RESUMO
This study investigated the toxicity of rats exposed to lead acetate (AcPb) during the second phase of brain development (8-12 days postnatal) in hematological and cerebral parameters. Moreover, the preventive effect of zinc chloride (ZnCl2) and N-acetylcysteine (NAC) was investigated. Pups were injected subcutaneously with saline (0.9% NaCl solution), ZnCl2 (27 mg/kg/day), NAC (5 mg/kg/day) or ZnCl2 plus NAC for 5 days (3rd-7th postnatal days), and with saline (0.9% NaCl solution) or AcPb (7 mg/kg/day) in the five subsequent days (8th-12th postnatal days). Animals were sacrificed 21 days after the last AcPb exposure. Pups exposed to AcPb presented inhibition of blood porphobilinogen-synthase (PBG-synthase) activity without changes in hemoglobin content. ZnCl2 pre-exposure partially prevented PBG-synthase inhibition. Regarding neurotoxicity biomarkers, animals exposed to AcPb presented a decrease in cerebrum acetylcholinesterase (AChE) activity and an increase in Pb accumulation in blood and cerebrum. These changes were prevented by pre-treatment with ZnCl2, NAC, and ZnCl2 plus NAC. AcPb exposure caused no alteration in behavioral tasks. In short, results show that AcPb inhibited the activity of two important enzymatic biomarkers up to 21 days after the end of the exposure. Moreover, ZnCl2 and NAC prevented the alterations induced by AcPb.
Assuntos
Acetilcisteína/uso terapêutico , Cérebro/efeitos dos fármacos , Cloretos/uso terapêutico , Intoxicação do Sistema Nervoso por Chumbo/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Compostos de Zinco/uso terapêutico , Acetilcolinesterase/metabolismo , Acetilcisteína/administração & dosagem , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Biomarcadores/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Cérebro/enzimologia , Cérebro/metabolismo , Cloretos/administração & dosagem , Cloretos/metabolismo , Cloretos/farmacocinética , Quimioterapia Combinada , Poluentes Ambientais/sangue , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Injeções Subcutâneas , Chumbo/sangue , Chumbo/metabolismo , Chumbo/toxicidade , Intoxicação do Sistema Nervoso por Chumbo/sangue , Intoxicação do Sistema Nervoso por Chumbo/metabolismo , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/metabolismo , Neurônios/enzimologia , Neurônios/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacocinética , Compostos Organometálicos/administração & dosagem , Sintase do Porfobilinogênio/antagonistas & inibidores , Sintase do Porfobilinogênio/sangue , Distribuição Aleatória , Ratos Wistar , Distribuição Tecidual/efeitos dos fármacos , Toxicocinética , Compostos de Zinco/administração & dosagem , Compostos de Zinco/metabolismo , Compostos de Zinco/farmacocinéticaRESUMO
In order to mark Triatoma brasiliensis, the vector of Chagas disease in Brazil, two chemical compounds, rubidium chloride (RbCl) and chromium chloride (CrCl3), were tested. First, 199 N2-N5 nymphs were fed on blood with 0.025M RbCl. Rb marker positivity ranged from 2.5% (N3)-70% (N2), with a maximum persistence of 98 days. Second, 265 N2-N5 nymphs were fed on blood containing 0.0015M CrCl3. Cr marker positivity ranged up to 93% (N5), with a maximum persistence of 119 days. Finally, we blood fed 213 T. brasiliensis to investigate whether CrCl3 altered the biology of this insect. The developmental time of T. brasiliensis was unaltered, but the survival of the Cr-marked group was lower than that of the control group. Differences in the mean fecundity of the control (mean of 156.1) and experimental (mean of 135.6) groups were not statistically significant and 100% of the egg batches of females Cr-marked as nymphs were positive. In conclusion, CrCl3 is a useful tool for marking T. brasiliensis nymphs due to its high positivity and persistence.
