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1.
Ther Umsch ; 76(4): 195-198, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31498041

RESUMO

Immunotherapy - immune-related adverse events and their management Abstract. Checkpoint-Inhibition has become an important part of modern oncological treatment strategies for many patients with cancer. The development of this new class of anti-cancer drugs has begun for ten years and showed meanwhile a specific new side effect profile. Since the mode of action of checkpoint inhibitors is immune modulation the side effects are particularly different to so far established anti-cancer drugs. Because of the immunological nature of side effects, the spectrum is wide, and the symptoms are amble. Additionally, the side effects can appear at very different time points after the administration of the checkpoint inhibitor. Therefore, the recognition and the management are a new challenge for the care teams. Only if the whole care team is able to understand, diagnose and efficiently manage the side effects the therapeutic potential of this new class of anti-cancer drugs can be made useful for the patients. The article aims to provide information for the care teams to recognize and manage side effects of checkpoint-inhibitors.


Assuntos
Imunoterapia/efeitos adversos , Imunoterapia/métodos , Neoplasias/terapia , Humanos , Fatores Imunológicos , Oncologia , Síndromes Neurotóxicas/etiologia
2.
Expert Opin Drug Saf ; 18(11): 1055-1063, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500468

RESUMO

Introduction: Ciprofloxacin, levofloxacin, and moxifloxacin belong to the fluoroquinolone class of antibiotics and are amongst the most commonly prescribed antibiotics. In 2018 and 2019, Food and Drug Administration (FDA) and the European Medicine Agency (EMA) requested that manufacturers harmonize FQ safety information related to neuropsychiatric, aortic dissection, and long-term disability. The authors hypothesize that FDA and EMA epidemiologists support a strong association between these drugs and the three toxicities. Areas covered: Studies of FQ-associated neuropsychiatric toxicity, long-term disability, and aortic ruptures/dissections. Clinical sources include FDA Advisory Committee documents, a 2014 Citizen Petition filed with the FDA requesting safety information additions to FQ labels for neuropsychiatric toxicities (partially granted in 2018), an under-review Citizen Petition under review by the FDA requesting a FQ Risk Evaluation and Mitigation Strategy, and safety notifications from the EMA. Expert opinion: FDA and the EMA report state that neuropsychiatric toxicity, long-term disability, and aortic dissections//aneurysms occur with all FQs. Disability and neuropsychiatric toxicity can occur after one dose or several months after FQs. United States' and European' regulators warn physicians not to prescribe FQs for uncomplicated acute urinary tract infection, sinusitis, or bronchitis, unless other possible choices are tried first, as risks outweigh benefits in these settings.


Assuntos
Ciprofloxacino/efeitos adversos , Levofloxacino/efeitos adversos , Moxifloxacina/efeitos adversos , Aneurisma Dissecante/induzido quimicamente , Animais , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Aneurisma Aórtico/induzido quimicamente , Ruptura Aórtica/induzido quimicamente , Ciprofloxacino/administração & dosagem , Avaliação da Deficiência , União Europeia , Humanos , Levofloxacino/administração & dosagem , Moxifloxacina/administração & dosagem , Síndromes Neurotóxicas/etiologia , Estados Unidos , United States Food and Drug Administration
3.
Life Sci ; 236: 116867, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31520598

RESUMO

AIM: Cyclophosphamide (CP) is a potent anticancer and immunosuppressant drug. Studies have shown significant oxidative stress and cognitive impairment but neuroinflammatory and histological aberrations with its administration is underexplored. Nerolidol (NER) is a lipophilic bioactive molecule with antioxidant and anti-inflammatory properties but it has not been explored for neuroprotective potential in CP-induced neurotoxic manifestations. Therefore, in the present study, we aimed to evaluate the neuroprotective potential of NER in CP-induced neuroinflammation and associated comorbid conditions like depression and cognitive dysfunctions. MATERIALS AND METHOD: In-silico study using Schrödinger software was used to assess the binding affinity of NER with Nrf2. In the In vivo study, NER 200 and 400 mg/kg p.o. were given from 1st day to 14th day. CP 200 mg/kg, i.p., was administered on the 7th day. After 24 h of the last dosing, neurobehavioral tests like spontaneous body alternation, passive avoidance and forced swim test were performed. On completion of study, mice were sacrificed, hippocampus and cortex were removed for biochemical estimations, histopathology and immunohistochemistry of p65 NF- κB and Nrf2. KEY FINDINGS: In-silico study showed significant binding of NER into the pocket domain of Nrf2. In-vivo study showed protective effect of NER against CP-induced neuroinflammation, oxidative stress, cognitive impairment and structural abnormalities in the hippocampus and cortex regions. SIGNIFICANCE: Findings of the study suggested that NER is a potential therapeutic molecule which can mitigate CP-induced neurotoxic manifestations via Nrf2 and NF-κB pathway. However, more detailed studies are needed to explicate the mechanism underlying its neuroprotective effect.


