RESUMEN
BACKGROUND: Rapid economic development in China has produced serious ecological, environmental, and health problems. Neurotoxicity has been recognized as a major public health problem. The Chinese government, research institutes, and scientists conducted extensive studies concerning the source, characteristics, and mechanisms of neurotoxicants. OBJECTIVES: This paper presents, for the first time, a comprehensive history and review of major sources of neurotoxicants, national bodies/legislation engaged, and major neurotoxicology research in China. METHODS: Peer-reviewed research and pollution studies by Chinese scientists from 1991 to 2015 were examined. PubMed, Web of Science and Chinese National Knowledge Infrastructure (CNKI) were the major search tools. RESULTS: The central problem is an increased exposure to neurotoxicants from air and water, food contamination, e-waste recycling, and manufacturing of household products. China formulated an institutional framework and standards system for management of major neurotoxicants. Basic and applied research was initiated, and international cooperation was achieved. The annual number of peer-reviewed neurotoxicology papers from Chinese authors increased almost 30-fold since 2001. CONCLUSIONS: Despite extensive efforts, neurotoxicity remains a significant public health problem. This provides great challenges and opportunities. We identified 10 significant areas that require major educational, environmental, governmental, and research efforts, as well as attention to public awareness. For example, there is a need to increase efforts to utilize new in vivo and in vitro models, determine the potential neurotoxicity and mechanisms involved in newly emerging pollutants, and examine the effects and mechanisms of mixtures. In the future, we anticipate working with scientists worldwide to accomplish these goals and eliminate, prevent and treat neurotoxicity. CITATION: Cai T, Luo W, Ruan D, Wu YJ, Fox DA, Chen J. 2016. The history, status, gaps, and future directions of neurotoxicology in China. Environ Health Perspect 124:722-732; http://dx.doi.org/10.1289/ehp.1409566.
Asunto(s)
Ecotoxicología , Sistema Nervioso/efectos de los fármacos , China , Monitoreo del Ambiente , Contaminación Ambiental , HumanosRESUMEN
Attention deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. Despite its prevalence, the critical factors involved in its development remain to be identified. It was recently suggested that epigenetic mechanisms probably contribute to the etiology of ADHD. The present study was designed to examine the associations of epigenetic markers with ADHD among Chinese Han children, aiming to establish the prediction model for this syndrome from the epigenetic perspective. We conducted a pair-matching case-control study, and the ADHD children were systematically evaluated via structured diagnostic interviews, including caregiver interviews, based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised criteria (DSM-IV-R). The expression levels of risk genes DAT1, DRD4, DRD5, as well as their promoter methylation, were determined respectively, followed by the expression profiles of histone-modifying genes p300, MYST4, HDAC1, MeCP2. The multivariate logistic regressions were performed to establish ADHD prediction models. All of the seven genes tested were identified as risk factors for ADHD. The methylation of one critical CpG site located upstream of DRD4 was shown to affect its transcription, suggesting a role in ADHD's development. Aberrant DNA methylation and histone acetylation were indicated in ADHD patients. In addition, a prediction model was established using the combination of p300, MYST4 and HDAC1, with the accuracy of 0.9338. This is, to our knowledge, the first study to clearly demonstrate the associations between epigenetic markers and ADHD, shedding light on the preliminary diagnosis and etiological studies of this widespread disorder.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Epigénesis Genética/fisiología , Trastorno por Déficit de Atención con Hiperactividad/inducido químicamente , Niño , China/epidemiología , China/etnología , Islas de CpG/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Femenino , Histona Acetiltransferasas/genética , Histona Desacetilasas/genética , Humanos , Plomo/toxicidad , Modelos Logísticos , Masculino , Proteína 2 de Unión a Metil-CpG/genética , ARN Mensajero/metabolismo , Receptores Dopaminérgicos/genética , Factores de Riesgo , Factores Sexuales , Metiltransferasa de ADN de Sitio Específico (Adenina Especifica)/genética , Estadística como AsuntoRESUMEN
Lead (Pb) exposure has been implicated in the impairment of synaptic plasticity in the developing hippocampus, but the mechanism remains unclear. Here, we investigated whether developmental lead exposure affects the dendritic spine formation through Wnt signaling pathway in vivo and in vitro. Sprague-Dawley rats were exposed to lead throughout the lactation period and Golgi-Cox staining method was used to examine the spine density of pyramidal neurons in the hippocampal CA1 area of rats. We found that lead exposure significantly decreased the spine density in both 14 and 21 days-old pups, accompanied by a significant age-dependent decline of the Wnt7a expression and stability of its downstream protein (ß-catenin). Furthermore, in cultured hippocampal neurons, lead (0.1 and 1 µM lead acetate) significantly decreased the spine density in a dose-dependent manner. Exogenous Wnt7a application attenuated the decrease of spine density and increased the stability of the downstream molecules in Wnt signaling pathway. Together, our results suggest that lead has a negative impact on spine outgrowth in the developing hippocampus through altering the canonical Wnt pathway.
