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2.
Toxicol Lett ; 334: 53-59, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956829

RESUMO

Methamphetamine (METH) consumption is a health problem that leads to neurological and psychiatric disturbances. The cellular alterations behind these conditions have been extensively investigated and it is now well-established that METH causes cerebrovascular alterations being a key feature in drug-induced neuropathology. Although promising advances in understanding the blood-brain barrier (BBB) alterations induced by METH, there is still no available approach to counteract or diminish such effects. Interestingly, several studies show that neuropeptide Y (NPY) has an important protective role against METH-induced neuronal and glial toxicity, as well as behavioral deficits. Despite these beneficial effects of the NPY system, nothing is known about its role in brain endothelial cells under conditions of METH exposure. Thus, our aim was to unravel the effect of NPY and its receptors against METH-induced endothelial cell dysfunction. For that, we used a human brain microvascular endothelial cell line (hCMEC/D3) and our results demonstrate that endothelial cells express both NPY Y1 (Y1R) and Y2 (Y2R) receptors, but only Y2R is upregulated after METH exposure. Moreover, this drug of abuse induced endothelial cell death and elicited the production of reactive oxygen species (ROS) by these cells, which were prevented by the activation of Y2R. Additional, cell death and oxidative stress triggered by METH were dependent on the concentration of the drug. In sum, with the present study we identified for the first time the NPY system, and particularly the Y2R subtype, as a promising target to protect against METH-induced neurovascular dysfunction.


Assuntos
Encéfalo/irrigação sanguínea , Estimulantes do Sistema Nervoso Central/toxicidade , Células Endoteliais/efeitos dos fármacos , Metanfetamina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Receptores de Neuropeptídeo Y/agonistas , Barreira Hematoencefálica/metabolismo , Encéfalo/citologia , Morte Celular/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Células Endoteliais/metabolismo , Humanos , Microvasos/citologia , Microvasos/efeitos dos fármacos , Microvasos/metabolismo , Neuropeptídeo Y/análogos & derivados , Neuropeptídeo Y/farmacologia , Fragmentos de Peptídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/genética , Regulação para Cima
3.
Chemosphere ; 254: 126882, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32957289

RESUMO

Methamphetamine, mainly consumed as an illicit drug, is a potent addictive psychostimulant that has been detected in surface water at concentrations ranging from nanograms to micrograms per litre, especially in Middle and East Europe. The aim of this study was to expose brown trout (Salmo trutta fario) to environmental (1 µg L-1) and higher (50 µg L-1) concentrations of methamphetamine for 35 days with a four-day depuration phase to assess the possible negative effects on fish health. Degenerative liver and heart alterations, similar to those described in mammals, were observed at both concentrations, although at different intensities. Apoptotic changes in hepatocytes, revealed by activated caspase-3, were found in exposed fish. The parent compound and a metabolite (amphetamine) were detected in fish tissues in both concentration groups, in the order of kidney > liver > brain > muscle > plasma. Bioconcentration factors ranged from 0.13 to 80. A therapeutic plasma concentration was reached for both compounds in the high-concentration treatment. This study indicates that chronic environmental concentrations of methamphetamine can lead to health issues in aquatic organisms.


Assuntos
Metanfetamina/toxicidade , Truta/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Europa (Continente) , Rim/patologia , Fígado/metabolismo , Truta/metabolismo
4.
Toxicol Lett ; 333: 150-158, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32768653