Assuntos
Cloretos/farmacocinética , Compostos de Cromo/farmacocinética , Corantes/farmacocinética , Insetos Vetores/fisiologia , Ninfa/fisiologia , Rubídio/farmacocinética , Triatoma/fisiologia , Animais , Doença de Chagas/transmissão , Feminino , Fertilidade/efeitos dos fármacos , Fertilidade/fisiologia , Insetos Vetores/efeitos dos fármacos , Ninfa/efeitos dos fármacos , Fatores de Tempo , Triatoma/efeitos dos fármacosRESUMO
In order to mark Triatoma brasiliensis, the vector of Chagas disease in Brazil, two chemical compounds, rubidium chloride (RbCl) and chromium chloride (CrCl3), were tested. First, 199 N2-N5 nymphs were fed on blood with 0.025M RbCl. Rb marker positivity ranged from 2.5 percent (N3)-70 percent (N2), with a maximum persistence of 98 days. Second, 265 N2-N5 nymphs were fed on blood containing 0.0015M CrCl3. Cr marker positivity ranged up to 93 percent (N5), with a maximum persistence of 119 days. Finally, we blood fed 213 T. brasiliensis to investigate whether CrCl3 altered the biology of this insect. The developmental time of T. brasiliensis was unaltered, but the survival of the Cr-marked group was lower than that of the control group. Differences in the mean fecundity of the control (mean of 156.1) and experimental (mean of 135.6) groups were not statistically significant and 100 percent of the egg batches of females Cr-marked as nymphs were positive. In conclusion, CrCl3 is a useful tool for marking T. brasiliensis nymphs due to its high positivity and persistence.
Assuntos
Animais , Feminino , Cloretos/farmacocinética , Compostos de Cromo/farmacocinética , Corantes/farmacocinética , Insetos Vetores/fisiologia , Ninfa/fisiologia , Rubídio/farmacocinética , Triatoma/fisiologia , Doença de Chagas/transmissão , Fertilidade , Fertilidade/fisiologia , Insetos Vetores , Ninfa , Fatores de Tempo , TriatomaRESUMO
Several studies have described mercury toxicity and the role of metallothioneins (MT) in the detoxification and regulation of metal homeostasis. However, little data exist on this topic during the specific post-natal developmental phase in young mammals. This developmental phase is particularly important since young animals are more sensitive to toxicants than adults. The objective of this work was to investigate whether MT participates in the mechanism of protection conferred by zinc pre-treatment on the toxic effects induced by mercury in neonate rats. Pups were exposed to ZnCl(2) (5 doses of 27 mg/kg/day, s.c.) and subsequently to HgCl(2) (5 doses of 5 mg/kg/day, s.c.); metal (Zn and Hg) and MT contents were analyzed in the liver, kidney, and blood. MT was induced in the liver and kidney of pups of both Zn-sal and Zn-Hg groups, although the greatest increase was in neonates exposed to Zn only. A direct relationship exists between MT and metals for both hepatic and renal tissues, which indicates that the increase in metal levels occurs in parallel to the increase in MT content. Although the heat-treated cytosolic fraction is rich in MT and metals, higher Zn and Hg contents were detected in the insoluble fraction of all tissues. These results suggest that MT is, at least in part, responsible for preventing Hg accumulation in the liver and blood and decreasing renal toxicity.
Assuntos
Cloretos/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Cloreto de Mercúrio/toxicidade , Intoxicação do Sistema Nervoso por Mercúrio , Metalotioneína/biossíntese , Compostos de Zinco/farmacologia , Animais , Animais Recém-Nascidos , Cloretos/sangue , Cloretos/farmacocinética , Cloretos/uso terapêutico , Feminino , Rim/crescimento & desenvolvimento , Rim/metabolismo , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Masculino , Cloreto de Mercúrio/sangue , Cloreto de Mercúrio/farmacocinética , Intoxicação do Sistema Nervoso por Mercúrio/etiologia , Intoxicação do Sistema Nervoso por Mercúrio/metabolismo , Intoxicação do Sistema Nervoso por Mercúrio/prevenção & controle , Ratos , Ratos Wistar , Compostos de Zinco/sangue , Compostos de Zinco/farmacocinética , Compostos de Zinco/uso terapêuticoRESUMO
The rat thiazide-sensitive Na-Cl cotransporter (rNCC) is expressed in the renal distal convoluted tubule and is the site of action of an important class of antihypertensive agents, the thiazide diuretics. The amino acid sequence contains two potential N-linked glycosylation consensus sites, N404 and N424. Either enzymatic deglycosylation or tunicamycin reduced the cotransporter to its core molecular weight (113 kD). Glycosylation site single mutants expressed in oocytes ran as thick bands at 115 kD, consistent with the high-mannose glycoprotein. The double mutant produced the single thin 113-kD band seen in the deglycosylated cotransporter. Functional expression of cotransporters in Xenopus laevis oocytes revealed that the mutants displayed drastically decreased thiazide-sensitive (22)Na(+) uptake compared with wild-type NCC. Analysis of enhanced green fluorescence protein (EGFP)-tagged cotransporters demonstrated that this decrease in function is predominantly secondary to decreased surface expression. The elimination of glycosylation in the double mutant increased thiazide sensitivity by more than two orders of magnitude and also increased Cl(-) affinity. Thus, we have demonstrated that rNCC is N-glycosylated in vivo at two sites, that glycosylation is essential for efficient function and surface expression of the cotransporter, and that the elimination of glycosylation allows much greater access of thiazide diuretics to their binding site.
