Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 8.183
Filtrar
1.
Nat Commun ; 15(1): 2000, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448437

RESUMO

Bioresorbable neural implants based on emerging classes of biodegradable materials offer a promising solution to the challenges of secondary surgeries for removal of implanted devices required for existing neural implants. In this study, we introduce a fully bioresorbable flexible hybrid opto-electronic system for simultaneous electrophysiological recording and optogenetic stimulation. The flexible and soft device, composed of biodegradable materials, has a direct optical and electrical interface with the curved cerebral cortex surface while exhibiting excellent biocompatibility. Optimized to minimize light transmission losses and photoelectric artifact interference, the device was chronically implanted in the brain of transgenic mice and performed to photo-stimulate the somatosensory area while recording local field potentials. Thus, the presented hybrid neural implant system, comprising biodegradable materials, promises to provide monitoring and therapy modalities for versatile applications in biomedicine.


Assuntos
Implantes Absorvíveis , Depressores do Sistema Nervoso Central , Animais , Camundongos , Optogenética , Artefatos , Encéfalo , Eletrônica , Camundongos Transgênicos
3.
Int J Mol Sci ; 25(1)2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38203763

RESUMO

Vitamin B12 (VitB12) is a micronutrient and acts as a cofactor for fundamental biochemical reactions: the synthesis of succinyl-CoA from methylmalonyl-CoA and biotin, and the synthesis of methionine from folic acid and homocysteine. VitB12 deficiency can determine a wide range of diseases, including nervous system impairments. Although clinical evidence shows a direct role of VitB12 in neuronal homeostasis, the molecular mechanisms are yet to be characterized in depth. Earlier investigations focused on exploring the biochemical shifts resulting from a deficiency in the function of VitB12 as a coenzyme, while more recent studies propose a broader mechanism, encompassing changes at the molecular/cellular levels. Here, we explore existing study models employed to investigate the role of VitB12 in the nervous system, including the challenges inherent in replicating deficiency/supplementation in experimental settings. Moreover, we discuss the potential biochemical alterations and ensuing mechanisms that might be modified at the molecular/cellular level (such as epigenetic modifications or changes in lysosomal activity). We also address the role of VitB12 deficiency in initiating processes that contribute to nervous system deterioration, including ROS accumulation, inflammation, and demyelination. Consequently, a complex biological landscape emerges, requiring further investigative efforts to grasp the intricacies involved and identify potential therapeutic targets.


Assuntos
Depressores do Sistema Nervoso Central , Deficiência de Vitamina B 12 , Humanos , Vitamina B 12 , Modelos Biológicos , Biotina , Sistema Nervoso
4.
Cells ; 12(20)2023 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-37887328

RESUMO

Three systemic biological systems, i.e., the nervous, the immune, and the cardiovascular systems, form a mutually responsive and forward-acting tissue network to regulate acute and chronic cardiovascular function in health and disease. Two sub-circuits within the cardiovascular system have been described, the artery brain circuit (ABC) and the heart brain circuit (HBC), forming a large cardiovascular brain circuit (CBC). Likewise, the nervous system consists of the peripheral nervous system and the central nervous system with their functional distinct sensory and effector arms. Moreover, the immune system with its constituents, i.e., the innate and the adaptive immune systems, interact with the CBC and the nervous system at multiple levels. As understanding the structure and inner workings of the CBC gains momentum, it becomes evident that further research into the CBC may lead to unprecedented classes of therapies to treat cardiovascular diseases as multiple new biologically active molecules are being discovered that likely affect cardiovascular disease progression. Here, we weigh the merits of integrating these recent observations in cardiovascular neurobiology into previous views of cardiovascular disease pathogeneses. These considerations lead us to propose the Neuroimmune Cardiovascular Circuit Hypothesis.


