousal (increased power in the delta band [0.5-4 Hz]) and alpha dropout (decreased alpha power [8-12 Hz]) are associated with noxious stimuli. The mechanisms of delta arousal are not well understood, but the midbrain reticular formation seems to play a role. Alpha dropout may indicate a return of thalamocortical communication, from an idling mode to an operational mode. Each of these EEG changes reflect an incomplete modulation of pain signals and can be mitigated by administration of opioid or the use of regional anaesthesia techniques. Future studies should evaluate whether titrating analgesic drugs in response to these EEG signals reduces postoperative pain and influences other postoperative outcomes, including the potential development of chronic pain.


Asunto(s)
Analgésicos/administración & dosificación , Anestesia General , Anestésicos Generales/administración & dosificación , Ondas Encefálicas/efectos de los fármacos , Encéfalo/efectos de los fármacos , Electroencefalografía , Monitorización Neurofisiológica Intraoperatoria , Nocicepción/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Dolor Postoperatorio/prevención & control , Encéfalo/fisiopatología , Relación Dosis-Respuesta a Droga , Humanos , Dolor Postoperatorio/fisiopatología , Estimulación Física , Valor Predictivo de las Pruebas , Factores de Tiempo , Resultado del Tratamiento
14.
Ecotoxicol Environ Saf ; 208: 111747, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396073

RESUMEN

Residues of the psychoactive drug diazepam (DZP) may pose potential risks to fish in aquatic environments, especially by disrupting their behavioral traits. In this study, female and male zebrafish were subjected to chronic exposure (21 days) to sublethal doses (120 and 12 µg/L) of DZP, aimed to compare the characteristics of their behavioral responses to DZP exposure, and to investigate the possible links between those behavioral responses and variations in their brain γ-aminobutyric acid (GABA) and acetylcholinesterase (AChE) levels. Chronic exposure to DZP significantly decreased the swimming velocity and locomotor activity of both genders, indicating a typical sedative effect. Compared with males, whose locomotor activity was only significantly decreased by exposure to DZP for 21 days, females became hypoactive on day 14 (i.e., more sensitive), and they developed tolerance to the hypoactive effect induced by 120 µg/L DZP by day 21. Exposure to DZP significantly disturbed the behavioral traits related to social interactions in females but not in males. Those results indicate that DZP exhibits sex-dependent effects on the behaviors of fish. Moreover, exposure to DZP for 21 days significantly disturbed almost all of the tested behavioral traits associated with courtship when both genders were put together. Sex-dependent responses in brain GABA and AChE levels due to DZP exposure were also identified. Significant relationships between the brain GABA/AChE levels and some behavioral parameters related to locomotor activity were detected in females, but not in males.


Asunto(s)
Diazepam/toxicidad , Pruebas de Toxicidad Crónica , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/fisiología , Acetilcolinesterasa/metabolismo , Animales , Encéfalo/efectos de los fármacos , Diazepam/administración & dosificación , Femenino , Masculino , Actividad Motora/efectos de los fármacos , Natación , Pez Cebra/metabolismo , Ácido gamma-Aminobutírico/farmacología
15.
Ecotoxicol Environ Saf ; 208: 111620, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396140