Assuntos
Proteínas de Transporte/metabolismo , Receptores de Droga/metabolismo , Simportadores , Tiadiazinas/metabolismo , Animais , Ligação Competitiva , Proteínas de Transporte/genética , Membrana Celular/metabolismo , Cloretos/farmacocinética , Feminino , Glicosilação , Masculino , Mutação , Ratos , Ratos Sprague-Dawley , Receptores de Droga/genética , Sódio/farmacocinética , Simportadores de Cloreto de Sódio , Membro 3 da Família 12 de Carreador de Soluto , Xenopus laevisRESUMO
Chronic exposure to manganese (Mn) positively correlates with the occurrence of Parkinsonism but little is known about mechanisms of its neurotoxicity. In the present study, we determined the clearance of Mn from rat substantia nigra after its nigral injection and correlated it with the establishment of apomorphine-induced rotational behaviour and loss of striatal tyrosine hydroxylase (TH) immunoreactivity. Our results suggest that Mn is slowly cleared from the substantia nigra, following a first-order kinetics with a t(1/2) of 3 days. Appearance of apomorphine-induced rotational behaviour and loss of TH immunoreactivity within the striatum follows metal clearance were both detected 24 hours after intra-nigral Mn microinjection and maximal 72 hours after injection. The present data suggest that the cellular mechanisms induced by Mn and leading to dopaminergic cell death, occurred shortly after its injection and that the metal concentration needs to reach a threshold value to induce neurotoxic effects. This would indicate that nigral damages are a direct consequence of Mn accumulation.
Assuntos
Intoxicação por Manganês/metabolismo , Manganês/farmacocinética , Neurônios/efeitos dos fármacos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Substância Negra/efeitos dos fármacos , Animais , Apomorfina/farmacologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Cloretos/farmacocinética , Cloretos/toxicidade , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Gliose/induzido quimicamente , Gliose/metabolismo , Gliose/fisiopatologia , Imuno-Histoquímica , Masculino , Compostos de Manganês/farmacocinética , Intoxicação por Manganês/fisiopatologia , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Microinjeções , Neurônios/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Ratos , Ratos Endogâmicos , Rotação , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Adult female rats, undernourished at perinatal age, were evaluated for anxiolytic action in the plus-maze test after acute and chronic administration of diazepam (DZP) and pentobarbital (PTB). Deprived (D) rats chronically treated with vehicle showed an increased anxiety as compared with control (C) animals. A single intraperitoneal (i.p.) administration of DZP (1 mg/kg) or PTB (7.5 mg/kg) produced similar anticonflict effect in both C and D rats. Tolerance to the anxiolytic effect of DZP and PBT developed in C rats after a 15-day administration schedule, whereas no tolerance was observed in D animals. Drug disposition was not altered after chronic treatment either in C or in D rats. Gamma-aminobutyric acid (GABA)-mediated chloride uptake in microsacs of cerebral cortex of naive D rats was decreased as compared with naive C rats. After chronic DZP administration (1 mg/kg/day i.p. for 15 days), GABA-mediated 36Cl- influx in brain cortex microsacs of C rats did not change; however, GABA efficacy was increased in microsacs of D animals. In addition, chronic DZP treatment induced GABA-benzodiazepine uncoupling in brain cortex of C rats, but not in D animals, as assessed by chloride uptake in microsacs. Chronic PTB treatment (7.5 or 30 mg/kg/day i.p. for 15 days) did not modify GABA stimulation or GABA-PTB interaction in cortical microsacs of C or D rats.