RESUMO

Methamphetamine (Meth), a highly addictive drug, can induce irreversible neuronal damage and cause neuropsychiatric and cognitive disorders. Meth's effects on modulating microglial neuroimmune functions and eliciting neuroinflammation have attracted considerable attention in recent years. Recent evident of the effect of the non-dependent domain containing adaptor inducing interferon (TRIF)/Pellino1 (Peli1) signaling axis on pro-inflammatory cytokine production provides novel clues for inflammation. Therefore, our study investigated Meth-induced neurotoxicity from a neuropathological perspective by examining TLR4-TRIF-Peli1 axis signaling activation. Meth significantly activated microglia accompanied by marked increase of TLR4 and TRIF expression, NF-kB and MAPK pathways activation and the production of IL-1ß, TNF-α and IL-6. Peli1 was involved in Meth-mediated neuroinflammation and knockdown of Peli1 strongly reversed NF-kB and MAPK pathways activation and pro-inflammatory cytokine excretion. Intriguingly, Peli1 upregulation induced by Meth was dependent on TRIF rather than the myloid differentiation factor 88 (MyD88) pathway, since the silencing of TRIF significantly suppressed Meth-induced Peli1 upregulation, while MyD88 knockdown had no obvious impact. Additionally, an in vivo study verified TLR4-TRIF-Peli1 axis activation and an enhanced level of downstream cytokine expression in the cortex after Meth treatment. Therefore, these findings provide new insight regarding the specific contributions of the TRIF-Peli1 pathway to Meth-mediated neuroinflammation.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Encéfalo/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Metanfetamina/toxicidade , Microglia/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Receptor 4 Toll-Like/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/genética , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Citocinas/genética , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Masculino , Camundongos Endogâmicos C57BL , Microglia/imunologia , Microglia/metabolismo , Proteínas Nucleares/genética , RNA Interferente Pequeno/genética , Transdução de Sinais , Receptor 4 Toll-Like/genética , Ubiquitina-Proteína Ligases/genética , Regulação para Cima
7.
Water Res ; 184: 116164, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32688152

RESUMO

Methamphetamine (METH) has been recognized as an emerging organic contaminant as it was widely detected in the aquatic environment via wastewater effluent discharge. However, the ecological hazard posed by METH at environmentally relevant concentrations was remained unclear. In this study, adult medaka fish were exposed to METH at environmental levels (0.05, 0.2, 0.5, 5 µg L-1) and high level (25 and 100 µg L-1) for 90 days to investigate its effect on ecologically behavioral functions, histopathology, bioconcentration, and transgenerational toxicity. The significant increase of locomotion activity, total distance, and max velocity of adult medaka were observed at low METH levels (0.2-0.5 µg L-1), while it markedly decreased at high levels (25-100 µg L-1). This effect may increase the predation risk of the fish. The significant alteration on the relative expressions of the genes (cacna1c, oxtr, erk1, and c-fos), as well as the contents of the proteins (oxytocin (OXT) and protein kinase A (PKA)) involved in Voltage Dependent Calcium Channel (VDCC) and Mitogen-Activated Protein Kinase (MAPK) signaling channel induced by METH could partly elucidate the underlying mechanisms of the changes of the behavioral traits. METH could induce obvious minimal gliosis, neuronal loss, and necrotic in brain tissues. Additionally, the significant increase of hepatic-somatic index (HSI) of male medaka at 0.2-5 µg L-1 groups, and the decrease of female medaka at 100 µg L-1 group indicated male fish was more susceptible to METH. Nephric-somatic index (NSI) of medaka markedly declined induced by METH at 0.05-100 µg L-1. The bioconcentration factor (BCF) (0.4-5.8) in medaka fish revealed the bioconcentration potential of METH in fish. This study for the first time demonstrated METH could induced the development defects of larvae in F1 generation at environmentally relevant concentrations, thereby resulting in a significant decrease in the capacity of fish to produce offspring. Meanwhile, the RQ values (>1) of METH in river in China, USA, and Australia showed a high teratogenic risk level, suggesting the ecosystem-levels consequence posed by METH should be concerned.


Assuntos
Metanfetamina , Oryzias , Poluentes Químicos da Água , Animais , Austrália , China , Ecossistema , Feminino , Masculino , Metanfetamina/toxicidade , Água , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
8.
J Pharmacol Sci ; 144(1): 1-8, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32576439