Assuntos
Doenças Cardiovasculares , Depressores do Sistema Nervoso Central , Humanos , Neuroimunomodulação , Sistema Nervoso Central , Coração , Depressores do Sistema Nervoso Central/farmacologia , Artérias
5.
J Anal Toxicol ; 47(8): 770-785, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37670456

RESUMO

In recent years, mitragynine has been consistently detected in driving under the influence of drug (DUID) cases. In this paper, we evaluate 3 years (2017-2019) worth of DUID data from arrested drivers in Orange County, CA, USA. From the 25,398 DUID cases received in those 3 years, there were 60 (0.24%) cases with detectable concentrations, >10 ng/mL, of mitragynine. The majority of drivers were male (90%) and were stopped during the week (81%), considered Monday 0000 to Friday 1159. The concentration range for all mitragynine cases was 10.5-960 ng/mL, with a mean of 109 ng/mL and a median of 58 ng/mL. Forty four of the 60 cases were also screened for 7-hydroxymitragynine, and 27 (63%) were positive. The police reports and drug recognition expert evaluations were collected and evaluated. No case contained solely mitragynine, and the most common drugs detected in combination were central nervous system depressants (ethanol, followed by benzodiazepines), stimulants (methamphetamine and cocaine) and opioids (fentanyl and indication of heroin). Two cases containing only one other psychoactive substance are discussed more thoroughly to attempt to identify the contributions of mitragynine to driving impairment. Collected demographic, toxicological and field observations are presented for all cases.


Assuntos
Condução de Veículo , Depressores do Sistema Nervoso Central , Transtornos Relacionados ao Uso de Substâncias , Masculino , Humanos , Feminino , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Etanol , Detecção do Abuso de Substâncias
6.
J Forensic Sci ; 68(6): 2205-2210, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37658657

RESUMO

Xylazine sedative, muscle relaxant, and analgesic used in a veterinary setting. Although xylazine was never approved for therapeutic use in humans, it has become popular in the street drug market as a cutting or bulking agent in the fentanyl and heroin supply. Recently, there has been a significant increase in the detection of xylazine in postmortem forensic toxicology casework. Xylazine can be identified during routine toxicology screening utilizing instrumentation such as gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. Using the Miami-Dade Medical Examiner's LIMS system, all cases received between 2015 and 2022 in which xylazine was reported were reviewed. The cases studied include accidental drug overdose deaths in Miami-Dade County as well as Collier County (Naples), Florida. In total, there are 170 cases; the majority are accidental polydrug overdoses involving White males between the ages of 25 and 44 years old. Of the 170 cases, 37% listed xylazine as the cause of death. 13% of cases contained only xylazine and fentanyl while the remaining 87% of deaths were attributed to polydrug toxicity involving two or more substances. The prevalence of xylazine can be attributed to its increasing popularity rather than an increase in caseload. In 2019, xylazine was present in only 4% of all accidental fentanyl overdoses. By 2021, this percentage has increased sixfold, with xylazine present in 24% of all accidental fentanyl overdoses. Despite a decrease in fentanyl overdoses in 2022, the percentage of xylazine detection remained the same.


Assuntos
Depressores do Sistema Nervoso Central , Overdose de Drogas , Masculino , Humanos , Adulto , Xilazina , Médicos Legistas , Prevalência , Florida/epidemiologia , Fentanila/análise , Overdose de Drogas/epidemiologia , Analgésicos Opioides/análise
7.
Molecules ; 28(18)2023 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-37764457

RESUMO

Influenza represents a profoundly transmissible viral ailment primarily afflicting the respiratory system. Neuraminidase inhibitors constitute a class of antiviral therapeutics employed in the management of influenza. These inhibitors impede the liberation of the viral neuraminidase protein, thereby impeding viral dissemination from the infected cell to host cells. As such, neuraminidase has emerged as a pivotal target for mitigating influenza and its associated complications. Here, we apply a de novo hybridization approach based on a breed-centric methodology to elucidate novel neuraminidase inhibitors. The breed technique amalgamates established ligand frameworks with the shared target, neuraminidase, resulting in innovative inhibitor constructs. Molecular docking analysis revealed that the seven synthesized breed molecules (designated Breeds 1-7) formed more robust complexes with the neuraminidase receptor than conventional clinical neuraminidase inhibitors such as zanamivir, oseltamivir, and peramivir. Pharmacokinetic evaluations of the seven breed molecules (Breeds 1-7) demonstrated favorable bioavailability and optimal permeability, all falling within the specified parameters for human application. Molecular dynamics simulations spanning 100 nanoseconds corroborated the stability of these breed molecules within the active site of neuraminidase, shedding light on their structural dynamics. Binding energy assessments, which were conducted through MM-PBSA analysis, substantiated the enduring complexes formed by the seven types of molecules and the neuraminidase receptor. Last, the investigation employed a reaction-based enumeration technique to ascertain the synthetic pathways for the synthesis of the seven breed molecules.