Assuntos
Disfunção Cognitiva/prevenção & controle , Ciclofosfamida/toxicidade , Inflamação/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imunossupressores/toxicidade , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Fármacos Neuroprotetores , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Transdução de Sinais
4.
Life Sci ; 232: 116606, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254586

RESUMO

AIMS: Bupivacaine, a common local anesthetic, can cause neurotoxicity and abnormal neuro-disorders. However, the precise underlying mechanisms have not been fully elucidated. In this study, we investigated the function of lncRNA MALAT1 in the bupivacaine-induced neurotoxicity process. MATERIALS AND METHODS: SH-SY5Y cells and neonatal mouse DRG neurons were cultured in vitro and treated with bupivacaine to establish a neurotoxicity model. Caspase3 activity and cell survival rates were detected to evaluate the function of lncRNA MALAT1. Western blotting was used to detect the expression levels of PDCD4 and cleaved-caspase-3. A dual-luciferase reporter assay was used to explore the potential binding target of lncRNA MALAT1. RESULTS: We found that the expression of lncRNA MALAT1 was upregulated upon exposure to bupivacaine. Knockdown of lncRNA MALAT1 significantly increased the cell death rates, and Caspase3 activity assays revealed that the apoptosis rates were manifestly increased in the MALAT1 downregulation group. In addition, we screened the possible target and found that miR-101-3p is the direct target of MALAT1 using a dual-luciferase reporter assay; these results suggest that lncRNA MALAT1 may function as a decoy to sponge miR-101-3p. Furthermore, we demonstrated that activation of the MALAT1/miR-101-3p/PDCD4 axis protected cells against bupivacaine treatment. CONCLUSION: We elucidated the function and mechanism of MALAT1 in bupivacaine-induced neurotoxicity. Targeting MALAT1 might provide new methods to prevent neurotoxicity.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Bupivacaína/toxicidade , MicroRNAs/metabolismo , Síndromes Neurotóxicas/etiologia , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/metabolismo , Anestésicos Locais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular Tumoral , Gânglios Espinais/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Camundongos , MicroRNAs/genética , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/genética , Regulação para Cima/efeitos dos fármacos
5.
Toxicol Lett ; 313: 42-49, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31154016

RESUMO

Astrocytes are the major glial cell type in the central nervous system (CNS), and the distal part of the astrocyte forms the blood-brain barrier with nearby blood vessels. They maintain the overall metabolism, growth, homeostasis of neurons, and signaling in the CNS. Ochratoxin A is considered a carcinogen and immunotoxic, nephrotoxic, and neurotoxic mycotoxin. Specifically, it exhibits neurotoxicity with high affinity for the brain. Despite some previous studies about the effects of ochratoxin A in glial cells, the intracellular working mechanism in astrocytes is not fully understood. In this study, we studied the specific working mechanism of ochratoxin A in the human astrocyte cell line, NHA-SV40LT. Ochratoxin A reduced cell proliferation with sub G0/G1 cell cycle arrest by inhibiting CCND1, CCNE1, CDK4, and MYC expression. It induced apoptosis of NHA-SV40LT cells through mitochondrial membrane potential (MMP) loss and up-regulation of BAX and TP53. In addition, ochratoxin A increased cytosolic and mitochondrial calcium levels, resulting in an increase in MMP2 and PLAUR mRNA expression in NHA-SV40LT cells. Furthermore, ochratoxin A regulated the phosphorylation of AKT, ERK1/2, and JNK signal molecules of human astrocytes. Collectively, ochratoxin A exerts neurotoxicity through anti-proliferation and mitochondria-dependent apoptosis in human astrocytes.