RESUMEN

Di(2-ethylhexyl) adipate (DEHA) is a widely used plasticizer and prevalent environmental contaminant. In this study, DEHA concentrations in the milk, cheese, and butter samples wrapped with food-grade commercial polyethylene films and stored at 4 °C for 30 days were detected using gas chromatographic analysis. Also, the effects of exposure to a high dose of DEHA for a long duration on the liver, brain, and heart of Wistar rats were assessed. Besides, the possible beneficial effect of Peganum harmala oil (PGO), in relieving DEHA induced adverse effects was explored. For this purpose, four groups (8 rats/group) were orally given physiological saline, PGO (320 mg/kg bwt), DEHA (2000 mg/kg bwt), or PGO + DEHA for 60 days. The results revealed that the DEHA concentrations in the tested dairy products were ordered as follows: (butter > cheese > milk). Notably, the detected levels in butter were higher than the specific migration limit in foods. DEHA induced a significant increase in the serum levels of glucose, alanine transaminase, aspartate transaminase, acetylcholine esterase, creatine kinase-myocardium bound, malondialdehyde, tumor necrosis factor-α, and interleukin-1ß. But, significant hypoproteinemia, hypoalbuminemia, hypoglobulinemia, and hypocholesterolemia were evident following DEHA exposure. A significant reduction in the serum level of superoxide dismutase, reduced glutathione, and brain-derived neurotrophic factor was recorded. Besides, a significant downregulation in hepatic CYP2E1, brain glial fibrillary acidic protein, and cardiac troponin I gene expression was noticed. Moreover, DEHA exposure induced a significant decrease in Bcl-2 immunolabeling, but Caspase-3 immunoexpression was increased. On the contrary, PGO significantly recused DEHA injurious impacts. Therefore, PGO could represent a promising agent for preventing DEHA-induced hepatotoxicity, neurotoxicity, and cardiotoxicity.


Asunto(s)
Adipatos/toxicidad , Encéfalo/efectos de los fármacos , Corazón/efectos de los fármacos , Hígado/efectos de los fármacos , Peganum/química , Aceites Vegetales/farmacología , Plastificantes/toxicidad , Adipatos/análisis , Anemia/sangre , Anemia/prevención & control , Animales , Glucemia/análisis , Encéfalo/metabolismo , Encéfalo/patología , Productos Lácteos/análisis , Embalaje de Alimentos , Hígado/metabolismo , Hígado/patología , Pruebas de Función Hepática , Masculino , Miocardio/metabolismo , Miocardio/patología , Estrés Oxidativo/efectos de los fármacos , Plastificantes/análisis , Ratas , Ratas Wistar , Factores de Tiempo
16.
Br J Anaesth ; 126(4): 835-844, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33386125

RESUMEN

BACKGROUND: Propofol, a commonly used intravenous anaesthetic, binds to type A gamma aminobutyric acid (GABA) receptors in mammalian brain. Previous work on its anaesthetic action has characterised either the biochemistry underlying propofol binding or the associated changes in brain network dynamics during sedation. Despite these advances, no study has focused on understanding how propofol action at the cellular level results in changes in brain network connectivity. METHODS: We used human whole-brain microarray data to generate distribution maps for genes that mark the primary GABAergic cortical interneurone subtypes (somatostatin, parvalbumin [PV], and 5-hydroxytryptamine 3A. Next, 25 healthy participants underwent propofol-induced sedation during resting state functional MRI scanning. We used partial least squares analysis to identify the brain regions in which connectivity patterns were most impacted by propofol sedation. We then correlated these multimodal cortical patterns to determine if a specific interneurone subtype was disproportionately expressed in brain regions in which connectivity patterns were altered during sedation. RESULTS: Brain networks that were significantly altered by propofol sedation had a high density of PV-expressing GABAergic interneurones. Brain networks that anticorrelated during normal wakefulness, namely the default mode network and attentional and frontoparietal control networks, increased in correlation during sedation. CONCLUSIONS: PV-expressing interneurones are highly expressed in brain regions with altered connectivity profiles during propofol-induced sedation. This study also demonstrates the utility of leveraging multiple datasets to address multiscale neurobiological problems.


Asunto(s)
Corteza Cerebral/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Interneuronas/efectos de los fármacos , Red Nerviosa/efectos de los fármacos , Parvalbúminas , Propofol/farmacología , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Femenino , Neuronas GABAérgicas/metabolismo , Humanos , Interneuronas/metabolismo , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/metabolismo , Parvalbúminas/metabolismo , Análisis por Matrices de Proteínas/métodos
17.
Psychopharmacology (Berl) ; 238(3): 845-855, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33410984

