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1.
Cell Physiol Biochem ; 54(2): 180-194, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32068980

RESUMO

BACKGROUND/AIMS: Still in 1999 the first hints were published for the pharmacoresistant Cav2.3 calcium channel to be involved in the generation of epileptic seizures, as transcripts of alpha1E (Cav2.3) and alpha1G (Cav3.1) are changed in the brain of genetic absence epilepsy rats from Strasbourg (GAERS). Consecutively, the seizure susceptibility of mice lacking Cav2.3 was analyzed in great detail by using 4-aminopyridine, pentylene-tetrazol, N-methyl-D-aspartate and kainic acid to induce experimentally convulsive seizures. Further, γ-hydroxybutyrolactone was used for the induction of non-convulsive absence seizures. For all substances tested, Cav2.3-competent mice differed from their knockout counterparts in the sense that for convulsive seizures the deletion of the pharmacoresistant channel was beneficial for the outcome during experimentally induced seizures [1]. The antiepileptic drug lamotrigine reduces seizure activity in Cav2.3-competent but increases it in Cav2.3-deficient mice. In vivo, Cav2.3 must be under tight control by endogenous trace metal cations (Zn2+ and Cu2+). The dyshomeostasis of either of them, especially of Cu2+, may alter the regulation of Cav2.3 severely and its activity for Ca2+ conductance, and thus may change hippocampal and neocortical signaling to hypo- or hyperexcitation. METHODS: To investigate by telemetric EEG recordings the mechanism of generating hyperexcitation by kainate, mice were tested for their sensitivity of changes in neuronal (intracerebroventricular) concentrations of the trace metal cation Zn2+. As the blood-brain barrier limits the distribution of bioavailable Zn2+ or Cu2+ into the brain, we administered micromolar Zn2+ ions intracerebroventricularly in the presence of 1 mM histidine as carrier and compared the effects on behavior and EEG activity in both genotypes. RESULTS: Kainate seizures are more severe in Cav2.3-competent mice than in KO mice and histidine lessens seizure severity in competent but not in Cav2.3-deficient mice. Surprisingly, Zn2+ plus histidine resembles the kainate only control with more seizure severity in Cav2.3-competent than in deficient mice. CONCLUSION: Cav2.3 represents one important Zn2+-sensitive target, which is useful for modulating convulsive seizures.


Assuntos
Canais de Cálcio Tipo R/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Convulsões/tratamento farmacológico , Zinco/uso terapêutico , Animais , Canais de Cálcio Tipo R/genética , Proteínas de Transporte de Cátions/genética , Eletroencefalografia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histidina/farmacologia , Íons/química , Ácido Caínico/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Convulsões/induzido quimicamente , Convulsões/patologia , Índice de Gravidade de Doença , Zinco/farmacologia , Ácido gama-Aminobutírico/metabolismo
2.
West Afr J Med ; 37(1): 7-12, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030705

RESUMO

BACKGROUND: Ketogenic diets (KD) have been used globally in epilepsy management. Similarly, supplementation of diets with magnesium has been associated with disease prevention and improvement. However, the effect of magnesium (Mg) supplementation in conjunction with KD on epilepsy has not yet been investigated. We hypothesized that magnesium supplementation in KD would improve the effectiveness of the diet. METHODS: Forty-eight male Wistar rats were used for the study. The animals were fed on 4 diet types: I-normal rat chow (ND), II-ND with Mg supplement (ND+Mg), III-medium chain ketogenic diet (KD) and IV-KD with Mg supplement (KD+Mg). Animals in each group were divided into 3: experimental, control and observatory. The experimental drug was intraperitoneal Pentylenetetrazole (PTZ) administered at 25 mg/kg. The rats were observed for 2 hours after the drug administration and induced seizures noted. The levels of serum electrolytes and plasma lipid levels were determined using standard methods. RESULTS: The seizure latency was significantly prolonged 60.8±0.5mins in group III compared with 8.7±2.1mins in group I (p<0.05). The seizure duration was 42.5±2.5mins in group III and 142.3±4.7 in group I (p<0.05). With Mg supplementation, seizure latency was 62.6±1.5mins in group IV and 7.9±0.7mins in group I (p<0.05). The seizure duration was 45.5±4.5min in group IV and 139.3±3.9mins in group II (p< 0.05). The KD-fed rats showed a tendency to develop dyslipidemia as evidenced by elevated Total Cholesterol /HDL and LDL/HDL (2.32±0.32 and 1.19±0.08) in group III, which was reversed in the KD+Mg fed group IV (1.96±0.32 and 1.08±0.09) with p<0.05. CONCLUSION: Mg supplementation of KD did not affect its antiseizure property and does not confer antiseizure effect on ND. Mg supplement showed a tendency to reduce derangement in lipid metabolism associated with KD.