Assuntos
Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Cálcio/metabolismo , Mitocôndrias/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Ocratoxinas/toxicidade , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Sinalização do Cálcio/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
6.
Expert Opin Drug Saf ; 18(7): 591-601, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31107108

RESUMO

INTRODUCTION: Epidural analgesia is a popular approach to postoperative and labor pain. Neurotoxicity and drug-specific systemic side effects can occur after epidural administration. As an increasing number of epidural drugs are studied and clinically applied, drug efficacy and safety evaluation are crucial. AREAS COVERED: In this narrative review, the authors provide a thorough overview on the safety of the most widely used epidural drugs, focusing on potential neurotoxicity, side effects, and complications in the adult, non-pregnant population. A combined text and MeSH heading search strategy was used to identify relevant publications. EXPERT OPINION: The search for the ideal epidural medication has resulted in a surplus of drug combinations with extensive heterogeneity amongst studies, while the value of investigating these is not always evident. Epidural drugs pose a potential threat of neurotoxicity and other side effects. Consequently, we should pursue safe epidural drug administration to patients and refrain from drugs with minimal proven benefit. Also, studies should compare epidural with systemic application. Because why use a drug epidurally, which can be safely used systemically? Future research should focus on providing solid evidence regarding efficacy of epidural analgesia compared to new and already existing modalities and optimizing presently used medicinal regimens.


Assuntos
Analgesia Epidural/métodos , Dor do Parto/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Adulto , Analgesia Epidural/efeitos adversos , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Feminino , Humanos , Síndromes Neurotóxicas/etiologia , Gravidez
7.
Life Sci ; 228: 145-151, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31047895

RESUMO

AIMS: Cisplatin (CP) is a widely used broad-spectrum antineoplastic agent used to treat a variety of human malignancies. Neurotoxicity is clinically evident in patients who have undergone a full course of chemotherapy. The aim of this study was to investigate the possible protective effects of thymoquinone (TQ) and geraniol (Ger) against CP-induced neurotoxicity in rats. MAIN METHODS: Forty male Wistar albino rats were allocated into four groups as follows: normal control, CP-induced neurotoxicity, CP + TQ and CP + Ger. KEY FINDINGS: Our results demonstrated that simultaneous treatment with either TQ or Ger and CP significantly abrogated oxidative stress and downregulated the apoptotic markers p38 mitogen-activated protein kinase (MAPK), STAT-1, p53, p21 and MMP9; FMO3, however, was insignificantly decreased. In addition to the biochemical results, we assessed the histopathological findings, which confirmed the protective effect of TQ and Ger against the brain damage induced by CP. SIGNIFICANCE: The results of the present study indicate that simultaneous treatment with either TQ or Ger as natural antioxidants can provide protection against cisplatin-induced neurotoxicity in rats by attenuating oxidative stress and cell apoptosis.


Assuntos
Antineoplásicos/toxicidade , Antioxidantes/uso terapêutico , Benzoquinonas/uso terapêutico , Encéfalo/efeitos dos fármacos , Cisplatino/toxicidade , Síndromes Neurotóxicas/tratamento farmacológico , Terpenos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Regulação para Baixo/efeitos dos fármacos , Masculino , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Fator de Transcrição STAT1/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
8.
Rinsho Shinkeigaku ; 59(5): 258-263, 2019 May 28.
Artigo em Japonês | MEDLINE | ID: mdl-31061301

RESUMO

A 79-year-old female was diagnosed with epilepsy because she experienced loss of consciousness twice in January and February and then had a seizure in June 2016. She was treated with 800 mg sodium valproate (sustained release). After 3 days, she experienced loss of appetite, and more than 3 days later, disturbance of consciousness. Serum valproic acid (VPA) concentration was 128.3 µg/ml and serum ammonia was 404 µmol/l. Cerebral edema and status epilepticus occurred. Severe neurological dysfunction remained, even after treatment with continuous hemodiafiltration and levocarnitine. VPA is widely used for the treatment of generalized epilepsy. VPA-induced hyperammonemic encephalopathy is a rare but serious adverse event of VPA. Thus, we must pay attention to serum ammonia levels when using VPA, even VPA monotherapy.