Assuntos
Depressores do Sistema Nervoso Central , Influenza Humana , Humanos , Neuraminidase/genética , Influenza Humana/tratamento farmacológico , Influenza Humana/genética , Simulação de Acoplamento Molecular , Hibridização Genética , Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-37328280

RESUMO

OBJECTIVE: This study aims to establish prevalence and associations of (1) influenza and influenza-like illness (IILI) presentations to Australian general practice (GP) registrars (trainees) and (2) the use of neuraminidase inhibitors (NAIs) by GP registrars for new presentations of IILI, for the 10 years leading up to the COVID-19 pandemic in Australia (2010-2019). DESIGN: This was a cross-sectional analysis of the Registrar Clinical Encounters in Training ongoing inception cohort study of the in-consultation experience and clinical behaviours of GP registrars. Data are collected by individual registrars three times (from 60 consecutive consultations each time) at 6 monthly intervals. Data include diagnoses/problems managed and medicines prescribed, along with multiple other variables. Univariate and multivariable logistic regression was used to establish associations of registrars seeing patients with IILI and of prescribing NAIs for IILI. SETTING: Teaching practices within the Australian general practitioner specialist vocational training programme. Practices were located in five of the six Australian states (plus one territory). PARTICIPANTS: GP registrars in each of their three compulsory 6-month GP training terms. RESULTS: From 2010 to 2019, 0.2% of diagnoses/problems seen by registrars were IILI. 15.4% of new IILI presentations were prescribed an NAI. IILI diagnoses were less likely in younger (0-14) and older (65+) age groups, and more likely in an area of higher socioeconomic advantage. There was considerable variation in NAI prescribing between regions. There was no significant association of prescribing NAIs with age or Aboriginal and/or Torres Strait Islander patients. CONCLUSIONS: IILI presentations were more likely among working-age adults and not among those groups at higher risk. Similarly, high-risk patient groups who would benefit most were not more likely to receive NAIs. The epidemiology and management of IILI has been distorted by the COVID-19 pandemic, but the burden of influenza in vulnerable populations must not be overlooked. Appropriately targeted antiviral therapy with NAIs influences outcomes for vulnerable patients. General practitioners manage the majority of IILI in Australia, and understanding GP IILI presentation and NAI prescribing patterns is a key first step to enabling sound and rational prescribing decisions for better patient outcomes.


Assuntos
Depressores do Sistema Nervoso Central , Medicina Geral , Clínicos Gerais , Influenza Humana , Adulto , Humanos , Antivirais/uso terapêutico , Austrália , Estudos de Coortes , COVID-19 , Estudos Transversais , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Neuraminidase , Pandemias
9.
Molecules ; 28(9)2023 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-37175176