RESUMO

Methamphetamine (METH) is a psychostimulant drug that acts on monoaminergic systems in the brain. There are several lines of evidence indicating the devastating effects of addictive drugs on the cerebellum. Moreover, it was shown that circular RNAs (circRNAs) have an important role in neurodegenerative disorders. Herein, we explored the effects of METH on neuronal degeneration, motor coordination and muscle activity. We also inspected METH-mediated changes in circRNA expression profiling in the cerebellum. Accordingly, exposure to METH triggered destructive effects on the coordination of movement of rats along with disturbed muscle activity. The fluorescent staining exhibited a significant increase in neurodegeneration in the cerebellum under the influence of METH. Besides, the number of calbindin positive Purkinje cells noticeably declined in METH-treated group compared with the control. In this regard, we identified and characterized differentially expressed (DE) circRNAs in the cerebellum under METH treatment, mainly located in dendritic spines. Moreover, based on feature and function analyzes of host genes of DE circRNAs, a large number of these genes were essentially involved in cell growth, death, inflammation and oxidative metabolism. Taken together, this data might imply the potential involvement of circRNAs in METH neurotoxicity as well as motor activity deficits.


Assuntos
Estimulantes do Sistema Nervoso Central/efeitos adversos , Cerebelo/metabolismo , Expressão Gênica/efeitos dos fármacos , Metanfetamina/efeitos adversos , Metanfetamina/toxicidade , Atividade Motora/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , RNA Circular/genética , RNA Circular/metabolismo , Animais , Cerebelo/citologia , Masculino , Degeneração Neural/genética , Células de Purkinje/patologia , RNA Circular/fisiologia , Ratos Sprague-Dawley
9.
Toxicol Lett ; 331: 188-199, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32569805

RESUMO

Methamphetamine (METH) is a highly addictive psychostimulant drug whose abuse can cause many health complications. Our previous studies have shown that METH exposure increases α-synuclein (α-syn) expression. Recently, it was shown that α-syn could be transferred from neurons to astrocytes via exosomes. However, the specific role of astrocytes in α-syn pathology involved in METH neurotoxicity remains unclear. The objective of this study was to determine whether exosomes derived from METH-treated neurons contain pathological α-syn and test the hypothesis that exosomes can transfer pathological α-syn from neurons to astrocytes. To this end, using animal and cell line coculture models, we show that exosomes isolated from METH-treated SH-SY5Y cells contained pathological α-syn. Furthermore, the addition of METH exosomes to the medium of primary cultured astrocytes induced α-syn aggregation and inflammatory responses in astrocytes. Then, we evaluated changes in nuclear receptor related 1 protein (Nurr1) expression and the levels of inflammatory cytokines in primary cultured astrocytes exposed to METH or α-syn. We found that METH or α-syn exposure decreased Nurr1 expression and increased proinflammatory cytokine expression in astrocytes. Our results indicate that α-syn can be transferred from neuronal cells to astrocytes through exosomes. When internalized α-syn accumulated in astrocytes, the cells produced inflammatory responses. Nurr1 may play a crucial role in this process and could be a therapeutic target for inflammatory damage caused by METH.


Assuntos
Astrócitos/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Exossomos/metabolismo , Metanfetamina/toxicidade , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/metabolismo , alfa-Sinucleína/metabolismo , Animais , Astrócitos/imunologia , Astrócitos/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Hipocampo/citologia , Humanos , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Neurônios/imunologia , Neurônios/metabolismo , Síndromes Neurotóxicas/imunologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Cultura Primária de Células , Sinucleinopatias/imunologia , Sinucleinopatias/metabolismo
10.
Toxicol Lett ; 331: 42-52, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32464236

RESUMO

Synthetic cathinones abuse remains a serious public health problem. Kidney injury has been reported in intoxications associated with synthetic cathinones, but the molecular mechanisms involved have not been explored yet. In this study, the potential in vitro nephrotoxic effects of four commonly abused cathinone derivatives, namely pentedrone, 3,4-dimethylmethcatinone (3,4-DMMC), methylone and 3,4-methylenedioxypyrovalerone (MDPV), were assessed in the human kidney HK-2 cell line. All four derivatives elicited cell death in a concentration- and time-dependent manner, in the following order of potency: 3,4-DMMC >> MDPV > methylone ≈ pentedrone. 3,4-DMMC and methylone were selected to further elucidate the mechanisms behind synthetic cathinones-induced cell death. Both drugs elicited apoptotic cell death and prompted the formation of acidic vesicular organelles and autophagosomes in HK-2 cells. Moreover, the autophagy inhibitor 3-methyladenine significantly potentiated cell death, indicating that autophagy may serve as a cell survival mechanism that protects renal cells against synthetic cathinones toxicity. Both drugs triggered a rise in reactive oxygen and nitrogen species formation, which was completely prevented by antioxidant treatment with N­acetyl­L­cysteine or ascorbic acid. Importantly, these antioxidant agents significantly aggravated renal cell death induced by cathinone derivatives, most likely due to their autophagy-blocking properties. Taken together, our results support an intricate control of cell survival/death modulated by oxidative stress, apoptosis and autophagy in synthetic cathinones-induced renal injury.