Assuntos
Dieta Cetogênica , Metabolismo dos Lipídeos/efeitos dos fármacos , Magnésio/farmacologia , Convulsões/dietoterapia , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Humanos , Lipídeos/sangue , Magnésio/administração & dosagem , Masculino , Pentilenotetrazol , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Convulsões/sangue , Convulsões/induzido quimicamente
3.
Toxicol Lett ; 325: 67-76, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017982

RESUMO

Racemic 3-quinuclidinyl-α-methoxydiphenylacetate (MB266) was synthesised. Its activity at muscarinic acetylcholine receptors (mAChRs), and muscle and neuronal nicotinic acetylcholine receptors (nAChRs), was compared to that of atropine and racemic 3-quinucidinyl benzilate (QNB) using a functional assay based on agonist-induced elevation of intracellular calcium ion concentration in CN21, Chinese Hamster Ovary (CHO) and SHSY5Y human cell lines. MB266 acted as an antagonist at acetylcholine receptors, displaying 18-fold selectivity for mAChR versus nAChR (compared to the 15,200-fold selectivity observed for QNB). Thus O-methylation of QNB reduced the affinity for mAChR antagonism and increased the relative potency at both muscle and neuronal nAChRs. Despite MB266 having a pharmacological profile potentially useful for the treatment of anticholinesterase poisoning, its administration did not improve the neuromuscular function in a soman-poisoned guinea-pig diaphragm preparation pretreated with the organophosphorus nerve agent soman. Consideration should be given to exploring the potential of MB266 for possible anticonvulsant action in vitro as part of a multi-targeted ligand approach.


Assuntos
Antídotos/farmacologia , Antídotos/uso terapêutico , Inibidores da Colinesterase/envenenamento , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Agentes Neurotóxicos/envenenamento , Antagonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/uso terapêutico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/uso terapêutico , Antídotos/síntese química , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Diafragma/efeitos dos fármacos , Cobaias , Humanos , Técnicas In Vitro , Masculino , Antagonistas Muscarínicos/síntese química , Músculo Esquelético/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Antagonistas Nicotínicos/síntese química , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Soman/envenenamento
4.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R369-R378, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913689

RESUMO

Activation of Toll-like receptors (TLRs) after hypoxic-ischemic brain injury can exacerbate injury but also alleviate cell loss, as recently demonstrated with the TLR7 agonist Gardiquimod (GDQ). However, TLR agonists also modulate vascular function and neuronal excitability. Thus, we examined the effects of TLR7 activation with GDQ on cardiovascular function and seizures after asphyxia in preterm fetal sheep at 0.7 gestation (104 days, term ∼147 days). Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion for 25 min or asphyxia followed by a continuous intracerebroventricular infusion of 3.34 mg of GDQ from 1 to 4 h after asphyxia. Fetuses were monitored continuously for 72 h postasphyxia. GDQ treatment was associated with sustained, moderate hypertension for 72 h (P < 0.05), with a transient increase in heart rate. Electroencephalographic (EEG) power was suppressed for the entire postasphyxial period in both groups, whereas EEG spectral edge transiently increased during the GDQ infusion compared with asphyxia alone (P < 0.05), with higher ß- and lower δ-EEG frequencies (P < 0.05). This increase in EEG frequency was not related to epileptiform activity. After the GDQ infusion, there was earlier onset of high-amplitude stereotypic evolving seizures, with increased numbers of seizures and seizure burden (P < 0.05). Hemodynamic function and seizure activity are important indices of preterm wellbeing. These data highlight the importance of physiological monitoring during preclinical testing of potential neuroprotective strategies.


Assuntos
Aminoquinolinas/toxicidade , Asfixia Neonatal/tratamento farmacológico , Hipertensão/induzido quimicamente , Imidazóis/toxicidade , Fármacos Neuroprotetores/toxicidade , Nascimento Prematuro , Convulsões/induzido quimicamente , Taquicardia/induzido quimicamente , Receptor 7 Toll-Like/agonistas , Animais , Animais Recém-Nascidos , Asfixia Neonatal/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Ondas Encefálicas/efeitos dos fármacos , Modelos Animais de Doenças , Idade Gestacional , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Medição de Risco , Convulsões/fisiopatologia , Carneiro Doméstico , Transdução de Sinais , Taquicardia/fisiopatologia , Fatores de Tempo
5.
Ann Neurol ; 87(1): 97-115, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31657482