RESUMEN

RATIONALE: Systemic administration of the tobacco smoke constituent nicotine stimulates brain reward function in rats. However, it is unknown if the inhalation of tobacco smoke affects brain reward function. OBJECTIVES: These experiments investigated if exposure to smoke from high-nicotine SPECTRUM research cigarettes increases reward function and affects the rewarding effects of nicotine in adult male and female Wistar rats. METHODS: Reward function after smoke or nicotine exposure was investigated using the intracranial self-stimulation (ICSS) procedure. A decrease in reward thresholds reflects an increase in reward function. In the first experiment, the rats were exposed to tobacco smoke for 40 min/day for 9 days, and the rewarding effects of nicotine (0.03-0.6 mg/kg) were investigated 3 weeks later. In the second experiment, the dose effects of tobacco smoke exposure (40-min sessions, 1-4 cigarettes burnt simultaneously) on reward function were investigated. RESULTS: Tobacco smoke exposure did not affect the nicotine-induced decrease in reward thresholds or response latencies in male and female rats. Smoke exposure lowered the brain reward thresholds to a similar degree in males and females and caused a greater decrease in latencies in females. There was a positive relationship between plasma nicotine and cotinine levels and the nicotine content of the SPECTRUM research cigarettes. Similar smoke exposure conditions led to higher plasma nicotine and cotinine levels in female than male rats. CONCLUSION: These findings indicate that tobacco smoke exposure enhances brain reward function but does not potentiate the rewarding effects of nicotine in male and female rats.


Asunto(s)
Encéfalo/efectos de los fármacos , Nicotina/administración & dosificación , Tiempo de Reacción/efectos de los fármacos , Recompensa , Contaminación por Humo de Tabaco/efectos adversos , Tabaquismo/psicología , Animales , Cotinina/sangre , Femenino , Masculino , Nicotina/sangre , Nicotina/farmacología , Ratas , Ratas Wistar , Autoestimulación/efectos de los fármacos , Tabaco , Tabaquismo/sangre
18.
Nutr Metab Cardiovasc Dis ; 31(1): 333-343, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33500109

RESUMEN

BACKGROUND AND AIMS: Diabetes is one of the most important risk factors and comorbidities of ischemic stroke. Endoplasmic reticulum stress (ERS) is considered to be the major injury mechanism of ischemic stroke with diabetes. Studies have found that incretin can inhibit ERS in ischemia-reperfusion injury of the liver and heart. We aimed to explore the effects of GLP-1/GIP double agonist DA3-CH and GLP-1 single agonist liraglutide on ERS and apoptosis in diabetic rats with cerebral ischemia-reperfusion injury. METHODS AND RESULTS: 72 Sprague-Dawley (SD) male rats were randomly divided into 4 groups: ① blank group (Sham group, n = 18); model group (Saline group, n = 18); DA3 treatment group (DA3 group, n = 18); liraglutide treatment group (Lir group, n = 18). The Sham group was not given any treatment and was only raised in the same environment as the other groups. The remaining 3 groups used STZ-induced diabetes models. After the successful membrane formation of diabetes, DA3-CH and liraglutide (10 mmol/kg, once-daily for 14 days) were injected intraperitoneally. Thereafter, rats were subjected to middle cerebral artery occlusion followed by 24-h reperfusion. Animals were evaluated for neurologic deficit score, infarct volume, and biomarker analyses of the brain after ischemia. The DA3-CH-treated and liraglutide-treated groups showed significantly reduced scores of neurological dysfunction and cerebral infarction size, and reduced the expression of ERS markers GRP78, CHOP and Caspase-12, and the expression of apoptosis marker bax. Anti-apoptotic markers bcl-2 and neuronal numbers increased significantly. CONCLUSIONS: DA3-CH and liraglutide have obvious neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes, which can reduce the infarct size and the neurological deficit score. Their exert neuroprotective effects in a rat model of cerebral ischemia-reperfusion injury with diabetes by inhibiting endoplasmic reticulum stress and thereby reducing apoptosis. DA3 is better than liraglutide.


