RESUMEN
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders with an incidence four times higher in boys than in girls. By analyzing the effect of sex in a mouse model of ASD, we were able to identify immune alterations that could underlie this sex bias. Pregnant mice were injected subcutaneously with 600â¯mg/kg of valproic acid (VPA) or saline at gestational day 12.5. Their male and female offspring were evaluated in a social interaction test at adulthood, and only male VPA mice showed reduced sociability levels and a lack of preference for the social stimulus over a novel object. We then analyzed the corticosterone (CORT) response to an inflammatory stimulus, as a measure of the hypothalamus-pituitary-adrenal (HPA) function, and the neuroinflammatory state in adult and young animals. Adult VPA males exhibited increased basal CORT levels, while VPA females showed levels comparable to controls. As male mice showed a blunted CORT response at PD21 when compared to female mice, we propose that this early dimorphism could explain the different effects of VPA on HPA function. In addition, prenatal VPA exposure resulted in altered astroglial and microglial cell density levels in the cerebellum and dentate gyrus of adult mice. These neuroinflammatory effects were more pronounced in females than males, and appeared at early developmental stages. Hence, these postnatal glial density differences could underlie the behavioral alterations observed in adulthood, when only males show a social deficit. Our work contributes to the understanding of biological mechanisms affected by VPA on male and female rodents and shed light on the study of possible resilience mechanisms in the female population and/or susceptibility to ASD in boys.
Asunto(s)
Trastorno del Espectro Autista/patología , Neuritis/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Resiliencia Psicológica/efectos de los fármacos , Conducta Social , Ácido Valproico/efectos adversos , Animales , Animales no Consanguíneos , Trastorno del Espectro Autista/inmunología , Trastorno del Espectro Autista/psicología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inducido químicamente , Femenino , Relaciones Interpersonales , Masculino , Ratones , Neuritis/fisiopatología , Neuritis/psicología , Embarazo , Efectos Tardíos de la Exposición Prenatal/inmunología , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/psicología , Caracteres SexualesRESUMEN
Abstract The present study was designed to test the hypothesis that high dose dexmedetomidine would increase the duration of antinociception to a thermal stimulus in a rat model of sciatic nerve blockade without causing nerve damage. The rats were anesthetized with isoflurane. After electromyography (EMG) recordings, right sciatic nerves were explored and perineural injections were delivered: Group D (n = 7), 40 µg µg kg-1 dexmedetomidine administration, Group II (n = 6), (0.2 mL) saline administration, Group III (n = 2), only surgically exploration of the right sciatic nevre. Time to paw withdrawal latency (PAW) to a thermal stimulus for both paws and an assessment of motor function were measured every 30 min after the nerve block until a return to baseline. The compound muscle action potential (CMAP) of right and left sciatic nerves were recorded 10 times per each nerve once more after perineural injections at 14 day. After EMG recordings, right and the part of left sciatic nerve were excised at a length of at minimum 15 mm for histopathological examination. Comparison of right/left CMAP amplitude ratios before and 14 days after the procedure showed a statistically significant difference (p = 0.000). There were no differences in perineural inflammation between the Group D, Group S, and Group E at 14 days.
Resumo O presente estudo foi desenvolvido para testar a hipótese de que dexmedetomidina em dose alta aumentaria a duração da antinocicepção a um estímulo térmico em modelo de rato de bloqueio do nervo ciático sem causar danos ao nervo. Os ratos foram anestesiados com isoflurano. Após os registros da eletromiografia (EMG), os nervos ciáticos direitos foram explorados e injeções perineurais foram administradas: Grupo D (n = 7) recebeu 40 µg/kg-1 de dexmedetomidina, Grupo II (n = 6) recebeu 0,2 mL de solução salina, Grupo III (n = 2) recebeu apenas exploração cirúrgica do nervo ciático direito. O tempo de latência de retirada da pata (LRP) a um estímulo térmico para ambas as patas e uma avaliação da função motora foram avaliados a cada 30 minutos após o bloqueio do nervo até o retorno à fase basal. O potencial de ação muscular composto (PAMC) dos nervos ciático direito e esquerdo foi registrado 10 vezes para cada nervo, mais uma vez, após as injeções perineurais no 14º dia. Após os registros da EMG, o nervo ciático direito e parte do esquerdo foram excisados com um comprimento de no mínimo 15 mm para exame histopatológico. A comparação das proporções da amplitude do PAMC direito/esquerdo antes e 14 dias após o procedimento mostrou uma diferença estatisticamente significativa (p = 0,000). Não houve diferenças em inflamação perineural entre os grupos D, S e E aos 14 dias.