RESUMO

OBJECTIVE: To investigate the network dynamics mechanisms underlying differential initiation of epileptic interictal spikes and seizures. METHODS: We performed combined in vivo 2-photon calcium imaging from different targeted neuronal subpopulations and extracellular electrophysiological recordings during 4-aminopyridine-induced neocortical spikes and seizures. RESULTS: Both spikes and seizures were associated with intense synchronized activation of excitatory layer 2/3 pyramidal neurons (PNs) and to a lesser degree layer 4 neurons, as well as inhibitory parvalbumin-expressing interneurons (INs). In sharp contrast, layer 5 PNs and somatostatin-expressing INs were gradually and asynchronously recruited into the ictal activity during the course of seizures. Within layer 2/3, the main difference between onset of spikes and seizures lay in the relative recruitment dynamics of excitatory PNs compared to parvalbumin- and somatostatin-expressing inhibitory INs. Whereas spikes exhibited balanced recruitment of PNs and parvalbumin-expressing INs, during seizures IN responses were reduced and less synchronized than in layer 2/3 PNs. Similar imbalance was not observed in layers 4 or 5 of the neocortex. Machine learning-based algorithms we developed were able to distinguish spikes from seizures based solely on activation dynamics of layer 2/3 PNs at discharge onset. INTERPRETATION: During onset of seizures, the recruitment dynamics markedly differed between neuronal subpopulations, with rapid synchronous recruitment of layer 2/3 PNs, layer 4 neurons, and parvalbumin-expressing INs and gradual asynchronous recruitment of layer 5 PNs and somatostatin-expressing INs. Seizures initiated in layer 2/3 due to a dynamic mismatch between local PNs and inhibitory INs, and only later spread to layer 5 by gradually and asynchronously recruiting PNs in this layer. ANN NEUROL 2020;87:97-115.


Assuntos
Interneurônios/fisiologia , Células Piramidais/fisiologia , Recrutamento Neurofisiológico/fisiologia , Convulsões/fisiopatologia , 4-Aminopiridina , Potenciais de Ação/fisiologia , Algoritmos , Animais , Feminino , Interneurônios/metabolismo , Aprendizado de Máquina , Masculino , Camundongos , Convulsões/induzido quimicamente , Somatostatina/metabolismo
6.
Eur J Med Chem ; 185: 111824, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708184

RESUMO

In searching for more effective and safer antiepileptic drugs, a series of 2,5-disubstituted [1,2,4]-triazolo[1,5-a]pyrimidine-7(4H)-one derivatives were designed and synthesized. Spontaneous Ca2+ oscillations (SCOs) of cortical neurons were used for in vitro phenotypic screening. Maximal electroshock test (MES) and pentylenetetrazole (PTZ) test were used to access their anticonvulsant activity, and rotarod test was used to estimate their neurotoxicity. The active compounds in in vitro model are specifically effective in pentylenetetrazole (PTZ)-induced epilepsy model but not maximal electroshock (MES) model, more importantly with lower neurotoxicity as compared to commonly used drugs. Among them, compound 5c and 5e showed significant anticonvulsant activities in PTZ-induced epilepsy model with ED50 values at 31.81 mg/kg and 40.95 mg/kg, respectively. These compounds have improved neurotoxicity with protective index (PI = TD50/ED50) values at 17.22 and 9.09, respectively. Finally we demonstrated that compound 5c and 5e mainly acted on GABAA receptor as positive modulators but not sodium channels. Thus the present study has provided potential candidates for further investigation in epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Atividade Motora/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Pirimidinas/farmacologia , Receptores de GABA-A/metabolismo , Convulsões/tratamento farmacológico , Triazóis/farmacologia , Animais , Anticonvulsivantes/química , Anticonvulsivantes/toxicidade , Células Cultivadas , Relação Dose-Resposta a Droga , Descoberta de Drogas , Eletrochoque , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Pentilenotetrazol , Substâncias Protetoras/química , Substâncias Protetoras/toxicidade , Pirimidinas/química , Pirimidinas/toxicidade , Convulsões/induzido quimicamente , Relação Estrutura-Atividade , Triazóis/química , Triazóis/toxicidade
7.
Artigo em Russo | MEDLINE | ID: mdl-31851178

RESUMO

There is a growing interest to the problem of drug-induced epileptic seizures (ES) due to their relatively high prevalence, poor prognosis, a large number of different drugs associated with the development of drug-induced ES, and low awareness among general practitioners. Drug-induced ES are most often associated with the use of antidepressants, antipsychotics, antiepileptic drugs (overdose or as a result of discontinuation), antibiotics, immunosuppressants and immunomodulators, antitumor agents, analgesics, central nervous system stimulators, anesthetics etc. The prevalence of drug-induced ES varies with different drugs. It is estimated that about 6.1% of the first occurring ES are drug-induced. Risk factors for drug-induced ES include a history of epilepsy or ES, cancer, blood-brain barrier dysfunction, several concomitant neurological diseases, mental disorders, childhood, old and very old age, fever, impaired liver metabolism in patients with liver diseases, impaired drug excretion in patients with kidney diseases, polypharmacy, pharmacokinetic properties of the drugs themselves, allowing them to penetrate the blood-brain barrier in the central nervous system (lipophilicity, transport and communication with blood plasma proteins), drug concentration in blood serum, method and frequency of drug administration, single and daily doses of drugs. No clinical guidelines for the management of patients with drug-induced ES are available. It is recommended to identify patients at risk: elderly patients, patients with impaired liver and kidney function and patients receiving drugs that can cause ES and/or lower the seizure threshold. Benzodiazepines are the first-line treatment in drug-induced status epilepticus, barbiturates and propofol are the second-line treatment. The general principles for the prevention of drug-induced ES include careful selection of the optimal dose of drugs that can cause ES, especially in patients with impaired liver and/or kidney function, monitoring of several parameters in blood serum (for example, liver enzymes, electrolytes, glucose etc.), monitoring of the blood plasma concentration of certain drugs, avoiding the simultaneous administration of several drugs that stimulate the central nervous system, and a rapid discontinuation of such drugs.