Asunto(s)
Plomo/toxicidad , Neurotoxinas/toxicidad , Sinapsis/efectos de los fármacos , Sinapsis/fisiología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Espinas Dendríticas/efectos de los fármacos , Embrión de Mamíferos/citología , Embrión de Mamíferos/efectos de los fármacos , Embrión de Mamíferos/fisiología , Células HEK293 , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/embriología , Hipocampo/crecimiento & desarrollo , Humanos , Plomo/metabolismo , Neurotoxinas/metabolismo , Células Piramidales/citología , Células Piramidales/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Proteínas Wnt/metabolismoRESUMEN
The increasing evidences showed that adverse early life events have profound long lasting consequences in adult rats including neural, behavioral, and cognitive effects. Early maternal separation was one of the models of adverse early life stress, but which period acts critically was unknown until now. The purpose of this paper was to explore the effects of maternal separation in different periods, that is, postnatal Day 2-9 and postnatal Day 14-21, on spatial learning and memory and long-term potentiation (LTP) in hippocampus of adolescent rats. Rat pups were assigned to three groups: early maternal separation from postnatal Day 2-9 (EMS2-9), separation from postnatal Day 14-21 (EMS14-21), and control (Con)--rats stayed with their mother all the time before weaning. Morris water maze test (MWM) and electrophysiological test were performed at 40-50 days of age. The results indicated that EMS14-21 impaired spatial learning and memory ability. For the excitatory postsynaptic potential long-term potentiation (EPSP LTP), both the two maternal separation groups showed decreased values compared to control group. In terms of population spike long-term potentiation (PS LTP), both the two maternal separation groups also showed lower values compared with control group, but only EMS14-21 group had significant difference compared with control group. In conclusion, our results revealed that EMS14-21 showed worst in both escape latency in Morris Water Maze test and LTP compared to control group and EMS2-9 group.
Asunto(s)
Potenciación a Largo Plazo/fisiología , Privación Materna , Aprendizaje por Laberinto/fisiología , Procesamiento Espacial/fisiología , Animales , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Lead (Pb) exposure was commonly considered as a high environmental risk factor for the development of attention-deficit/hyperactivity disorder (ADHD). However, the molecular basis of this pathological process still remains elusive. In light of the role of epigenetics in modulating the neurological disease and the causative environment, the alterations of histone modifications in the hippocampus of rats exposed by various doses of lead, along with concomitant behavioral deficits, were investigated in this study. According to the free and forced open field test, there showed that in a dosage-dependent manner, lead exposure could result in the increased locomotor activity of rats, that is, hyperactivity: a subtype of ADHD. Western blotting assays revealed that the levels of histone acetylation increased significantly in the hippocampus by chronic lead exposure, while no dramatic changes were detected in terms of expression yields of ADHD-related dopaminergic proteins, indicating that histone acetylation plays essential roles in this toxicant-involved pathogenesis. In addition, the increased level of histone acetylation might be attributed to the enzymatic activity of p300, a typical histone acetyltransferase, as the transcriptional level of p300 was significantly increased upon higher-dose Pb exposure. In summary, this study first discovered the epigenetic mechanism bridging the environmental influence (Pb) and the disease itself (ADHD) in the histone modification level, paving the way for the comprehensive understanding of ADHD's etiology and in further steps, establishing the therapy strategy of this widespread neurological disorder.