Asunto(s)
Animales , Masculino , Nervio Ciático/efectos de los fármacos , Analgésicos no Narcóticos/farmacología , Dexmedetomidina/farmacología , Tiempo de Reacción , Análisis de Varianza , Ratas Sprague-Dawley , Extremidad Inferior , Estimulación Eléctrica , Electromiografía , Bloqueo Nervioso/métodos , Neuritis/inducido químicamenteRESUMEN
The present study was designed to test the hypothesis that high dose dexmedetomidine would increase the duration of antinociception to a thermal stimulus in a rat model of sciatic nerve blockade without causing nerve damage. The rats were anesthetized with isoflurane. After electromyography (EMG) recordings, right sciatic nerves were explored and perineural injections were delivered: Group D (n=7), 40µgµgkg-1 dexmedetomidine administration, Group II (n=6), (0.2mL) saline administration, Group III (n=2), only surgically exploration of the right sciatic nevre. Time to paw withdrawal latency (PAW) to a thermal stimulus for both paws and an assessment of motor function were measured every 30min after the nerve block until a return to baseline. The compound muscle action potential (CMAP) of right and left sciatic nerves were recorded 10 times per each nerve once more after perineural injections at 14 day. After EMG recordings, right and the part of left sciatic nerve were excised at a length of at minimum 15mm for histopathological examination. Comparison of right/left CMAP amplitude ratios before and 14 days after the procedure showed a statistically significant difference (p=0.000). There were no differences in perineural inflammation between the Group D, Group S, and Group E at 14 days.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Dexmedetomidina/farmacología , Nervio Ciático/efectos de los fármacos , Análisis de Varianza , Animales , Estimulación Eléctrica , Electromiografía , Extremidad Inferior , Masculino , Bloqueo Nervioso/métodos , Neuritis/inducido químicamente , Ratas Sprague-Dawley , Tiempo de ReacciónRESUMEN
BACKGROUND: The use of isoflurane sedation for prolonged periods in the critical care environment is increasing. However, isoflurane-mediated neurotoxicity has been widely reported. The goal of the present study was to determine whether long-term exposure to low-dose isoflurane in mechanically ventilated rodents is associated with evidence of neurodegeneration or neuroinflammation. METHODS: Adult female Sprague-Dawley rats were used in this study. Experimental animals (n=11) were induced with 1.5% isoflurane, intubated, and given a neuromuscular blockade with α-cobratoxin. EEG electrodes were surgically implanted, subcutaneous precordial EKG Ag wire electrodes, and bladder, femoral artery, and femoral vein cannulas permanently placed. After these procedures, the isoflurane concentration was reduced to 0.5% and, in conjunction with the neuromuscular blockade, continued for 7 days. Arterial blood gases and chemistry were measured at 3 time points and core body temperature servoregulated and maintenance IV fluids were given during the 7 days. Experimental animals and untreated controls (n=9) were euthanized on day 7. RESULTS: Immunohistochemical and cytochemical assays did not detect evidence of microgliosis, astrocytosis, neuronal apoptosis or necrosis, amyloidosis, or phosphorylated-tau accumulation. Blood glucose levels were significantly reduced on days 3/4 and 6/7 and partial pressure of oxygen was significantly reduced, but still within the normal range, on day 6/7. All other blood measurements were unchanged. CONCLUSIONS: No neuropathologic changes consistent with neurotoxicity were detected in the brain after 1 week of continuous exposure to 0.5% isoflurane in healthy rats. These data suggest that even long exposures to low concentrations of isoflurane have no overt consequences on neuropathology.
Asunto(s)
Anestésicos por Inhalación/efectos adversos , Sedación Consciente/efectos adversos , Isoflurano/efectos adversos , Síndromes de Neurotoxicidad/patología , Animales , Apoptosis/efectos de los fármacos , Análisis de los Gases de la Sangre , Glucemia/metabolismo , Electroencefalografía/efectos de los fármacos , Femenino , Gliosis/inducido químicamente , Gliosis/patología , Necrosis , Neuritis/inducido químicamente , Neuritis/patología , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/patología , Ratas , Ratas Sprague-DawleyRESUMEN
Mexico City (MC) residents exposed to fine particulate matter and endotoxin exhibit inflammation of the olfactory bulb, substantia nigra, and vagus nerve. The goal of this study was to model these endpoints in mice and examine the neuroprotective effects of chocolate. Mice exposed to MC air received no treatment or oral dark chocolate and were compared to clean-air mice either untreated or treated intraperitoneally with endotoxin. Cyclooxygenase-2 (COX-2), interleukin 1 beta (IL-1ß), and CD14 messenger RNA (mRNA) were quantified after 4, 8, and 16 months of exposure in target brain regions. After 16 months of exposure, the dorsal vagal complex (DVC) exhibited significant inflammation in endotoxin-treated and MC mice (COX-2 and IL-1ß P<.001). Mexico City mice had olfactory bulb upregulation of CD14 (P=.002) and significant DVC imbalance in genes for antioxidant defenses, apoptosis, and neurodegeneration. These findings demonstrate sustained DVC inflammation in mice exposed to MC air, which is mitigated by chocolate administration.