Assuntos
Epilepsia , Convulsões , Idoso , Anticonvulsivantes/efeitos adversos , Antidepressivos/efeitos adversos , Antipsicóticos/efeitos adversos , Criança , Humanos , Prevalência , Fatores de Risco , Convulsões/induzido quimicamente
8.
Am J Case Rep ; 20: 1949-1955, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31879415

RESUMO

BACKGROUND Trazodone is widely used in the treatment of depression, anxiety, and insomnia. It is thought to have a safe cardiac profile due to the relative lack of anticholinergic effects. Publications about cardiac toxicities of trazodone are scant. CASE REPORT A 55-year-old woman presented with acute disorder of consciousness secondary to an intentional trazodone overdose. She was found to have seizure activity without cerebral edema. The initial electrocardiogram was unremarkable, with a normal QTc interval. She eventually developed QTc prolongation that evolved into ventricular tachycardia, and then into a transient right bundle-branch block, left anterior fascicular block, and variable degrees of atrioventricular nodal blocks at 12-24 h after ingestion. She then developed generalized tonic-clonic seizures, cardiogenic shock, and respiratory arrest. She was intubated and treated with antiepileptics, norepinephrine, and dopamine infusion. QTc interval prolongation gradually resolved and the various forms of heart block did not recur after at 24-36 h. She did not require transcutaneous pacing, and was successfully extubated with intact neurological function. CONCLUSIONS Fatal arrhythmias can occur in trazodone overdose. Close monitoring and supportive care are crucial for patient survival.


Assuntos
Ansiolíticos/efeitos adversos , Bloqueio de Ramo/induzido quimicamente , Overdose de Drogas/complicações , Síndrome do QT Longo/induzido quimicamente , Convulsões/induzido quimicamente , Taquicardia Ventricular/induzido quimicamente , Trazodona/efeitos adversos , Anticonvulsivantes/uso terapêutico , Bloqueio de Ramo/diagnóstico por imagem , Bloqueio de Ramo/tratamento farmacológico , Dopamina/uso terapêutico , Eletrocardiografia , Feminino , Humanos , Síndrome do QT Longo/diagnóstico por imagem , Síndrome do QT Longo/tratamento farmacológico , Pessoa de Meia-Idade , Norepinefrina/uso terapêutico , Taquicardia Ventricular/diagnóstico por imagem , Taquicardia Ventricular/tratamento farmacológico
9.
Yakugaku Zasshi ; 139(11): 1397-1402, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685736

RESUMO

Patients with epilepsy are often affected by not only seizures but also a variety of cognitive and psychiatric comorbidities that further impair their quality of life. However, it is unclear whether epilepsy is associated with psychic function. The aim of the present study was to clarify the effects of kindling-induced epileptic seizures on psychic functioning, using behavioral pharmacological tests. Pentylenetetrazol (PTZ)-kindled mice displayed impaired motor coordination (in the rotarod test), and social approach impairment (in the three-chamber social test) compared with vehicle mice. Intraperitoneal ABT-418 treatment (0.05 mg/kg) alleviated these behavioral abnormalities in PTZ-kindled mice. Immunolabeling of tissue sections demonstrated that expression of the α4 subunit of the α4ß2 nicotinic acetylcholine receptor in the piriform cortex was significantly decreased in PTZ-kindled mice. In contrast, expression of the synaptic adhesion molecule neuroligin 3 (NLG3) was significantly higher in the piriform cortex of PTZ-kindled mice compared with vehicle mice. Collectively, our findings suggest that attention deficit/hyperactivity disorder (ADHD)-like or autistic-like behavioral abnormalities associated with epilepsy are closely linked to downregulation of the α4 subunit of the α4ß2 receptor and upregulation of NLG3 in the mouse piriform cortex. In summary, this study indicates that ABT-418 is a good candidate for the treatment of patients with epilepsy complicated by psychiatric symptoms such as autism and ADHD.