Assuntos
Alcaloides/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Drogas Ilícitas/toxicidade , Rim/efeitos dos fármacos , Alcaloides/química , Benzodioxóis/química , Benzodioxóis/toxicidade , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Rim/metabolismo , Rim/patologia , Metanfetamina/análogos & derivados , Metanfetamina/química , Metanfetamina/toxicidade , Metilaminas/química , Metilaminas/toxicidade , Pentanonas/química , Pentanonas/toxicidade , Pirrolidinas/química , Pirrolidinas/toxicidade , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
11.
PLoS One ; 15(5): e0233010, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32396581

RESUMO

Methamphetamine use has increased over the past decade and the first use of methamphetamine is most often when women are of reproductive age. Methamphetamine accumulates in the liver; however, little is known about the effect of methamphetamine use on hepatic drug metabolism. Methamphetamine was administered on 3 occassions to female Dunkin Hartley guinea pigs of reproductive age, mimicking recreational drug use. Low doses of test drugs caffeine and midazolam were administered after the third dose of methamphetamine to assess the functional activity of cytochrome P450 1A2 and 3A, respectively. Real-time quantitative polymerase chain reaction was used to quantify the mRNA expression of factors involved in glucocorticoid signalling, inflammation, oxidative stress and drug transporters. This study showed that methamphetamine administration decreased hepatic CYP1A2 mRNA expression, but increased CYP1A2 enzyme activity. Methamphetamine had no effect on CYP3A enzyme activity. In addition, we found that methamphetamine may also result in changes in glucocorticoid bioavailability, as we found a decrease in 11ß-hydroxysteroid dehydrogenase 1 mRNA expression, which converts inactive cortisone into active cortisol. This study has shown that methamphetamine administration has the potential to alter drug metabolism via the CYP1A2 metabolic pathway in female guinea pigs. This may have clinical implications for drug dosing in female methamphetamine users of reproductive age.


Assuntos
Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP3A/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metanfetamina/administração & dosagem , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/sangue , Estimulantes do Sistema Nervoso Central/toxicidade , Citocromo P-450 CYP1A2/genética , Feminino , Cobaias , Humanos , Taxa de Depuração Metabólica , Redes e Vias Metabólicas/efeitos dos fármacos , Metanfetamina/sangue , Metanfetamina/toxicidade , Modelos Animais , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
PLoS One ; 15(5): e0229389, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469882

RESUMO

Links between crystalline methamphetamine (CM) use and criminal offending are often drawn in the media; however, there has been little scientific research into this relationship. The aim of this study was to ascertain the prevalence and correlates of lifetime CM use among a sample of young people in detention in Australia and to examine whether an association exists between lifetime CM use and recidivism in this population.The sample included 202 young people (164 males) in youth detention in the state of Victoria, Australia. Participants were administered questionnaires related to lifetime substance use and socio-environmental experiences. Lifetime mental health data and offending data were obtained for each participant from public mental health and policing databases. More than one third (38%) of the sample reported lifetime CM use. In multivariate logistic regression analyses, older age, male gender, polysubstance use, and high levels of community disorganisation were associated with CM use. The presence of a psychiatric diagnosis over the lifetime was not significantly associated with CM use. CM use was also not significantly associated with violent recidivism. Efforts to address CM use and related harm in detained youth should include community-based strategies to reduce CM use among this vulnerable population following their release from detention. However, the findings suggest that CM use on its own is unlikely to be an important consideration for professionals concerned with determining which young people should be selected for treatment designed to reduce the risk of violent recidivism.