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Trastorno por Déficit de Atención con Hiperactividad/inducido químicamente , Conducta Animal/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Hipocampo/efectos de los fármacos , Histonas/metabolismo , Hipercinesia/inducido químicamente , Intoxicación del Sistema Nervioso por Plomo en la Infancia/etiología , Actividad Motora/efectos de los fármacos , Compuestos Organometálicos/toxicidad , Efectos Tardíos de la Exposición Prenatal , Acetilación , Factores de Edad , Animales , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Interacción Gen-Ambiente , Hipocampo/metabolismo , Hipocampo/fisiopatología , Hipercinesia/genética , Hipercinesia/metabolismo , Hipercinesia/fisiopatología , Hipercinesia/psicología , Intoxicación del Sistema Nervioso por Plomo en la Infancia/genética , Intoxicación del Sistema Nervioso por Plomo en la Infancia/metabolismo , Intoxicación del Sistema Nervioso por Plomo en la Infancia/fisiopatología , Intoxicación del Sistema Nervioso por Plomo en la Infancia/psicología , Masculino , Exposición Materna , Embarazo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D4/efectos de los fármacos , Receptores de Dopamina D4/metabolismo , Factores de Transcripción p300-CBP/genética , Factores de Transcripción p300-CBP/metabolismoRESUMEN
Normally long-term depression (LTD) is difficult to be induced in naïve adult rats in vivo, but it can be induced in the juvenile females and acute-stressed adult males. Using these rats as LTD models, we find in our previous study that LTD induction by the classical low-frequency stimuli (LFS) may be associated with sleep. During sleep, endogenous field potential oscillations presented in the neocortical and hippocampal circuits play important roles in synaptic downscaling as well as memory consolidations. Generally, LTD can be considered as a special synaptic downscaling and the classical LFS is very similar to such endogenous oscillations. Thus, we speculate whether we can design a new LFS which is more similar to such oscillations and whether LTD can be induced by it in naïve adult rats? In this study, we found that in the naïve adult rats anesthetized in sleep stage, the classical LFS could not induce LTD, however, a low-intensity LFS, an endogenous oscillation-like one, could induce LTD. Furthermore, in the rats anesthetized in wakefulness stage, neither the classical nor the low-intensity LFS could induce LTD. Our study showed that in the naïve adult rats, LTD could be induced by the oscillation-like LFS in the sleep stage anesthesia, suggesting that LTD may physiologically occur during sleep and be inhibited in wakefulness stage. Our study suggested that in the hippocampus LTD may be a potential long-term synaptic plasticity underlying sleep-dependent memory consolidations.
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Potenciales de Acción/fisiología , Relojes Biológicos/fisiología , Estimulación Eléctrica/métodos , Hipocampo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Red Nerviosa/fisiología , Animales , Femenino , Masculino , Ratas , Ratas WistarRESUMEN
Lead pollution is a very serious problem in China with the rapid economic development. A large amount of lead has been released into the environment due to mineral processing activities and has impacted water resources, soils, vegetables, and crops. The gasoline with lead has been banned in China since July 1, 2000. Though a noticeable decrease of lead poisoning rates has been evidenced, the children's blood lead levels are still significantly higher than those in developed countries. Therefore, lowering the lead exposure in childhood continues to be an important public health objective in China. There is also a lot that remains to be done to reduce children's exposure to lead. In this section, five scientists from China presented latest research results regarding the current situation of lead poisoning in China, the mechanisms involved in lead-induced neurotoxicity, and the new advances related to the potential therapy methods. Their researches may pave new way not only for the prevention of lead poisoning but also for the treatment of affected children in China and other countries.
Asunto(s)
Desarrollo Infantil/efectos de los fármacos , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Ambientales/efectos adversos , Intoxicación del Sistema Nervioso por Plomo en la Infancia/etiología , Plomo/efectos adversos , Sistema Nervioso/efectos de los fármacos , Factores de Edad , Animales , Pueblo Asiatico , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/fisiopatología , Niño , China/epidemiología , Modelos Animales de Enfermedad , Humanos , Intoxicación del Sistema Nervioso por Plomo en la Infancia/etnología , Intoxicación del Sistema Nervioso por Plomo en la Infancia/metabolismo , Intoxicación del Sistema Nervioso por Plomo en la Infancia/fisiopatología , Sistema Nervioso/crecimiento & desarrollo , Sistema Nervioso/metabolismo , Sistema Nervioso/fisiopatología , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Ratas , Medición de Riesgo , Factores de Riesgo , Transmisión Sináptica/efectos de los fármacos , Factores de TiempoRESUMEN
Although long-term depression (LTD) is generally considered as one of the underlying mechanisms of learning and memory, the induction of it in vivo seems difficult. Evidence demonstrates that the total synaptic weight is associated with circadian rhythm, with up-regulation in wakefulness and down-regulation during sleep, suggesting that the induction of LTD may also be affected by it. In this study, we found that in two well-established rat models, low-frequency stimuli (LFS) induced LTD upon daytime anesthesia, but not at night. Upon further study, we found that the induction of LTD could not be blocked at night if we deprived sleep of the rats during the daytime. These results indicate that the induction of LTD is facilitated by daytime or sleep deprivation. Since rats both in the daytime and after sleep deprivation share the same character of high sleep pressure, our results suggest that LTD is actually facilitated by high sleep pressure. Our study also provides a possible explanation why some labs can induce LTD in vivo while others cannot. Sleep pressure should be taken into account as one of the key factors on the induction of LTD in vivo.