Assuntos
Epilepsia/psicologia , Excitação Neurológica , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/etiologia , Pentilenotetrazol , Receptores Nicotínicos/metabolismo , Convulsões/psicologia , Animais , Moléculas de Adesão Celular Neuronais/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Córtex Piriforme/metabolismo , Desempenho Psicomotor/efeitos dos fármacos , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Qualidade de Vida , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/etiologia , Comportamento Social
10.
Rev Assoc Med Bras (1992) ; 65(9): 1188-1192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618336

RESUMO

OBJECTIVE: We aimed to explore the effects of neuropeptides ghrelin, obestatin, and vasoactive intestinal peptide (VIP) on seizures and plasma concentrations of neuroinflammation biomarkers including calcitonin gene-related peptide (CGRP), substance-P (SP), and interleukin-1 beta (IL-1ß) in pentylenetetrazol-induced seizures in rats. METHODS: Ghrelin (80 µg/kg), obestatin (1 µg/kg), VIP (25 ng/kg) or saline were administered to rats intraperitoneally 30 min before pentylenetetrazole (PTZ, 50 mg/kg) injections. Stages of epileptic seizures were evaluated by Racine's scale, and plasma CGRP, SP, and IL-1ß concentrations were measured using ELISA. RESULTS: Both obestatin and VIP shortened onset-time of generalized tonic-clonic seizure, respectively, moreover VIP also shortened the onset-time of first myoclonic-jerk induced by PTZ. While PTZ increased plasma CGRP, SP and IL-1ß concentrations, ghrelin reduced the increases evoked by PTZ. While VIP further increased PTZ-evoked CGRP levels, it diminished IL-1ß concentrations. However, obestatin did not change CGRP, SP, and IL-1ß concentrations. CONCLUSION: Our results suggest that ghrelin acts as an anticonvulsant, obestatin acts as a proconvulsant, and VIP has dual action on epilepsy. Receptors of those neuropeptides may be promising targets for epilepsy treatment.


Assuntos
Convulsivantes/efeitos adversos , Neuropeptídeos/efeitos dos fármacos , Pentilenotetrazol/efeitos adversos , Hormônios Peptídicos/farmacologia , Convulsões/induzido quimicamente , Animais , Biomarcadores/sangue , Peptídeo Relacionado com Gene de Calcitonina/sangue , Peptídeo Relacionado com Gene de Calcitonina/efeitos dos fármacos , Modelos Animais de Doenças , Grelina/farmacologia , Inflamação , Interleucina-1beta/sangue , Interleucina-1beta/efeitos dos fármacos , Masculino , Mioclonia , Distribuição Aleatória , Ratos Wistar , Convulsões/metabolismo , Substância P/sangue , Substância P/efeitos dos fármacos , Fatores de Tempo , Peptídeo Intestinal Vasoativo/farmacologia
11.
J Vet Emerg Crit Care (San Antonio) ; 29(6): 680-685, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31637833

RESUMO

OBJECTIVE: To describe a case of mannitol overdose associated with acute kidney injury (AKI), hypertonic hyponatremia, and neurologic abnormalities in a dog. CASE SUMMARY: A 10-year-old intact male Shiba Inu dog was referred to the emergency service of a veterinary teaching hospital for inappetence and acute onset of seizures. The dog had received 2 IV boluses of 3 g/kg of mannitol in less than 24 hours for a glaucoma crisis. Twelve hours after the second injection, the dog became inappetant and developed 2 generalized seizures. Seizure activity was treated with diazepam (0.5 mg/kg IV). Serum biochemistry profile showed severe hyponatremia and hypochloremia, mild hypokalemia, marked increased creatinine (381 µmol/L [44-133 µmol/L]) and moderately increased BUN (13.8 mmol/L [1.6-10.9 mmol/L]). Urinalysis revealed a urine specific gravity of 1.018, glucosuria, proteinuria, pigmenturia and the presence of vacuolized tubular epithelial cells. A presumptive diagnosis of mannitol intoxication was made based on the high dose of mannitol, severe hyponatremia, neurological abnormalities suggestive of intracranial disease, AKI, and urine cytology. Initial calculated plasma osmolality was 263.4 mOsm/kg and measured plasma osmolality was 332 mOsm/kg with an osmolal gap of 68.6 mOsm/kg, confirming the presence of an unmeasured solute attributed to mannitol. Treatment consisted of fluid therapy and supportive care. On day 3, osmolal gap had resolved and serum creatinine concentration returned to normal within 12 days. NEW OR UNIQUE INFORMATION PROVIDED: Mannitol intoxication has been reported in human medicine. This case report is, to our knowledge, the first to describe AKI, hypertonic hyponatremia, and neurological abnormalities secondary to mannitol overdose in a dog.


Assuntos
Lesão Renal Aguda/veterinária , Doenças do Cão/induzido quimicamente , Hiponatremia/veterinária , Manitol/toxicidade , Convulsões/veterinária , Lesão Renal Aguda/induzido quimicamente , Animais , Anticonvulsivantes/uso terapêutico , Creatinina , Diazepam/uso terapêutico , Cães , Overdose de Drogas , Hipopotassemia/complicações , Hiponatremia/induzido quimicamente , Masculino , Manitol/administração & dosagem , Concentração Osmolar , Convulsões/induzido quimicamente , Urinálise
12.
J Vet Emerg Crit Care (San Antonio) ; 29(6): 674-679, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31642158