RESUMO

Essential oils are a mixture of natural aromatic volatile oils extracted from plants. The use of essential oils is ancient, and has prevailed in different cultures around the world, such as those of the Egyptians, Greeks, Persians, and Chinese. Today, essential oils are used in traditional and complimentary medicines, aromatherapy, massage therapies, cosmetics, perfumes and food industries. The screening effect of essential oils has been studied worldwide. They demonstrate a range of biological activities, such as antiparasitic, antifungal, antibacterial, antiviral, antioxidant, anti-inflammatory, anticancer, antiaging, and neuroprotective properties. In this scoping review, we provide a 10-year updated comprehensive assessment of volatile oils and their effects on the nervous system. MEDLINE, Scopus, and Google Scholar were systematically and strategically searched for original studies investigating these effects from 2012 to 2022. Approximately seventy studies were selected as included studies. Among these studies, several outcomes were reported, including antistress, antianxiety, analgesic, cognitive, and autonomic effects. Some essential oils showed developmental benefits, with the potential to induce neurite outgrowth. The neurotransmitter receptor level can also be modified by essential oil application. Physiological and pathophysiological outcome measures were reported. For physiological outcomes, arousal, cognitive performance, circadian eating behavior, emotional modulation, consumer acceptance, preferences, and willingness to buy were investigated. For pathophysiological conditions, pain, depression, anxiety, stress, sleep disorder, mental fatigue, agitated behavior, and quality of life were measured. In conclusion, essential oils showed promising effects on the nervous system, which can be further applied to their use in functional foods, drinks, and alternative therapy.


Assuntos
Aromaterapia , Depressores do Sistema Nervoso Central , Óleos Voláteis , Humanos , Óleos Voláteis/farmacologia , Óleos Voláteis/uso terapêutico , Qualidade de Vida , Ansiedade , Sistema Nervoso
10.
Biomed Res Int ; 2023: 4522446, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37096224

RESUMO

Sonneratia caseolaris (L.) is a common mangrove plant which has significant medicinal value in traditional medicine. Ethanol extract from the fruits of S. caseolaris (SCE) was used in this project to explore its different pharmacological effects considering its traditional usage. In the castor oil-induced diarrheal method, SCE significantly lengthened the latency of the first defecation period up to 95.8 and 119.4 min as well as lowering stool count by 43.3% and 64.4% at the doses of 250 and 500 mg/kg, respectively. In evaluating the neuropharmacological effect using the open-field model, a significant central nervous system (CNS) depressant nature was observed after a reduction in the no. of squares crossed by mice at various time intervals. In evaluating the blood coagulation effect, SCE significantly reduced blood clotting time at 5.86, 5.52, and 5.01 min at 25, 50, and 100 mg/ml doses, respectively. In the assessment of the anthelmintic effect, SCE significantly killed Paramphistomum cervi (P. cervi) where the death times of the nematodes were 40.3, 36.8, and 29.9 min at 12.5, 25, and 50 mg/ml doses, respectively. The extract showed a very poor cytotoxic effect in brine shrimp lethality bioassay. In molecular docking analysis, maslinic acid, oleanolic acid, luteolin, luteolin 7-O-ß-glucoside, myricetin, ellagic acid, and R-nyasol showed the best binding affinities with the selected proteins which might be the credible reasons for eliciting pharmacological responses. Among these seven compounds, only luteolin 7-O-ß-glucoside had two violations in Lipinski's rule of five.


Assuntos
Depressores do Sistema Nervoso Central , Frutas , Animais , Camundongos , Simulação de Acoplamento Molecular , Luteolina , Extratos Vegetais/farmacologia
11.
Pharmacol Res ; 190: 106714, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36863429

RESUMO

Ischemic stroke is closely associated with gut microbiota dysbiosis and intestinal barrier dysfunction. Prebiotic intervention could modulate the intestinal microbiota, thus considered a practical strategy for neurological disorders. Puerariae Lobatae Radix-resistant starch (PLR-RS) is a potential novel prebiotic; however, its role in ischemic stroke remains unknown. This study aimed to clarify the effects and underlying mechanisms of PLR-RS in ischemic stroke. Middle cerebral artery occlusion surgery was performed to establish a model of ischemic stroke in rats. After gavage for 14 days, PLR-RS attenuated ischemic stroke-induced brain impairment and gut barrier dysfunction. Moreover, PLR-RS rescued gut microbiota dysbiosis and enriched Akkermansia and Bifidobacterium. We transplanted the fecal microbiota from PLR-RS-treated rats into rats with ischemic stroke and found that the brain and colon damage were also ameliorated. Notably, we found that PLR-RS promoted the gut microbiota to produce a higher level of melatonin. Intriguingly, exogenous gavage of melatonin attenuated ischemic stroke injury. In particular, melatonin attenuated brain impairment via a positive co-occurrence pattern in the intestinal microecology. Specific beneficial bacteria served as leaders or keystone species to promoted gut homeostasis, such as Enterobacter, Bacteroidales_S24-7_group, Prevotella_9, Ruminococcaceae and Lachnospiraceae. Thus, this new underlying mechanism could explain that the therapeutic efficacy of PLR-RS on ischemic stroke at least partly attributed to gut microbiota-derived melatonin. In summary, improving intestinal microecology by prebiotic intervention and melatonin supplementation in the gut were found to be effective therapies for ischemic stroke.