Assuntos
Anticonvulsivantes/efeitos adversos , Cardiomiopatias/induzido quimicamente , Carnitina/deficiência , Epilepsia Generalizada/tratamento farmacológico , Hiperamonemia/induzido quimicamente , Doenças Musculares/induzido quimicamente , Síndromes Neurotóxicas/etiologia , Ácido Valproico/efeitos adversos , Idoso , Amônia/sangue , Anticonvulsivantes/administração & dosagem , Biomarcadores/sangue , Carnitina/administração & dosagem , Transtornos da Consciência/etiologia , Feminino , Humanos , Hiperamonemia/sangue , Hiperamonemia/diagnóstico , Estado Epiléptico/etiologia , Ácido Valproico/administração & dosagem
9.
Expert Opin Drug Metab Toxicol ; 15(6): 487-497, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31116618

RESUMO

Introduction: Platinum-drugs (Cisplatin, Carboplatin, Oxaliplatin) are widely used in Medical Oncology departments to treat common neoplasms whose survival has greatly increased in the last few years. Thus, there is a growing population of cancer survivors who were treated with them and whose Quality of Life can be impaired by neurological late toxicities. Areas covered: Essential clinical information of natural history, predisposing factors, assessment issues and lacks in treatment for peripheral neurotoxicity are here reported. An overview of preclinical pathogenetic observations is also given to drive future drug discovery. Expert opinion: To unravel needs and lacks for platinum-induced neurotoxicity a great effort is still to be done. A coordinated and combined effort of clinical and preclinical researchers is required. The newborn multidisciplinary Toxic Neuropathy Consortium - Special Interest Group of the Peripheral Nerve Society - seems a virtuous alliance that might find answers to meet clinical and scientific needs in this field.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Animais , Antineoplásicos/administração & dosagem , Sobreviventes de Câncer , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Humanos , Neoplasias/patologia , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Qualidade de Vida
10.
BMC Pharmacol Toxicol ; 20(1): 17, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953563

RESUMO

BACKGROUND: Carbon monoxide poisoning is a common emergency worldwide, which carries high morbidity and mortality. Some patients who recover from the insult of acute carbon monoxide toxicity may later develop delayed neuropsychiatric sequelae (DNS) after a lucid period in the form of cognitive impairments, a broad spectrum of neurological deficits and affective disorders. Here, we present the first case of DNS following carbon monoxide poisoning in Sri Lanka and epidemiology of the exposure of nine (9) more victims. CASE PRESENTATION: A 55-year-old patient and nine other people developed effects of carbon monoxide poisoning in two different occasions after sleeping few hours in the same room in their work place in Sri Lanka. These patients developed spectrum of symptoms with the acute carbon monoxide poisoning. However, one patient developed neurological deterioration pertaining to delayed neuropsychiatric sequelae (DNS) after 1 month of lucid interval. His MRI scan of the brain showed diffuse high signal intensity involving subcortical white matter, globus pallidus on FLAIR and T2W images. These areas showed high signals in DWI images with no significant changes appreciated on ADC map. There was no abnormal contrast enhancement appreciated in the above areas. EEG showed generalized slow waves. He gradually deteriorated over next 2 weeks, exhibited athetoid movements of his feet and hands and went into rigid akinetic mute state. He could not response to any stimulation and even displayed decorticated-like posture and died. Others had normal MRI brain finding at 8 weeks of acute toxicity and all were neurologically normal after 1 year. CONCLUSION: Though, it is uncommon in a tropical country like Sri Lanka, clinicians should have high degree of suspicion with the correct circumstances, as it is a challenge for the emergency physicians, even in countries with higher rate of CO poisoning. The exact mechanisms of acute and delayed toxicity, preventive methods and the suggested treatments are yet to be elucidated and this needs further attention and studies.