Asunto(s)
Contaminación del Aire/efectos adversos , Tronco Encefálico/efectos de los fármacos , Cacao , Encefalitis/prevención & control , Fármacos Neuroprotectores/administración & dosificación , Salud Urbana , Nervio Vago/efectos de los fármacos , Contaminación del Aire/legislación & jurisprudencia , Animales , Tronco Encefálico/inmunología , Tronco Encefálico/metabolismo , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Encefalitis/inducido químicamente , Endotoxinas/análisis , Endotoxinas/toxicidad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Receptores de Lipopolisacáridos/genética , Receptores de Lipopolisacáridos/metabolismo , México , Ratones , Ratones Endogámicos BALB C , Neuritis/inducido químicamente , Neuritis/prevención & control , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/metabolismo , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/inmunología , Bulbo Olfatorio/metabolismo , Especificidad de Órganos , Material Particulado/química , Material Particulado/toxicidad , ARN Mensajero/metabolismo , Nervio Vago/inmunología , Nervio Vago/metabolismoRESUMEN
Alzheimer disease (AD) is the most common form of dementia in the elderly, and the neuro-pathological hallmarks of AD include neurofibrillary tangles (NFT), and deposition of beta-amyloid (Abeta) in extracellular plaques. In addition, chronic inflammation due to recruitment of activated glial cells to amyloid plaques are an invariant component in AD, and several studies have reported that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may provide a measure of protection against AD. In this report we have investigated whether phosphoinositide 3-kinase gamma (PI3Kgamma), which is important in inflammatory cell migration, plays a critical role in the neuro-inflammation, synaptic dysfunction, and cognitive deficits induced by intracerebroventricular injection of Abeta(1-40) in mice. We found that the selective inhibitor of PI3Kgamma, AS605240, was able to attenuate the Abeta(1-40)-induced accumulation of activated astrocytes and microglia in the hippocampus, and decrease immuno-staining for p-Akt and cyclooxygenase-2 (COX-2). Interestingly, Abeta(1-40) activated macrophages treated with AS605240 or another PI3Kgamma inhibitor, AS252424, displayed impaired chemotaxis in vitro, but their expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) was unaffected. Finally, AS605240 prevented Abeta(1-40)-induced cognitive deficits and synaptic dysfunction, but failed to modify scopolamine-induced amnesia. Our data suggests that inhibition of PI3Kgamma may represent a novel therapeutic target for treating AD patients.
Asunto(s)
Péptidos beta-Amiloides/toxicidad , Cognición/efectos de los fármacos , Neuritis/enzimología , Neuritis/psicología , Fragmentos de Péptidos/toxicidad , Fosfatidilinositol 3-Quinasas/fisiología , Animales , Supervivencia Celular/efectos de los fármacos , Quimiotaxis de Leucocito/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase Ib , Ciclooxigenasa 2/metabolismo , Inhibidores Enzimáticos/farmacología , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Interleucina-1beta/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neuritis/inducido químicamente , Neuroglía/efectos de los fármacos , Neuroglía/inmunología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sinapsis/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In the absence of information on functional manifestations of carotid body (CB) inflammation, we studied an experimental model in which lipopolysaccharide (LPS) administration to pentobarbitone-anaesthetized cats was performed by topical application upon the CB surface or by intravenous infusion (endotoxaemia). The latter caused: (i) disorganization of CB glomoids, increased connective tissue, and rapid recruitment of polymorphonuclear cells into the vascular bed and parenchyma within 4 h; (ii) increased respiratory frequency and diminished ventilatory chemoreflex responses to brief hypoxia (breathing 100% N(2) for 10 s) and diminished ventilatory chemosensory drive (assessed by 100% O(2) tests) during normoxia and hypoxia; (iii) tachycardia, increased haematocrit and systemic hypotension in response to LPS i.v.; and (iv) increased basal frequency of carotid chemosensory discharges during normoxia, but no change in maximal chemoreceptor responses to brief hypoxic exposures. Lipopolysaccharide-induced tachypnoea was prevented by prior bilateral carotid neurotomy. Apoptosis was not observed in CBs from cats subjected to endotoxaemia. Searching for pro-inflammatory mediators, tumour necrosis factor-alpha (TNF-alpha) was localized by immunohistochemistry in glomus and endothelial cells; reverse transcriptase-polymerase chain reaction revealed that the CB expresses the mRNAs for both type-1 (TNF-R1) and type-2 TNF-alpha receptors (TNF-R2); Western blot confirmed a band of the size expected for TNF-R1; and histochemistry showed the presence of TNF-R1 in glomus cells and of TNF-R2 in endothelial cells. Experiments in vitro showed that the frequency of carotid nerve discharges recorded from CBs perfused and superfused under normoxic conditions was not significantly modified by TNF-alpha, but that the enhanced frequency of chemosensory discharges recorded along responses to hypoxic stimulation was transiently diminished in a dose-dependent manner by TNF-alpha injections. The results suggest that the CB may operate as a sensor for immune signals, that the CB exhibits histological features of acute inflammation induced by LPS, that TNF-alpha may participate in LPS-induced changes in chemosensory activity and that some pathophysiological reactions to high levels of LPS in the bloodstream may originate from changes in CB function.