Assuntos
Depressores do Sistema Nervoso Central , Microbioma Gastrointestinal , AVC Isquêmico , Melatonina , Pueraria , Animais , Ratos , Disbiose/microbiologia , AVC Isquêmico/tratamento farmacológico , Melatonina/farmacologia , Melatonina/uso terapêutico , Prebióticos , Amido Resistente , Depressores do Sistema Nervoso Central/farmacologia , Depressores do Sistema Nervoso Central/uso terapêutico
12.
Cent Nerv Syst Agents Med Chem ; 23(1): 48-56, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36825716

RESUMO

BACKGROUND: Convolvulus pluricaulis is a native plant that is commonly mentioned in Ayurveda as a Rasayana and is primarily recommended for use in mental stimulation and rejuvenation therapy. Convolvulus pluricaulis is used as a brain tonic. The plant is reported to be a prominent memory-improving drug. It is used as a psychostimulant and tranquilizer. It is reported to reduce mental tension. OBJECTIVE: The present study aimed to explore the protective effect of hydroalcoholic extract from the leaves of Convolvulus pluricaulis along with CNS depressant and anti-anxiety activities, in models of mice. METHODS: The extract from leaves of Convolvulus pluricaulis were sequentially isolated with a mixture of water and alcohol solution in the soxhlet apparatus. An acute toxicity study was conducted as per OECD guidelines no. 423, in which 18 Albino male mice were treated with different doses (1, 10, 100, 500, 1000, and 2000 mg/kg) of hydroalcoholic extract of Convolvulus pluricaulis and assessed for toxicity parameters for 14 days. Various psychomotor activities of hydroalcoholic extract from leaves of Convolvulus pluricaulis for 100, 200, and 300 mg/kg doses were performed in mice by using various tests like actophotometer, open field, rota-rod, grip strength tests, elevated plus maze, hole board test, inclined plane, chimney test. RESULTS: The hydroalcoholic extract from leaves of Convolvulus pluricaulis was found to fall under category 4 in the acute toxicity study. Therefore, 100, 200, and 300 mg/kg doses of hydroalcoholic extract of leaves of Convolvulus pluricaulis were selected for the further pharmacological study. The results of psychomotor tests (actophotometer, open field, rota-rod, grip strength, hole board test, inclined plane, chimney test, elevated plus maze, light-dark model) for test doses 100, 200, and 300 in mice showed CNS depressant and anti-anxiety effects. CONCLUSION: Hydroalcoholic extract from leaves of Convolvulus pluricaulis at the 100, 200, and 300 mg/kg doses has shown CNS depressant and anti-anxiety effects in mice models.


Assuntos
Ansiolíticos , Depressores do Sistema Nervoso Central , Convolvulus , Camundongos , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Folhas de Planta
13.
J Anal Toxicol ; 47(4): e44-e47, 2023 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-36847150

RESUMO

Gamma-hydroxybutyrate (GHB) is a central nervous system depressant that has gained popularity as an illicit recreational drug. We describe a case of an elderly woman who was found unconscious in her home. The paramedics initially suspected an intracranial incident. A head computed tomography was negative, as was the initial urinary drug screening. The diagnosis of GHB intoxication was made with the detection of GHB in a urine sample obtained 28-29 hours after the assumed time of intake. Our case underscores the importance of considering drug testing in a broad range of patients and shows that elderly patients may have an extended detection window of GHB.