Assuntos
Comportamento Criminoso/efeitos dos fármacos , Delinquência Juvenil/psicologia , Metanfetamina/toxicidade , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Adulto , Analgésicos Opioides/efeitos adversos , Austrália/epidemiologia , Cannabis/efeitos adversos , Comportamento Criminoso/fisiologia , Feminino , Medicina Legal , Humanos , Delinquência Juvenil/legislação & jurisprudência , Masculino , Saúde Mental , Abuso Físico/psicologia , Polícia/estatística & dados numéricos , Saúde Pública , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Inquéritos e Questionários , Adulto Jovem
13.
J Neuroimmunol ; 344: 577232, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32311585

RESUMO

Neuron-Glial2 (NG2) expressing cells are described as the oligodendrocyte precursor cells in the brain. This study aimed to investigate the possible involvement of NG2 cells under the methamphetamine (METH)-induced neurotoxicity and neuroprotective capacity of melatonin. The results showed that the levels of NG2 in rat brain gradually increase from postnatal day 0 to postnatal day 8 and then the lower levels of NG2 are shown in adults. In adult rats, the levels of NG2 and COX-2 in the brain were significantly increased in lipopolysaccharide treatment. Pretreatment of 10 mg/kg melatonin prior to treating with METH was able to reduce an increase in the levels of NG2 and activation in astrocyte and microglia. These findings would extend the contribution of NG2 expressing cells in the adult brain during pathological conditions such as neuroinflammation.


Assuntos
Antígenos/biossíntese , Encéfalo/metabolismo , Estimulantes do Sistema Nervoso Central/toxicidade , Melatonina/farmacologia , Metanfetamina/toxicidade , Neuroglia/metabolismo , Proteoglicanas/biossíntese , Animais , Encéfalo/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Masculino , Melatonina/uso terapêutico , Neuroglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Sprague-Dawley
14.
Artigo em Inglês | MEDLINE | ID: mdl-32245179

RESUMO

Methamphetamine (METH), a central nervous system stimulant used as a recreational drug, is frequently found in surface waters at potentially harmful concentrations. To determine effects of long-term exposure to environmentally relevant levels on nontarget organisms, we analysed cardiac and locomotor responses of signal crayfish Pacifastacus leniusculus to acute stress during a 21-day exposure to METH at 1 µg L-1 followed by 14 days depuration. Heart rate and locomotion were recorded over a period of 30 min before and 30 min after exposure to haemolymph of an injured conspecific four times during METH exposure and four times during the depuration phase. Methamphetamine-exposed crayfish showed a weaker cardiac response to stress than was observed in controls during both exposure and depuration phases. Similarly, methamphetamine-exposed crayfish, during METH exposure, showed lower locomotor reaction poststressor application in contrast to controls. Results indicate biological alterations in crayfish exposed to METH at low concentration level, potentially resulting in a shift in interactions among organisms in natural environment.


Assuntos
Astacoidea , Metanfetamina , Poluentes Químicos da Água , Animais , Feminino , Masculino , Metanfetamina/toxicidade , Estresse Fisiológico , Poluentes Químicos da Água/toxicidade
15.
Mol Immunol ; 121: 159-166, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32222586