RESUMO

OBJECTIVE: To describe the use of extracorporeal therapy (ECT) to treat severe cannabinoid intoxication in a dog with severe hyperlipidemia. CASE SUMMARY: A 7-month-old female intact Labrador Retriever presented with seizures and severe hyperesthesia that were refractory to multiple anticonvulsant medications and required induction of general anesthesia with propofol and mechanical ventilation. The dog's urine yielded a strong positive signal for delta-9-tetrahydrocannabinol (THC) on urine drug test and exposure to THC oil was confirmed by the owner. Bloodwork revealed severe hyperlipidemia such that IV lipid emulsion was considered contraindicated. The dog was treated with a 3-hour ECT session, using charcoal hemoperfusion and hemodialysis in series. Neurologic signs improved during the session and mechanical ventilation was discontinued. Immediately after the session, the dog's mentation was significantly improved and seizures and hyperesthesia had ceased, although the dog remained moderately ataxic. The dog was hospitalized for 36 hours following the ECT session for continued monitoring. The dog fully recovered and was successfully discharged. NEW OR UNIQUE INFORMATION PROVIDED: To the authors' knowledge, this is the first published report to document ECT to treat THC intoxication in veterinary medicine. ECT may be considered as a treatment option for severe THC intoxication that is refractory to standard therapy or where severe hyperlipidemia precludes use of IV lipid emulsions.


Assuntos
Canabinoides/toxicidade , Doenças do Cão/induzido quimicamente , Hemoperfusão/veterinária , Diálise Renal/veterinária , Respiração Artificial/veterinária , Convulsões/veterinária , Animais , Anticonvulsivantes/uso terapêutico , Carvão Vegetal/uso terapêutico , Doenças do Cão/terapia , Cães , Feminino , Propofol/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
13.
J Forensic Sci ; 64(6): 1950-1952, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31643086

RESUMO

4-bromo-2,5-dimethoxyphenethylamine (2C-B) is a designer drug. In Europe, 2C-B is easily obtained and used for recreational purposes. It is known for its stimulating effects similar to those of 3,4-methylenedioxymethamphetamine, although in higher doses it has more hallucinogenic effects. Here, we report a case of 2C-B ingestion, confirmed by liquid chromatography-tandem mass spectrometry, in an 18-year-old man. The neurological consequences were severe, including the development of serotonin syndrome and severe brain edema. Supportive therapy resulted in a stable condition, although, after several months, the patient still suffered from severe neurological impairment due to the drug-induced toxicity. This case showed that 2C-B could not be identified with the drugs of abuse screening routinely used in Dutch hospitals. The use of 2C-B carries many risks, with potentially profound neurological damage, that both consumers and healthcare physicians are unaware of.


Assuntos
Edema Encefálico/induzido quimicamente , Drogas Desenhadas/efeitos adversos , Dimetoxifeniletilamina/efeitos adversos , Convulsões/induzido quimicamente , Síndrome da Serotonina/induzido quimicamente , Adolescente , Cromatografia Líquida , Humanos , Masculino , Transtornos Relacionados ao Uso de Substâncias/complicações , Espectrometria de Massas em Tandem
14.
Nat Neurosci ; 22(11): 1892-1902, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31611708

RESUMO

Blood vessels in the CNS form a specialized and critical structure, the blood-brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells with peripheral endothelial cells. We also assessed the regulation of CNS endothelial gene expression in models of stroke, multiple sclerosis, traumatic brain injury and seizure, each having profound BBB disruption. We found that although each is caused by a distinct trigger, they exhibit strikingly similar endothelial gene expression changes during BBB disruption, comprising a core BBB dysfunction module that shifts the CNS endothelial cells into a peripheral endothelial cell-like state. The identification of a common pathway for BBB dysfunction suggests that targeting therapeutic agents to limit it may be effective across multiple neurological disorders.


Assuntos
Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Células Endoteliais/metabolismo , Esclerose Múltipla/metabolismo , Convulsões/metabolismo , Acidente Vascular Cerebral/metabolismo , Transcriptoma/genética , Animais , Biotina/metabolismo , Encéfalo/metabolismo , Infarto da Artéria Cerebral Média , Ácido Caínico , Camundongos , Camundongos Transgênicos , Esclerose Múltipla/induzido quimicamente , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Permeabilidade , Toxina Pertussis , Convulsões/induzido quimicamente , Transdução de Sinais
15.
Artigo em Inglês | MEDLINE | ID: mdl-31470499

RESUMO

OBJECTIVE: Previous research has demonstrated that patients with a history of organophosphate poisoning tend to have a higher risk of neurological disorder. However, research on the rate of seizure development in patients after organophosphate poisoning is lacking. This study examined whether individuals with organophosphate poisoning have an increased risk of seizures through several years of follow-up. PATIENTS AND METHODS: We conducted a retrospective study on a cohort of 45,060 individuals (9012 patients with a history of organophosphate poisoning and 36,048 controls) selected from the Taiwan National Health Insurance Research Database. The individuals were observed for a maximum of 12 years to determine the rate of new-onset seizure disorder. We selected a comparison cohort from the general population that was randomly frequency-matched by age, sex, and index year and further analyzed the risk of seizures using a Cox regression model adjusted for sex, age, and comorbidities. RESULTS: During the study period, the risk of seizure development was 3.57 times greater in patients with organophosphate poisoning compared with individuals without, after adjustments for age, sex, and comorbidities. The absolute incidence of seizures was highest in individuals aged 20 to 34 years in both cohorts (adjusted hazard ratio = 13.0, 95% confidence interval = 5.40-31.4). A significantly higher seizure risk was also observed in patients with organophosphate poisoning and comorbidities other than cirrhosis. CONCLUSIONS: This nationwide retrospective cohort study demonstrates that seizure risk is significantly increased in patients with organophosphate poisoning compared with the general population.