Assuntos
Depressores do Sistema Nervoso Central , Drogas Ilícitas , Oxibato de Sódio , Humanos , Feminino , Idoso , Oxibato de Sódio/urina , Drogas Ilícitas/urina , Detecção do Abuso de Substâncias/métodos
14.
Insect Mol Biol ; 32(3): 251-262, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36636859

RESUMO

Animal behaviour regulation is a complex process involving many factors, and the nervous system is an essential factor in this process. In many species, pathogens can alter host behaviour by affecting the host's nervous system. An interesting example is that the silkworm shows enhanced locomotor behaviour after being infected with the nucleopolyhedrosis virus. In this study, we analysed the transcriptome of the silkworm brain at different time points after infection and found that various genes related to behaviour regulation changed after infection. In-depth analysis showed that the tyrosine hydroxylase gene might be a key candidate gene, and the content of dopamine, its downstream metabolite, increased significantly in the brain of silkworms infected with the virus. After the injection of tyrosine hydroxylase inhibitor into the infected silkworm, the dopamine content in the silkworm brain decreased and the locomotor behaviour caused by the virus was blocked successfully. These results confirm that tyrosine hydroxylase is involved in regulating enhanced locomotor behaviour after virus infection in silkworms. Furthermore, the tyrosine hydroxylase gene was specifically overexpressed in the brain of the silkworm, and the transgenic silkworm was enhanced in locomotor behaviour and foraging behaviour. These results suggest that the tyrosine hydroxylase gene plays a vital role in regulating insect behaviour.


Assuntos
Bombyx , Depressores do Sistema Nervoso Central , Animais , Bombyx/genética , Bombyx/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo , Dopamina/metabolismo , Encéfalo/metabolismo , Animais Geneticamente Modificados
15.
Psychopharmacology (Berl) ; 240(1): 171-183, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36538099

RESUMO

RATIONALE: One hallmark of addiction is an altered neuronal reward processing. In healthy individuals (HC), reduced activity in fronto-striatal regions including the insula has been observed when a reward anticipation task was performed repeatedly. This effect could indicate a desensitization of the neural reward system due to repetition. Here, we investigated this hypothesis in a cohort of patients with alcohol use disorder (AUD), who have been treated with baclofen or a placebo. The efficacy of baclofen in AUD patients has been shown to have positive clinical effects, possibly via indirectly affecting structures within the neuronal reward system. OBJECTIVES: Twenty-eight recently detoxified patients (13 receiving baclofen (BAC), 15 receiving placebo (PLA)) were investigated within a longitudinal, double-blind, and randomized pharmaco-fMRI design with an individually adjusted daily dosage of 30-270 mg. METHODS: Brain responses were captured by functional magnetic resonance imaging (fMRI) during reward anticipation while participating in a slot machine paradigm before (t1) and after 2 weeks of individual high-dose medication (t2). RESULTS: Abstinence rates were significantly higher in the BAC compared to the PLA group during the 12-week high-dose medication phase. At t1, all patients showed significant bilateral striatal activation. At t2, the BAC group showed a significant decrease in insular activation compared to the PLA group. CONCLUSIONS: By affecting insular information processing, baclofen might enable a more flexible neuronal adaptation during recurrent reward anticipation, which could resemble a desensitization as previously observed in HC. This result strengthens the modulation of the reward system as a potential mechanism of action of baclofen. TRIAL REGISTRATION: Identifier of the main trial (the BACLAD study) at clinical.gov: NCT0126665.


Assuntos
Alcoolismo , Depressores do Sistema Nervoso Central , Humanos , Baclofeno/farmacologia , Baclofeno/uso terapêutico , Alcoolismo/diagnóstico por imagem , Alcoolismo/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Projetos Piloto , Etanol , Depressores do Sistema Nervoso Central/farmacologia , Poliésteres/farmacologia , Poliésteres/uso terapêutico , Recompensa , Antecipação Psicológica
16.
Leg Med (Tokyo) ; 60: 102175, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36417774