Assuntos
Animais Recém-Nascidos/fisiologia , Ansiolíticos/administração & dosagem , Diazepam/administração & dosagem , Distúrbios Nutricionais/fisiopatologia , Pentobarbital/administração & dosagem , Fenômenos Fisiológicos da Nutrição Animal , Animais , Ansiolíticos/farmacocinética , Ansiolíticos/farmacologia , Encéfalo/metabolismo , Cloretos/farmacocinética , Diazepam/farmacocinética , Diazepam/farmacologia , Sinergismo Farmacológico , Tolerância a Medicamentos/fisiologia , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Pentobarbital/farmacocinética , Pentobarbital/farmacologia , Ratos , Ratos Wistar , Fatores de Tempo , Ácido gama-Aminobutírico/farmacologiaRESUMO
In the present report we studied the GABA-stimulated 36Cl- uptake during chick optic lobe development in order to establish the ontogenetic profile of the functional GABAA receptor complex. A concentration-dependent stimulation of 36Cl- influx by GABA was demonstrated, starting at developmental stages as early as 10 days of incubation. The maximal GABA-induced 36Cl- uptake changed significantly during ontogeny with highest values near hatching. However, GABA potency to stimulate ion influx remained unchanged. We also examined the effect of two neurosteroids, allopregnanolone and epipregnanolone, on GABA-stimulated 36Cl- influx at three developmental stages (embryonic day 14, post-hatching day 1 and adult stage). Both steroids enhanced ion uptake in a concentration-dependent manner, exerting greater stimulatory effects at early developmental stages. Allopregnanolone displayed EC50 values lower than epipregnanolone at all three time points and was also more potent at post-hatching stages. Analysis of the GABA concentration-effect curve disclosed that both steroid decreased EC50 values for GABA stimulation while Emax levels were unaffected. In conclusion, our results showed an early appearance of the GABA-associated chloride channel together with the ability of neurosteroids to modulate GABA-gating of such channel.
Assuntos
Cloretos/farmacocinética , Moduladores GABAérgicos/farmacologia , Lobo Óptico de Animais não Mamíferos/embriologia , Lobo Óptico de Animais não Mamíferos/metabolismo , Pregnanolona/farmacologia , Ácido gama-Aminobutírico/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Embrião de Galinha , Canais de Cloreto/fisiologia , Lobo Óptico de Animais não Mamíferos/química , Receptores de GABA-A/fisiologiaRESUMO
Rats chronically treated with diazepam (2 mg/kg per day, i.p.) for 21 days were tested 96 h after the last injection in both the forced swim test (inescapable stress) and in an active avoidance test (escapable stress). The influence of carbamazepine (7.5 mg/kg, i.p.) administered 25 min prior to each behavioral task was investigated. Withdrawn animals showed a reduced time spent in immobility in the forced swim test and an enhanced latency to escape in the active avoidance test. Both behavioral effects were normalized by a single carbamazepine administration. An additional experiment was performed to investigate the effect of a forced swim experience on cortical chloride uptake following GABA (gamma-aminobutyric acid) stimulation 96 h after diazepam withdrawal, and the influence of a single administration of carbamazepine on these effects. An increased chloride uptake was observed in vehicle-treated rats but not in diazepam-withdrawn animals following the swimming experience. Carbamazepine pretreatment enhanced chloride uptake after diazepam withdrawal but did not modify chloride flux in stressed or unstressed vehicle-treated rats. These results support the hypothesis that diazepam withdrawal affects the ability to develop adaptive responses to stress and that carbamazepine can normalize such an alteration.
Assuntos
Analgésicos não Narcóticos/farmacologia , Ansiolíticos/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Carbamazepina/farmacologia , Diazepam/efeitos adversos , Estresse Fisiológico/tratamento farmacológico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Cloretos/farmacocinética , Masculino , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia , Estimulação Química , Estresse Fisiológico/etiologia , Síndrome de Abstinência a Substâncias/etiologia , Natação , Fatores de Tempo , Ácido gama-Aminobutírico/farmacologiaRESUMO
In the conducting airway, the epithelial electrolyte transport processes play an important role in determining the composition of the respiratory tract fluid. Apical membrane Cl- and Na+ channels control the secretion and absorption of epithelial cells. Defective regulation of these channels is a prominent characteristic of cystic fibrosis.