Asunto(s)
Cuerpo Carotídeo/metabolismo , Cuerpo Carotídeo/patología , Neuritis/metabolismo , Neuritis/patología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Cuerpo Carotídeo/fisiopatología , Gatos , Movimiento Celular/fisiología , Modelos Animales de Enfermedad , Electrofisiología , Inflamación/metabolismo , Inflamación/fisiopatología , Lipopolisacáridos , Masculino , Neuritis/inducido químicamente , Neutrófilos/patología , Ventilación Pulmonar/fisiología , ARN Mensajero/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores Tipo II del Factor de Necrosis Tumoral/metabolismoRESUMEN
Introducción. El uso de medios de contraste no iónicos tiene efectos colaterales. Objetivo. Reportar un caso de aracnoiditis química y neuritis óptica después del empleo de medio de contraste no iónico (MCNI). Reporte del caso. Una paciente de 28 años de edad con historia de paraperesia postraumática fue enviada a una UCI después de presentar súbitamente convulsiones tónico-clónicas, mientras se le efectuaban una mielotomografía con MCNI. A su ingreso se encontró: TA 70/40 mmHg, 4 puntos en la escala de coma de Glasgow, postura de descerebración, rigidez de nuca y papiledema. La TAC cerebral mostró la presencia de medio de contraste en el espacio subaracnoideo y en las cisternas. Al 5o. días de estancia se encontró estable y había buena recuperación neurológica, excepto que tenia amaurosis (se diagnosticó neuropatía óptica retrobulbar). Conclusión. La aracnoiditis química y la neuropatía óptica retrobulbar pueden ocurrir después del ascenso inadvertido de MCNI
Asunto(s)
Humanos , Femenino , Adulto , Aracnoiditis/inducido químicamente , Medios de Contraste , Mielografía/efectos adversos , Sistema Nervioso , Neuritis/inducido químicamenteRESUMEN
Dois pacientes, uma mulher de 40 anos e um homem de 75 anos, apresentavam polineurite sensitivo-motora, cujo único antecedentes era o uso de amiodarona há 4 e 6 anos respectivamente. O ENMG revelou quadro neuropático tipo axonal. A biópsia do nervo sural mostrou rarefaçäo axonal, mielínica e amielínica, bem como inclusöes lamelares osmiofílicas nas células de Schwann e no endotélio venular. Com a retirada da amiodarona houve regressäo da polineurite. A semelhança do que foi descrito na neuropatia pelo maleato de perhexiline e pela cloroquina, a amiodarona constitui constitui importante fator de induçäo de neurolipidose medicamentosa
Asunto(s)
Adulto , Anciano , Humanos , Masculino , Femenino , Amiodarona/efectos adversos , Neuritis/inducido químicamente , Amiodarona/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Axones/ultraestructura , Lípidos/metabolismo , Nervio Sural/patologíaRESUMEN
Três pacientes em uso de amiodarona para tratamento de arritmia cardíaca refratária apresentaram manifestaçöes neurológicas. Dois desenvolveram quadro polineurítico após 4 e 6 anos de uso do medicamento. O terceiro apresentou quadro de discinesia associado a grau moderado de neuropatia e ataxia após 2 meses de uso de amiodarona. A biopsia do nervo sural em dois casos revelou rarefaçäo axonal associada a inclusöes lamelares e corpos densos, osmioílicos nas células de Schwann e no endotélio venular (um paciente). A interrupçäo do uso do cloridrato de amiodarona provocou regressäo dos sintomas neurológicos
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Anciano , Discinesia Inducida por Medicamentos/etiología , Amiodarona/efectos adversos , Neuritis/inducido químicamente , Nervio Sural , Sistema Nervioso Central/efectos de los fármacos , Electrocardiografía , Nervios PeriféricosRESUMEN
O estudo evolutivo de pacientes na fase crônica da doença de Chagas, feito antes e após o tratamento experimental com benzonidazol, evidenciou ser esta droga tóxica para o sistema nervoso periférico, dose dependente, com possível efeito cumulativo em vários pacientes. A polineuropatia foi predominantemente do tipo axonal e mais severa nos pacientes já com evidências neurofisiológicas de desnervaçäo periférica antes do tratamento