Asunto(s)
Encéfalo/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Hipoglucemiantes/farmacología , Incretinas/farmacología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Liraglutida/farmacología , Péptidos/farmacología , Daño por Reperfusión/prevención & control , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Ratas Sprague-Dawley , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de la Hormona Gastrointestinal/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Transducción de Señal , Estreptozocina
19.
BMC Neurol ; 21(1): 8, 2021 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-33407227

RESUMEN

BACKGROUND: Clinically, bromadiolone poisoning is characterized by severe bleeding complications in various organs and tissues. Bromadiolone-induced toxic encephalopathy is extremely rare. Here, we report a special case of bromadiolone-induced reversible toxic encephalopathy in a patient who had symmetrical lesions in the deep white matter. CASE PRESENTATION: A 23-year-old woman mainly presented with dizziness, fatigue, alalia and unsteady gait after the ingestion of bromadiolone. The laboratory examinations showed normal coagulation levels. Brain magnetic resonance imaging (MRI) showed apparent diffusion restriction in the bilateral deep white matter. The clinical manifestations and MRI alterations were reversible within one month of treatment with vitamin K. The neuropsychological assessment showed no neurodegenerative changes at the 2-year follow-up. CONCLUSION: With the increased use of bromadiolone as a rodenticide, more cases of ingestion have been reported annually over the past several years. Bromadiolone-induced toxic encephalopathy has no special clinical manifestations and is potentially reversible with timely treatment. Because of the reversible restricted diffusion on diffusion-weighted images (DWI) and low apparent diffusion coefficient (ADC) values, transient intramyelinic cytotoxic oedema is thought to be the cause rather than persistent ischaemia. The underlying pathophysiological mechanism is still unknown and may be coagulant-independent. This clinical case extends the current knowledge about neurotoxicity in cases of bromadiolone poisoning and indicates that MRI is useful for the early detection of bromadiolone-induced toxic encephalopathy.


Asunto(s)
4-Hidroxicumarinas/envenenamiento , Encéfalo/patología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Rodenticidas/envenenamiento , Antifibrinolíticos/uso terapéutico , Encéfalo/efectos de los fármacos , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Humanos , Síndromes de Neurotoxicidad/tratamiento farmacológico , Intento de Suicidio , Vitamina K 1/uso terapéutico , Adulto Joven
20.
Psychopharmacology (Berl) ; 238(3): 725-734, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33410983

RESUMEN

RATIONALE: Mu opioid receptor agonists are indispensable for the treatment of pain, but clinical use carries the inherent risk of transition from effective treatment to abuse. Abuse potential appears to increase rapidly during periods of initial opioid exposure in humans, and this increase in opioid reward during initial opioid exposure can be modeled in rats using an intracranial self-stimulation (ICSS) procedure. OBJECTIVES: The goal of the present study was to examine temporal parameters of this phenomenon. METHODS: Adult male Sprague-Dawley rats responded for electrical brain stimulation using a frequency-rate ICSS procedure. In the first experiment, rats received daily morphine injections for 6 days, and morphine effects on ICSS were re-determined 1 day, 1 week, or 1 month after the repeated morphine treatment regimen to evaluate the persistence of enhanced opioid reward. In the second experiment, rats received six repeated morphine injections with different interdose intervals (two per day, one per day, every other day, every fourth day), and morphine effects were re-determined 1 day after the last dose to determine dosing frequencies sufficient to produce enhanced opioid reward. RESULTS: Results of the first experiment indicated that enhanced opioid reward was greatest 1 day after the morphine treatment regimen and completely dissipated after 4 weeks. The second experiment indicated that all dosing frequencies tested were sufficient to produce enhanced reward. CONCLUSIONS: Taken together, these results suggest that enhancement of opioid reward after initial opioid exposure is relatively transient but can be produced by a range of different dosing frequencies.


Asunto(s)
Analgésicos Opioides/farmacología , Morfina/farmacología , Receptores Opioides mu/agonistas , Recompensa , Autoestimulación/efectos de los fármacos , Analgésicos Opioides/administración & dosificación , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estimulación Eléctrica , Masculino , Morfina/administración & dosificación , Dolor/tratamiento farmacológico , Dolor/metabolismo , Dolor/psicología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo
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