Assuntos
Intoxicação por Organofosfatos/complicações , Organofosfatos/toxicidade , Convulsões/induzido quimicamente , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Incidência , Masculino , Intoxicação por Organofosfatos/patologia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Convulsões/epidemiologia , Taiwan/epidemiologia , Adulto Jovem
16.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 48(3): 303-309, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31496163

RESUMO

OBJECTIVE: To determine the correlation of phosphorylated ribosomal S6 protein (P-S6) content in blood and brain tissue in mice and rats with seizure. METHODS: Seizure models were induced by intraperitoric injection of kainic acid (KA) in C57BL/mice and SD rats. Flow cytometry was used to detect the content of P-S6 in blood; Western blot was used to detect the expression of P-S6 in brain tissues. The correlation between P-S6 expression in blood and in brain tissue was examine by Pearson analysis, and the correlation between P-S6 expression in blood and the severity of seizure was also observed. RESULTS: Western blotting analysis showed that the expression of P-S6 was significantly increased in peripheral blood and brain tissue in mice 1 h after KA-induced seizure,and the expression levels increased to (1.49±0.45) times (P<0.05) and (2.55±0.66) times (P <0.01) of the control group, respectively. Flow cytometry showed that the positive percentage and average fluorescence intensity of P-S6 in the blood of mice increased significantly 1 h after KA-induced seizures (P<0.01), which was consistent with the expression of P-S6 in brain tissue (r=0.8474, P<0.01). Flow cytometry showed that the average fluorescence intensity of P-S6 in blood increased from 14.89±9.75 to 52.35±21.72 (P<0.01) in rats with seizure, which was consistent with the change of P-S6 in brain tissue (r=0.9385, P<0.01). Rats with higher levels of seizure were of higher levels of P-S6 in peripheral blood. CONCLUSIONS: Consistent correlation of P-S6 expression is demonstrated in peripheral blood and in brain tissue after KA-induced seizure, suggesting that the expression of P-S6 in blood can accurately reflect the changes of mTOR signaling pathway in brain tissue.


Assuntos
Encéfalo , Regulação da Expressão Gênica , Ácido Caínico , Convulsões , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Ratos , Ratos Sprague-Dawley , Convulsões/sangue , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
17.
Life Sci ; 232: 116667, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31326567

RESUMO

AIMS: Gamma amino butyric acid (GABA) imbalance plays a critical role in most neurological disorders including epilepsy. This study assessed the involvement of mild exercise on GABA imbalance following by seizure induction in rats. MAIN METHODS: Seizure was induced by pentylentetrazole (PTZ) injection. Animals were divided into sham, seizure, exercise (EX), co-seizure-induced exercise (Co-SI EX) and Pre-SI EX groups. In the Co-SI EX group, doing exercise and seizure induction was carried out during four weeks. Animals in the Pre-SI EX group exercised in week 1 to week 8 and seizures were induced in week 5 to week 8. Seizure properties, neural viability and expressions of glutamic acid decarboxylase 65 (GAD65) and GABAA receptor α1 in the hippocampus were assessed. KEY FINDINGS: Seizure severity reduced and latency increased in the Co-SI EX and Pre-SI EX groups compared to seizure group. The mean number of dark neurons decreased in all exercise groups compared to seizure group in both CA1 and CA3 areas. The gene level of GAD65 and GABAA receptor α1 was highly expressed in the Co-SI EX group in the hippocampal area. Distribution of GAD65 in the both CA1 and CA3 areas increased in the EX and Co-SI EX groups. GABAA receptor α1 was up-regulated in the CA3 area of Co-SI EX group and down-regulated in the CA1 and CA3 areas of Pre-SI EX group. SIGNIFICANCE: These findings suggest that exercise develop anti-epileptic as well as neuroprotective effects by modulating of GABA disinhibition.