RESUMO

Methamphetamine (METH) is a major public health and safety problem worldwide. METH is psychostimulant that activates microglia via the toll-like receptor (TLR) 4/MD2 complex, modulating the abundant production of pro-inflammatory cytokines in the central nervous system (CNS). The TLR4/MD2 complex on the surface of microglia recognizes pathogen-associated molecular patterns such as lipopolysaccharide (LPS) resulting in brain tissue inflammation and neuronal damage. Since METH has been associated with microglia-induced neurotoxicity, we hypothesized that METH impairs the expression of TLR4 and activation of NF-κB in NR-9460 microglia-like cells after LPS challenge. We demonstrated that METH decreases the distribution and expression of TLR4 receptors on the surface of microglia-like cells after incubation with endotoxin. Moreover, METH impairs the TLR4/MD2 complex signaling pathways, compromises the activation of NF-κB, and reduces the production of pro-inflammatory mediators in microglia-like cells upon LPS stimulation. Interestingly, microglia-like cells treated with METH and challenged with LPS showed considerable cellular morphological changes including enlarged nuclei and ruffled surface. Our results suggest that METH may have a significant impact on microglial-induced neuroinflammation, neurotoxicity, and the CNS defense against infection. It also highlights the importance of studying the effects of METH on the molecular and cellular components of users' CNS immunity. Finally, animal studies exploring the role of METH on the effectors functions of microglia after antigenic exposure are necessary to understand drug-related inflammation and neural damage in users.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Encefalite/induzido quimicamente , Metanfetamina/toxicidade , Microglia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Citocinas/imunologia , Citocinas/metabolismo , Encefalite/imunologia , Encefalite/patologia , Humanos , Lipopolissacarídeos/imunologia , Camundongos , Microglia/citologia , Microglia/imunologia , NF-kappa B/imunologia , NF-kappa B/metabolismo , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo
16.
Food Chem Toxicol ; 137: 111179, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32035215

RESUMO

Methamphetamine (METH) is a highly addictive stimulant that results in serious and persistent neurotoxic effects. Studies have indicated that luteolin, a flavonoid, may confer neuroprotection against neurotoxicity. Nevertheless, the effects of luteolin on METH-induced neurotoxicity have not been sufficiently verified. In the present study, Sprague Dawley rats were pretreated with luteolin (100 mg/kg) or sodium dodecyl sulfate water, followed by administration of METH (15 mg/kg) or saline. Rat striata were then collected for RNA-sequencing and subsequent analyses. A total of 347 differentially expressed genes (DEGs) were identified in the METH group with 20 pathways, including the phosphoinositol 3 kinase (PI3K)/protein kinase B (Akt), found to be enriched by the KEGG analysis. Seventy-five of the 347 DEGs were modulated in luteolin-pretreated rats, which were enriched into 12 pathways, containing the PI3K/Akt. Results further showed that luteolin pretreatment significantly repressed the METH-induced increases of PI3K, Akt, p-Akt, p53, Bax, caspase 3, normalized the ratio of p-Akt/Akt, and autophagy-related proteins (Beclin1, Atg5 and LC3-II) expression. Taken together, these findings indicate that luteolin attenuates METH-induced apoptosis and autophagy by suppressing the PI3K/Akt pathway. In this case, it exerts protection against METH-induced neurotoxicity. This provides a platform for development of potential therapies for METH treatment.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Luteolina/uso terapêutico , Metanfetamina/toxicidade , Síndromes Neurotóxicas/prevenção & controle , Substâncias Protetoras/uso terapêutico , Animais , Expressão Gênica/efeitos dos fármacos , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Análise de Componente Principal , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
17.
Emergencias (Sant Vicenç dels Horts) ; 32(1): 26-32, feb. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-185850

RESUMO

Objetivo: Investigar si existen diferencias clínicas y toxicológicas en pacientes intoxicados por anfetamina (ANF) y metanfetamina (MANF) atendidos en servicios de urgencias. Método: Estudio observacional retrospectivo de intoxicaciones por ANF y MANF con confirmación analítica en Baleares (2013-2018). Se compararon variables clínicas, toxicológicas y de manejo clínico entre grupos. Resultados: 1) Se incluyeron 120 pacientes, 86 (71,7%) grupo ANF y 34 (28,3%) grupo MANF. 2) La confirmación de derivados anfetamínicos se realizó por cromatografía de gases-espectrometría de masas en 787 muestras de orina previamente positivas mediante un método de cribado cualitativo. Se confirmaron 154 (19,6%) muestras. De ellas, 34 fueron excluidas. 3) Se encontraron diferencias significativas entre ANF y MANF en: edad (32,3 vs 28,4 años); sexo (72,1 vs 94,1% hombres); nacionalidad española (64,0 vs 29,4%); en motivos de admisión: alteración de conducta (15,1 vs 0%) y palpitaciones (1,2 vs 20,6%); y en características clínicas: agitación (27,9 vs 8,8%). No hubo diferencias de manejo clínico. El 76,6% de casos fueron polintoxicaciones, más comunes en ANF (82,6 vs 61,8%). En estos casos se detectó principalmente cocaína (63,0%), cannabis (48,9%), MDMA (38,0%) y alcohol (35,9%). La mayor asociación del cannabis con el grupo de ANF fue estadísticamente significativa (45,3 vs 17,6%). La causa de los falsos positivos se identificó en el 78,7% de muestras, siendo el MDMA (71,2%) la principal. Conclusiones: Se observaron diferencias entre ANF y MANF en cuanto a variables demográficas y motivo de asistencia; no obstante en esta serie hubo un alto porcentaje de polintoxicaciones