Assuntos
Intoxicação por Monóxido de Carbono/complicações , Síndromes Neurotóxicas/etiologia , Intoxicação por Monóxido de Carbono/epidemiologia , Exposição Ambiental/efeitos adversos , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Neurotóxicas/epidemiologia , Sri Lanka/epidemiologia
11.
Toxicol Lett ; 308: 50-55, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30940550

RESUMO

Tetramethylenedisulfotetramine (TMDT) is a synthetic neurotoxic rodenticide and potential chemical threat agent. Signs of TMDT poisoning include convulsions which can progress into status epilepticus and death. Although clinical reports clearly show that poisoning via food and drink is the main route of exposure, experimental studies have primarily utilized parenteral routes. Here we used two different modes of oral administration of TMDT and compared the toxic outcomes with two different parenteral routes. Adult male mice were given various doses of TMDT either perorally in peanut butter or cereal pellets, or injected intraperitoneally (i.p.) or subcutaneously (s.c.). All routes produced the complete TMDT syndrome including twitches, clonic and tonic-clonic seizures and death. However potencies varied with the following rank order: i.p. > s.c. > oral (cereal)>>oral (peanut butter). Our data clearly show that ingestion of TMDT with peanut butter markedly reduces the overall syndrome severity relative to oral exposure via cereals. No significant differences were observed by substituting peanut oil for water as a vehicle for i.p. administered TMDT. In conclusion, high vs low fat food can differentially affect TMDT onset of action, probably due to differences in availability from the gastrointestinal tract. These results should be considered when searching for effective treatments for TMDT poisoning.


Assuntos
Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/envenenamento , Modelos Animais de Doenças , Síndromes Neurotóxicas/etiologia , Administração Oral , Animais , Relação Dose-Resposta a Droga , Humanos , Injeções Intralinfáticas , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Envenenamento/etiologia
12.
Environ Toxicol Pharmacol ; 69: 36-43, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30953932

RESUMO

Alumina nanoparticles (NP-Al2O3) are widely used but their environmental effects are unknown, so they can become potentially dangerous. The aim of this study was to evaluate the toxicity of a nanoceramic catalyst Ni/γ-Al2O3 (NC) and NPs involved in their synthesis, γ-Al2O3 support (SPC) and NiO/γ-Al2O3 precursor (PC) on Rhinella arenarum embryo-larval development. The NPs toxicity significantly increased over time obtaining a similar sensitivity to PC and NC (336 h-LC50 = 4.03 and 5.11 mg/L respectively) and very low sensitivity to SPC (336 h-LC50 = 90.83 mg/L). Embryos exposed to SPC and PC exhibited general underdevelopment, axial flexures and behavioral alterations. Pharyngeal and intestinal epithelia alterations at the level of cell surface as dissociation, apoptosis and numerous lysosomes were observed at light and transmission electronic microscopy. Images of scanning electron microscope with backscattered electron detector revealed the presence of nickel in the intestinal epithelium. The increased toxicity of PC could be due to the presence of Ni as oxide which could interfere with vital functions such as breathing and feeding. Taking into account the exponential production and use of these NPs it is expected that their pollution levels will considerably increase and amphibians will be more exposed and at higher risk.


Assuntos
Óxido de Alumínio/toxicidade , Bufonidae , Cerâmica/toxicidade , Nanoestruturas/toxicidade , Níquel/toxicidade , Teratogênios/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Larva/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/veterinária
13.
Toxicol Lett ; 311: 37-48, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31029751

RESUMO

Polybrominated diphenyl ether-153 (BDE-153) has been demonstrated to induce neuronal apoptosis in rat cerebral cortex and primary neurons, however, the roles of mitochondria and endoplasmic reticulum (ER) remain unclear in the BDE-153-induced neuronal apoptosis. To this purpose, we observed the mitochondria and ER ultrastructure changes in the neuronal apoptosis in rats following BDE-153 treatment, detected the mitochondrial membrane potential (MMP), Ca2+-Mg2+-ATP enzyme activity, and the changes of mitochondria and ER apoptosis related molecules in rat cerebral cortex and in primary neurons following BDE-153 treatment. Results showed that compared to the control group, neuronal apoptosis was significantly increased in a dose-dependent manner in rat cerebral cortex and in primary neurons following BDE-153 treatment. In comparison with control, BDE-153 treatment induced remarkable ultrastructural changes in ER rather than in mitochondria, and the severity of ER damage was worse with the increasing BDE-153 dose. Meanwhile, ER apoptosis related molecules including caspase-12 (at mRNA level), cleaved caspase-12 (at protein level), and Tmem132a (at mRNA and protein levels) were significantly increased in the cerebral cortex in rats following BDE-153 treatment, while procaspase-12 protein was significantly decreased, comparing with control. In contrast, mitochondria apoptosis related molecules (MMP, Ca2+-Mg2+-ATP enzyme activity, cyt-C protein, caspase-3, 8, 9 mRNA, caspase-8, 9 enzyme activities) did not significantly changed in the cerebral cortex of rats or in primary neurons following BDE-153 treatment, except for the elevated caspase-3 mRNA and enzyme activity. Therefore, we conclude that BDE-153 induced neuronal apoptosis was dependent on p53, and mediated more by ER than mitochondria in the cerebral cortex of rats and in primary neurons. The findings suggest that ER is a potential sensitive target of BDE-153 neurotoxicity, providing a scientific evidence for the mechanism and intervention study on PBDE's neurotoxicity.