RESUMO

Alcohol is often found in the blood of the deceased. To cover up the true cause of victim's death, postmortem instillation of alcohol occurs in some criminal cases. Explaining the finding of alcohol is extremely vital in forensic practice. This study aims to evaluate whether ethyl glucuronide (EtG) and ethyl sulfate (EtS) in blood and vitreous humor (VH) can be used to distinguish alcoholic death and postmortem alcohol instillation. Saline or 12.6 g/kg ethanol (antemortem alcohol poisoning group) was introduced into rabbits' stomachs 2 h before sacrificed. Same amount of ethanol was introduced into rabbits' stomachs at 0 h, 0.5 h, 1 h and 2 h after death in four subgroups of postmortem alcohol instillation group, respectively. Cardiac blood and VH were collected at 10 min, 4 h, 10 h and 24 h after death in blank and antemortem alcohol poisoning group, and after instillation of alcohol in postmortem alcohol instillation group. Blood was also collected at 34 h. Ethanol and EtG levels in blood and VH and EtS in VH in antemortem alcohol poisoning group were overlapped with those in postmortem alcohol instillation group. The contents of EtG and EtS in blood in antemortem alcohol poisoning group (mean ≥ 7.833 µg/mL for EtG and ≥ 19.990 µg/mL for EtS) were much higher than those in postmortem alcohol instillation group (mean ≤ 0.118 µg/mL for EtG and ≤ 0.091 µg/mL for EtS), but apparent decomposition was observed in EtG, which might lead to misinterpretation. Blood EtS showed better stability and could be used to distinguish alcoholic death and postmortem alcohol instillation.


Assuntos
Depressores do Sistema Nervoso Central , Coelhos , Animais , Consumo de Bebidas Alcoólicas , Espectrometria de Massas em Tandem , Etanol , Glucuronatos , Biomarcadores
17.
Neurology ; 100(9): e884-e898, 2023 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-36450601

RESUMO

BACKGROUND AND OBJECTIVES: The objective of this study was to compare the utilization and costs (total and out-of-pocket) of new-to-market neurologic medications with existing guideline-supported neurologic medications over time. METHODS: We used a healthcare pharmaceutical claims database (from 2001 to 2019) to identify patients with both a diagnosis of 1 of 11 separate neurologic conditions and either a new-to-market medication or an existing guideline-supported medication for that condition. Neurologic conditions included orthostatic hypotension, spinal muscular atrophy, Duchenne disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, myasthenia gravis, Huntington disease, tardive dyskinesia, transthyretin amyloidosis, and migraine. New-to-market medications were defined as all neurologic medications approved by the US Food and Drug Administration (FDA) between 2014 and 2018. In each year, we determined the median out-of-pocket and standardized total costs for a 30-day supply of each medication. We also measured the proportion of patients receiving new-to-market medications compared with all medications specific for the relevant condition. RESULTS: We found that the utilization of most new-to-market medications was small (<20% in all but 1 condition), compared with existing, guideline-supported medications. The out-of-pocket and standardized total costs were substantially larger for new-to-market medications. The median (25th percentile, 75th percentile) out-of-pocket costs for a 30-day supply in 2019 were largest for edaravone ($712.8 [$59.8-$802.0]) and eculizumab ($91.1 [$3.0-$3,216.4]). For new-to-market medications, the distribution of out-of-pocket costs was highly variable and the trends over time were unpredictable compared with existing guideline-supported medications. DISCUSSION: Despite the increasing number of FDA-approved neurologic medications, utilization of newly approved medications in the privately insured population remains small. Given the high costs and similar efficacy for most of the new medications, limited utilization may be appropriate. However, for new medications with greater efficacy, future studies are needed to determine whether high costs are a barrier to utilization.