Objective: To determine whether clinical and toxicologic findings differed between cases of amphetamine (AMP) and methamphetamine (mAMP) poisoning attended in 2 Balearic Island hospital emergency departments. Methods: Retrospective observational study of AMP and mAMP cases with laboratory confirmation between 2013 and 2018. We compared clinical and toxicologic variables as well as clinical management between groups. Results: 1) A total of 120 cases were found: 86 (71.7%) with AMP poisoning and 34 (28.3%) with mAMP poisoning. 2) Drug poisoning was confirmed by gas chromatography associated with mass spectrometry (GC–MS) in 787 urine samples found to be positive during screening. One hundred fifty-four (19.6%) were confirmed by GC–MS. Thirtyfour of them did not meet the inclusion criteria. 3) Significant differences between AMP and mAMP cases were found for age (32.3 vs 28.4 y, respectively); sex (72.1% vs 94.1% men); and Spanish nationality (64.0% vs 29.4%). Reasons for admission and clinical features also differed: the reasons were aberrant behavior (15.1% in the AMP group vs 0% in the mAMP group) and palpitations (1.2% vs 20.6%); agitation was observed in 27.9% and 8.8%, respectively. Clinical management was similar in the 2 groups. Multiple drug poisoning was detected in 76.6% patients and was more common in patients in the AMP group (82.6% vs 61.8%). The additional drugs in these cases were mainly cocaine (63.0%), cannabis (48.9%), 3,4-methylenedioxy-N-methamphetamine (MDMA) (38.0%), and alcohol (35.9%). Cannabis was detected in a significantly higher proportion in the AMP group (45.3%) than in the mAMP group (17.6%). False positives were found in 78.7% of the samples. The culprit drug was most often MDMA (71.2%). Conclusions: AMP poisonings were associated with age over 30 years, Spanish nationality, aberrant behavior, agitation, multiple drug findings, and the use of cannabis. Poisonings caused by mAMP abuse were associated with age under 30 years, non-Spanish nationality, palpitations, and single-drug use


Assuntos
Humanos , Masculino , Feminino , Adulto , Anfetamina/toxicidade , Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Serviços Médicos de Emergência , Metanfetamina/toxicidade , Estudos Retrospectivos , Unidades de Terapia Intensiva , Acidente Vascular Cerebral/complicações
18.
Hum Exp Toxicol ; 39(5): 712-720, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31928234

RESUMO

As an extremely addictive psychostimulant drug and an illicit dopaminergic neurotoxin, methamphetamine (METH) conducts to enhance satisfaction, feelings of alertness through influencing monoamine neurotransmitter systems. Long-lasting exposure to METH causes psychosis and increases the risk of neurodegeneration. 6-Formyl-5-isopropyl-3-hydroxymethyl-7-methyl-1H-indene (FIHMI) is a novel compound with potent antioxidant properties. This study was to investigate whether FIHMI could mitigate METH-induced photoreceptor cell toxicity. METH-caused cell toxicity was established in 661W cells and protective effects of FIHMI at different concentrations (1-10 µM) was examined. FIHMI significantly attenuated the METH-caused cell damage in 661W cells, evidenced by increasing cell viability and mitochondrial membrane potential, decreasing cytochrome c release and DNA fragmentation, inhibiting activities of caspase 3/9, and changing expression of apoptosis-related protein. Furthermore, FIHMI treatment decreased mRNA expression of Beclin-1 and LC3B protein expression in METH-induced 661W cells suggesting autophagy is reduced. FIHMI decreased the oxidative stress through increasing protein expression of nuclear factor (erythroid-derived 2)-like 2. These data demonstrated FIHMI could inhibit oxidative stress, which may also play an essential role in the regulation of METH-triggered apoptotic response, providing the scientific rational to develop FIHMI as the therapeutic agent to alleviate METH-induced photoreceptor cell toxicity.