Assuntos
Apoptose/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Degeneração Neural , Neurônios/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Bifenil Polibromatos/toxicidade , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/ultraestrutura , Relação Dose-Resposta a Droga , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neurônios/metabolismo , Neurônios/ultraestrutura , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Ratos Sprague-Dawley , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
14.
Chemosphere ; 226: 817-824, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30965253

RESUMO

Reptiles, the most diverse taxon of terrestrial vertebrates, might be particularly vulnerable to soil pollution. Reptiles especially lizards have been rarely evaluated in ecotoxicological studies, and there is a very limited report for effects of soil pesticide contaminants on lizards. In this study, male and female lizards (Eremias argus) were exposed to Glufosinate-ammonium (GLA) and l- Glufosinate-ammonium (L-GLA) for 60 days. Slower sprint speed, higher frequency of turning back and reduced brain index were observed in treatment groups. The accumulation of GLA in the brain of lizard was higher than that of L-GLA. Moreover, the activities of neurotoxicity-related enzymes and biomarkers of oxidative stress were also investigated. In summary, the neurotoxic effects of lizards have been observed after exposure to GLA and L-GLA. Based on the result of the Integrated Biomarker Response (IBR), males were more sensitive to contaminants than females. On the other hand, the neurotoxic pathways by GLA and L-GLA triggered were slightly different: GLA mainly acted on glutamine synthetase (GS), acetylcholinesterase (AchE) and Catalase (CAT) and L-GLA aimed at AchE, Na+/K+-ATPase, Superoxide dismutase (SOD) and Malondialdehyde (MDA). In summary, the accumulation of GLA and L-GLA in lizard's brain induced neurotoxicity by altering the levels of enzymes related to nervous system and antioxidant activity and further resulted in the decrease of brain index and locomotor performance.


Assuntos
Aminobutiratos/toxicidade , Poluição Ambiental/efeitos adversos , Lagartos/metabolismo , Locomoção/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Aminobutiratos/farmacocinética , Aminobutiratos/farmacologia , Animais , Encéfalo/enzimologia , Encéfalo/metabolismo , Ecotoxicologia , Feminino , Lagartos/fisiologia , Masculino , Síndromes Neurotóxicas/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/metabolismo , Fatores Sexuais
15.
J Pharmacol Sci ; 139(3): 186-192, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30850243

RESUMO

BACKGROUND: Local anesthetics (LAs) may generate neurotoxicity in neurons. In the current study, we explored the mechanisms by which microRNA-132 (miR-132) regulated the neurotoxicity of human neuroblastoma cells (SH-SY5Y) induced by bupivacaine (BUP). METHODS: CCK-8, flow cytometry, EdU detection, qRT-PCR and western blotting were used to explore the cell viability, apoptosis and gene expression, respectively. RESULTS: In this study, we found that 600 µM BUP dramatically inhibited SH-SY5Y cells viability. In addition, BUP induced cell apoptosis and neurotoxicity via increasing active caspase-3 and cleaved PARP1 levels. More importantly, the level of miR-132 was significantly up-regulated in BUP-treated cells, which was significantly reversed by miR-132 inhibitor. In addition, dual-luciferase assay indicated IGF1R was the directly binding target of miR-132 in cells. Our study further indicated that the level of IGF1R was markedly decreased by BUP interference, while miR-132 inhibitor exerted the opposite effect. Furthermore, BUP induced apoptosis and neurotoxicity in SH-SY5Y cells were attenuated by IGF1, which further confirmed IGF1R was the downstream target of BUP in SH-SY5Y cells. CONCLUSION: In the present study, miR-132 played important roles in regulating BUP-induced neurotoxicity through IGF1R and may act as a promising molecular target for the treatment of human neurotoxicity induced by BUP.