Assuntos
Depressores do Sistema Nervoso Central , Doenças do Sistema Nervoso , Doença de Parkinson , Humanos , Custos e Análise de Custo , Gastos em Saúde , Preparações Farmacêuticas , Estudos Retrospectivos , Custos de Cuidados de Saúde
18.
Neuropsychopharmacol Rep ; 43(1): 77-84, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36524248

RESUMO

Binge-like exposure to ethanol during the brain growth spurt triggers apoptotic neurodegeneration in multiple brain regions, including the retrosplenial cortex, a brain region that is part of the hippocampal-diencephalic-cingulate memory network. This is mediated, in part, by reduced Ca2+ influx through N-methyl-d-aspartate (NMDA) receptors followed by a decrease in the activation of pro-survival genes. Here, we tested whether a positive allosteric modulator of NMDA receptors could counteract the inhibitory effect of ethanol on developing retrosplenial cortex pyramidal neurons. We used patch-clamp electrophysiological techniques in acute slices from postnatal day 6-8 mice to test the effect of the positive allosteric modulator GNE-9278 on ethanol-induced inhibition of NMDA receptor function. GNE-9278 dose-dependently increased the amplitude, decay time, and total charge of NMDA excitatory postsynaptic currents. At a concentration of 5 µmol L-1 , GNE-9278 significantly reduced the 90 mmol L-1 ethanol-induced inhibition of NMDA excitatory postsynaptic current amplitude, decay time, and total charge. Current-clamp experiments showed that 5 µmol L-1 GNE-9278 ameliorated the 90 mmol L-1 ethanol-induced inhibition of synaptically-evoked action potential firing and compound excitatory postsynaptic potential amplitude. These findings indicate that positive allosteric modulators mitigate ethanol-induced hypofunction of NMDA receptors in developing cerebral cortex neurons, an effect that could ameliorate its pro-apoptotic effects during the late stages of fetal development.


Assuntos
Depressores do Sistema Nervoso Central , Etanol , Animais , Camundongos , Receptores de N-Metil-D-Aspartato/metabolismo , Giro do Cíngulo/metabolismo , N-Metilaspartato/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Neurônios/metabolismo
19.
Int J Mol Sci ; 25(1)2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-38203282

RESUMO

Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory synaptic transmission in glutamatergic neurons. The number and subunit composition of AMPARs are fundamental to synaptic plasticity and the formation of entire neural networks. Accordingly, the insertion and functionalization of AMPARs at the postsynaptic membrane have become a core issue related to neural circuit formation and information processing in the central nervous system. In this review, we summarize current knowledge regarding the related mechanisms of AMPAR expression and trafficking. The proteins related to AMPAR trafficking are discussed in detail, including vesicle-related proteins, cytoskeletal proteins, synaptic proteins, and protein kinases. Furthermore, significant emphasis was placed on the pivotal role of the actin cytoskeleton, which spans throughout the entire transport process in AMPAR transport, indicating that the actin cytoskeleton may serve as a fundamental basis for AMPAR trafficking. Additionally, we summarize the proteases involved in AMPAR post-translational modifications. Moreover, we provide an overview of AMPAR transport and localization to the postsynaptic membrane. Understanding the assembly, trafficking, and dynamic synaptic expression mechanisms of AMPAR may provide valuable insights into the cognitive decline associated with neurodegenerative diseases.


Assuntos
Depressores do Sistema Nervoso Central , Receptores de AMPA , Sistema Nervoso Central , Neurônios , Cognição , Aprendizagem
20.
Int Rev Neurobiol ; 165: 17-34, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36208899

RESUMO

Coronavirus disease 2019 (Covid-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is primarily regarded as a respiratory disease; however, multisystemic involvement accompanied by a variety of clinical manifestations, including neurological symptoms, are commonly observed. There is, however, little evidence supporting SARS-CoV-2 infection of central nervous system cells, and neurological symptoms for the most part appear to be due to damage mediated by hypoxic/ischemic and/or inflammatory insults. In this chapter, we report evidence on candidate neuropathological mechanisms underlying neurological manifestations in Covid-19, suggesting that while there is mostly evidence against SARS-CoV-2 entry into brain parenchymal cells as a mechanism that may trigger Parkinson's disease and parkinsonism, that there are multiple means by which the virus may cause neurological symptoms.


Assuntos
COVID-19 , Depressores do Sistema Nervoso Central , Doenças do Sistema Nervoso , Doença de Parkinson , Sistema Nervoso Central , Humanos , SARS-CoV-2
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...