Assuntos
Antioxidantes/farmacologia , Indenos/farmacologia , Metanfetamina/toxicidade , Células Fotorreceptoras/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Células Fotorreceptoras/fisiologia
19.
Toxicol Lett ; 319: 213-224, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31783120

RESUMO

The upregulated α-synuclein (α-syn) and Tau co-occur in methamphetamine (METH) abusers' brains. Here, we designed experiments mainly to investigate whether α-syn and Tau interact in METH exposure. We detected the expression of α-syn, total Tau, and phosphorylation of Tau at Serine 396 (pSer396 Tau) under in vitro and in vivo conditions after METH exposure to determine the co-occurrence of α-syn and Tau. We also explored the effect of α-syn or Tau on one another by silencing and knocking-out one of them in METH treatment. We found that METH increased the α-syn, total Tau, and pSer396 Tau protein level in SH-SY5Y cells, primary cultured neurons, and in mice brains. In additional, reducing α-syn level can relieve and even normalize the pSer396 Tau and total Tau overexpression after treatment of METH. Furthermore, knocking out Tau can effectively inhibit METH induced overexpression of α-syn in mice brains. Finally, knocking out α-syn or Tau can effectively reduce METH-induced neurotoxicity in mice brains. This research could provide potential therapeutic approaches targeting the vicious circle between α-syn and Tau in METH abusers and patients with neurodegenerative disorders.


Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Metanfetamina/toxicidade , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , alfa-Sinucleína/biossíntese , Proteínas tau/biossíntese , Animais , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Inativação Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndromes Neurotóxicas/psicologia , Cultura Primária de Células , RNA Interferente Pequeno , alfa-Sinucleína/genética , Proteínas tau/genética , Proteínas tau/metabolismo
20.
Hum Exp Toxicol ; 39(3): 301-310, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31726888

RESUMO

Methamphetamine (METH) is an illicit dopaminergic neurotoxin and is an extremely addictive psychostimulant drug that influences monoamine neurotransmitter system of the brain and is responsible for enhancing energy and satisfaction and feelings of alertness. Long-lasting exposure to METH causes psychosis and increases the risk of Parkinson's disease. Studies have revealed that obestatin (OB) is a novel endogenous ligand, which may have neuroprotective effects. Hence, we hypothesized that OB might appropriately limit METH-induced neurotoxicity via the control of apoptotis and autophagy. In the current study, PC12 cells were exposed to both METH (0.5, 1, 2, 3, 4, and 6 mmol/L) and pretreatment OB (1, 10, 100, and 200 nmol/L) in vitro for 24 h to determine appropriate dose, and then downstream pathways were measured to investigate apoptosis and autophagy. The results have shown that OB reduced the apoptotic response post-METH exposure in PC12 cells by developing cell viability and diminishing apoptotic rates. Furthermore, the study has exhibited OB decreased gene expression of Beclin-1 by real-time polymerase chain reaction and LC3-II by Western blotting in METH-induced PC12 cells, which demonstrated that autophagy is reduced. The study is proposed that OB is useful in reducing oxidative stress, which may also play an essential role in the regulation of METH-triggered apoptotic response. So these data indicate that OB could potentially alleviate METH-induced neurotoxicity via the reduction of apoptotic and autophagy responses.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Grelina/farmacologia , Metanfetamina/toxicidade , Neurônios/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Grelina/administração & dosagem , Metanfetamina/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Células PC12 , Ratos
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