Assuntos
Anestésicos Locais/toxicidade , Bupivacaína/toxicidade , MicroRNAs/genética , Síndromes Neurotóxicas/etiologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Humanos , Neuroblastoma/metabolismo , Síndromes Neurotóxicas/genética , Receptores de Somatomedina/metabolismo , Regulação para Cima/genética
16.
Medicine (Baltimore) ; 98(8): e14629, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813198

RESUMO

RATIONALE: This is the first reported severe thallium poisoning patient successfully treated with Prussian blue (PB) and plasma exchange (PE). PATIENT CONCERNS: A 42-year-old woman in a coma owing to severe thallium poisoning was admitted to our department after day 44 of poisoning. At admission, blood and urine thallium concentrations were 380.0 and 2580.0 ng/mL, respectively. DIAGNOSIS: The patient was diagnosed with toxic encephalopathy induced by thallium poisoning; in addition, she was also diagnosed with bilateral pneumonia, respiratory failure, moderate anemia, hypoproteinemia, and electrolyte imbalance based on her chest X-ray, blood gas analysis, Hb level, albumin levels, and serum electrolyte results. INTERVENTIONS: The patient was intubated and treated with PB (6600 mg/d, 15 days in total) combined with PE (once daily, 5 days in total) as well as other symptomatic supportive care measures. OUTCOMES: After treatments, her blood and urinary thallium concentrations gradually decreased and on the 13th day after admission, the blood thallium concentration decreased to 0 ng/mL. The oxygenation index gradually improved, meantime, the patient gradually regained consciousness, and on the 50th day of admission, the patient's consciousness reverted to a clear-headed state. The patient recovered mostly after 37 months of follow-up. LESSONS: Through this case, we learned that the gradual reduction in blood and urine thallium concentration and the patient's improved condition is correlated with PB and PE treatment. For patients with severe thallium poisoning, this treatment method might be effective; but the exact curative effect is unconfirmed, requiring further research to verify.


Assuntos
Coma/terapia , Ferrocianetos/uso terapêutico , Síndromes Neurotóxicas/diagnóstico , Troca Plasmática/métodos , Tálio/envenenamento , Adulto , Coma/induzido quimicamente , Feminino , Humanos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/terapia , Tálio/sangue , Tálio/urina
17.
BMJ Case Rep ; 12(3)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30826778

RESUMO

Neurotoxicity is a rare but significant side effect of metronidazole. We present, here, a case of a 34-year-old man, presenting with garbled speech and word finding difficulty. He was taking metronidazole for the last 3 months for stage 4 decubitus ulcers. MRI of the brain showed abnormal signal intensities in the splenium of the corpus callosum and dentate nuclei of the cerebellum. The diagnosis of metronidazole-induced neurotoxicity was made based on MRI findings. The antibiotic was stopped leading to resolution of abnormal MRI findings. We advocate that metronidazole can be associated with severe neurotoxicity, but its prompt cessation leads to better outcome and prognosis.


Assuntos
Anti-Infecciosos/efeitos adversos , Metronidazol/efeitos adversos , Síndromes Neurotóxicas/etiologia , Distúrbios da Fala/induzido quimicamente , Adulto , Diagnóstico Diferencial , Humanos , Masculino , Síndromes Neurotóxicas/diagnóstico , Fala/efeitos dos fármacos , Distúrbios da Fala/diagnóstico
18.
Environ Sci Pollut Res Int ; 26(9): 9174-9183, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30719664