Assuntos
Condicionamento Físico Animal , Convulsões/induzido quimicamente , Transdução de Sinais , Ácido gama-Aminobutírico/metabolismo , Animais , Modelos Animais de Doenças , Expressão Gênica , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/metabolismo , Masculino , Pentilenotetrazol/administração & dosagem , Pentilenotetrazol/toxicidade , Ratos , Ratos Wistar , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Convulsões/metabolismo
18.
Chem Pharm Bull (Tokyo) ; 67(7): 699-706, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257325

RESUMO

In our search for novel orally active α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, we found that conversion of an allyl group in the lead compound 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (4) to a 2-cyanoethyl group significantly increased inhibitory activity against AMPA receptor-mediated kainate-induced toxicity in rat hippocampal cultures. Here, we synthesized 10 analogs bearing a 2-cyanoethyl group and administered them to mice to evaluate their anticonvulsant activity in maximal electroshock (MES)- and pentylenetetrazol (PTZ)-induced seizure tests, and their effects on motor coordination in a rotarod test. 3-{(4-Oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)[4-(trifluoromethoxy)phenyl]amino}propanenitrile (25) and 3-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)(4-oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)amino]propanenitrile (27) exhibited potent anticonvulsant activity in both seizure tests and induced minor motor disturbances as indicated in the rotarod test. The protective index values of 25 and 27 for MES-induced seizures (10.7 and 12.0, respectively) and PTZ-induced seizures (6.0 and 5.6, respectively) were considerably higher compared with those of YM928 (5) and talampanel (1).


Assuntos
Anticonvulsivantes/síntese química , Nitrilos/química , Receptores de AMPA/antagonistas & inibidores , Administração Oral , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microssomos Hepáticos/metabolismo , Nitrilos/farmacologia , Nitrilos/uso terapêutico , Pentilenotetrazol/toxicidade , Ratos , Ratos Wistar , Receptores de AMPA/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/veterinária , Relação Estrutura-Atividade
19.
Exp Brain Res ; 237(10): 2481-2493, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321447

RESUMO

Kainic acid (KA)-induced seizures and other experimental models of epilepsy have been proven to be instrumental in identifying novel targets that could be responsible for human icto- and epileptogenesis. We have previously shown that the ablation of pharmacoresistant voltage-gated Ca2+ channels with Cav2.3 as central ion-conducting pore (R-type Ca2+ channel) reduces the sensitivity towards KA-induced epilepsy in mice. In vivo, Cav2.3 channels are thought to be under tight allosteric control by endogenous loosely bound trace metal cations (Zn2+ and Cu2+) that suppress channel gating via a high-affinity trace metal-binding site. Metal dyshomeostasis in the brain, which is a common feature of (KA-induced) seizures, could therefore alter the normal function of Cav2.3 channels and may shift hippocampal and neocortical signaling towards hyperexcitation. To investigate the role of loosely bound metal ions for KA-induced hyperexcitation in vivo, we examined the effects of manipulating brain trace metal homeostasis in mice. To this end, we developed a murine system for intracerebroventricular administration of trace metal ions and/or histidine (His), which can bind Zn2+ and Cu2+ and is involved in their transendothelial transport at the blood-brain barrier. Unexpectedly, our preliminary findings indicate that application of His alone but not in the presence of Zn2+ has substantial beneficial effects on the outcome of KA-induced epilepsy in mice. As such, our results emphasize previous findings on the complex, two-sided role of loosely bound metal ions with regard to neuronal excitation and degeneration under pathophysiological conditions.


Assuntos
Hipocampo/efeitos dos fármacos , Histidina/farmacologia , Íons/metabolismo , Convulsões/tratamento farmacológico , Animais , Modelos Animais de Doenças , Histidina/administração & dosagem , Ácido Caínico/farmacologia , Camundongos Endogâmicos C57BL , Convulsões/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos
20.
Cell Mol Biol (Noisy-le-grand) ; 65(5): 59-63, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31304908

RESUMO

Epilepsy is a common chronic disease of the central nervous system that can last for years or even decades, causing serious adverse effects on the body, mind, and psychology of patients. Traditional antiepileptic drugs can effectively control seizures, but because of large individual differences, serious adverse reactions, narrow therapeutic window and other shortcomings, more effective, new treatment drugs are looked for. Streptocaulon griffithii is a plant of Asclepiadaceae. 16-O-acetyldigitoxigenin (ACE) is a strong cardiac glycoside isolated from methanol extract of Streptocaulon griffithii. The aim of this study was to investigate the antiepileptic effect of ACE on Pilocarpine (Pilo) induced epilepsy in mice, and to explore the effect of mTOR signaling pathway on its antiepileptic effect. The results showed that ACE had antiepileptic and neuroprotective effects on Pilo induced epilepsy mice. ACE attenuates Pilo induced seizures by inhibiting the activation of p-mTOR/p-70S6K pathway, and inhibits Pilocarpine induced brain damage by inhibiting mTOR signaling pathway. These results suggest that ACE has a promising future in the treatment of epilepsy and other nervous system diseases.


Assuntos
Anticonvulsivantes/farmacologia , Digitoxigenina/análogos & derivados , Digitoxigenina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Anticonvulsivantes/uso terapêutico , Apocynaceae/química , Caspase 3/metabolismo , Digitoxigenina/uso terapêutico , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pilocarpina/administração & dosagem , Pilocarpina/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo
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