RESUMO

Aluminum (Al) had well-identified adverse influences on the nervous system mainly through the creation of reactive oxygen species (ROS). Melatonin works as an antioxidant through the inhibition of ROS and attenuating peroxidation of lipids. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a pivotal transcription factor which controls the transcription of antioxidant enzymes. This study was conducted to determine the potential neuroprophylactic impacts of melatonin in aluminum chloride (AlCl3)-initiated neurotoxicity including potential mechanism(s) of action and relevant signaling in rats. Thirty-six male rats were distributed into 4 groups: Control; AlCl3 (50 mg/kg bwt, i.p, 3 times weekly for 3 months); melatonin (5 mg/kg bwt, i.p daily for 2 weeks before AlCl3 and sustained for the next 3 months); and melatonin with AlCl3. Neuronal alterations were histopathologically and biochemically evaluated. The neuronal antioxidant-related genes and relevant Nrf2 protein expression were determined by real-time PCR and Western blotting, respectively. The current data showed a substantial increase in brain damage biomarkers, acetylecholinesterase (AchE) activity, and malondialdehyde (MDA) content while the enzymatic antioxidant expression as glutathione-s-transferase (GST), catalase (CAT), and superoxide dismutase (SOD) were substantially attenuated in the aluminum-treated group, with cleared histopathological changes as inflammatory cell infiltration with neuronal degeneration. Supplementation of melatonin resulted in an obvious amelioration in all previous abnormal alteration observed in AlCl3-treated rats rather than increased Al burden and/or altered Fe and Cu homeostasis with upregulating both total and phosphorylated Nrf2 expression. Therefore, the study concluded that melatonin has a potential ability to be neuroprophylactic against Al-induced neurotoxic effect and oxidative damage in the rat brain through upregulating and instigating Nrf2 signaling apart from metal chelation.


Assuntos
Cloreto de Alumínio/toxicidade , Antioxidantes/metabolismo , Melatonina/administração & dosagem , Fator 2 Relacionado a NF-E2/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Síndromes Neurotóxicas/tratamento farmacológico , Animais , Catalase/genética , Catalase/metabolismo , Fator de Transcrição de Proteínas de Ligação GA/genética , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/genética , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo
19.
J Neurosurg Anesthesiol ; 31(1): 163-165, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30767942

RESUMO

The potential for long-term neurotoxic effects of anesthetics on the developing human brain has led to intensified research in this area. To date, the human evidence has been inconclusive, but a large body of animal evidence continues to demonstrate cause for concern. On April 14 and 15, 2018 the sixth biennial Pediatric Anesthesia and Neurodevelopmental Assessment (PANDA) study symposium was held at Morgan Stanley Children's Hospital of New York. This symposium brought together clinicians and researchers and served as a platform to review preclinical and clinical data related to anesthesia and neurotoxicity in developing brains. The program participants included many active investigators in the field of anesthesia neurotoxicity as well as stakeholders from different backgrounds with the common interest of potential anesthetic neurotoxicity in children. The moderated poster session included presentations of preclinical animal research studies. These studies focused on defining the anesthetic-induced neurotoxicity phenotype, understanding the mechanism of injury and discovering potential inhibitors of neurotoxic effects.


Assuntos
Anestesia/efeitos adversos , Anestésicos/efeitos adversos , Deficiências do Desenvolvimento/induzido quimicamente , Adolescente , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Síndromes Neurotóxicas/etiologia
20.
Oxid Med Cell Longev ; 2019: 2593742, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30728884

RESUMO

Excessive drinking can damage brain tissue and cause cognitive dysfunction. Studies have found that the early stage of neurodegenerative disease is closely related to heavy drinking. Acetaldehyde (ADE) is the main toxic metabolite of alcohol. However, the exact mechanisms of ADE-induced neurotoxicity are not fully clear. In this article, we studied the cytotoxic effect of ADE in HT22 cells and primary cultured cortical neuronal cells. We found that ADE exhibited cytotoxicities against HT22 cells and primary cultured cortical neuronal cells in dose-dependent manners. Furthermore, ADE induced apoptosis of HT22 cells by upregulating the expression of caspase family proapoptotic proteins. Moreover, ADE treatment could significantly increase the intracellular Ca2+ and reactive oxygen species (ROS) levels and activate endoplasmic reticulum stress (ERS) in HT22 cells. ADE upregulated ERS-related CHOP expression dose-dependently in primary cultured cortical neuronal cells. In addition, inhibition of ROS with antioxidant N-acetyl-L-cysteine (NAC) reduced the accumulation of ROS and reversed ADE-induced increase of ERS-related protein and apoptosis-related protein levels. Mitigation of ERS with ERS inhibitor 4-PBA obviously suppressed ADE-induced apoptosis and the expression of ERS-related proteins. Therefore, ADE induces neurotoxicity of HT22 cells via oxidative stress- and Ca2+ imbalance-mediated ERS.


Assuntos
Acetaldeído/efeitos adversos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Estresse Oxidativo/fisiologia , Animais , Humanos , Camundongos , Síndromes Neurotóxicas/patologia , Ratos
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