Asunto(s)
Oscuridad , Hipocampo/fisiología , Luz , Depresión Sináptica a Largo Plazo , Privación de Sueño , Animales , Femenino , Masculino , Ratas , Ratas WistarRESUMEN
Lead (Pb) exposure during development has been associated with impaired long-term potentiation (LTP). Hypothyroidism happening upon subjects with occupational exposure to Pb is suggestive of an adverse effect of Pb on thyroid homeostasis, leading to the hypothesis that Pb exposure may alter thyroid hormone homeostasis. Hippocampus is one of the targets of Pb exposure, and is sensitive to and dependent on thyroid hormones, leading us to explore whether levothyroxine (L-T(4)) administration could alter the thyroid disequilibrium and impairment of LTP in rat hippocampus caused by Pb exposure. Our results show that Pb exposure caused a decrease in triiodothyronine (T(3)) and tetraiodothyronine (T(4)) levels accompanied by a dramatic decrease of TSH and application of L-T(4) restored these changes to about control levels. Hippocampal and blood Pb concentration were significantly reduced following L-T(4) treatment. L-T(4) treatment rescued the impairment of LTP induced by the Pb exposure. These results suggest that Pb exposure may lead to thyroid dysfunction and induce hypothyroidism and provide a direct electrophysiological proof that L-T(4) relieves chronic Pb exposure-induced impairment of synaptic plasticity.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Hipotiroidismo/inducido químicamente , Intoxicación del Sistema Nervioso por Plomo/tratamiento farmacológico , Tiroxina/uso terapéutico , Animales , Región CA1 Hipocampal/química , Región CA1 Hipocampal/fisiopatología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipotiroidismo/complicaciones , Plomo/análisis , Plomo/sangre , Intoxicación del Sistema Nervioso por Plomo/fisiopatología , Ratas , Ratas Wistar , Hormonas Tiroideas/sangre , Tiroxina/farmacologíaRESUMEN
Chronic lead exposure causes a variety of impairments in learning and memory and cognitive function. Synaptic plasticity in hippocampus is an extensively studied cellular model of learning and memory, which includes long-term potentiation (LTP) and long-term depression (LTD) in two forms. Depotentiation (DP) is another form of synaptic plasticity. Previous studies show that chronic lead exposure can damage the induction of LTP/LTD in hippocampal CA1 and dentate gyrus (DG) areas. In the present study, we investigated the repair and protection on lead-caused synaptic plasticity impairment by galantamine, using field potential recording on chronic lead exposure rats. The results showed that chronic lead exposure impaired LTP/DP induction in DG area of the hippocampus, and galantamine caused a significant increase on the amplitudes of LTP/DP of lead-exposed rats, but only a small increase in non-exposed group. These results suggest that galantamine could reverse the lead-induced impairments of synaptic plasticity in rats and might be an effective medicine to cure the cognitive deficits induced by lead.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Giro Dentado/efectos de los fármacos , Galantamina/farmacología , Plomo/toxicidad , Plasticidad Neuronal/efectos de los fármacos , Sinapsis/efectos de los fármacos , Animales , Giro Dentado/metabolismo , Giro Dentado/fisiopatología , Estimulación Eléctrica/métodos , Femenino , Intoxicación del Sistema Nervioso por Plomo/tratamiento farmacológico , Intoxicación del Sistema Nervioso por Plomo/etiología , Intoxicación del Sistema Nervioso por Plomo/metabolismo , Intoxicación del Sistema Nervioso por Plomo/fisiopatología , Masculino , Plasticidad Neuronal/fisiología , Ratas , Ratas Wistar , Sinapsis/fisiologíaRESUMEN
This study was carried out to investigate whether the congenital HCMV infection affect the induction and maintenance of LTP /DP. Rat models of Sprague-Dawley rats congenitally infected by HCMV were made. Field excitatory postsynaptic potentials (EPSPs) were recorded in the hippocampal slices of offspring rats (50-65days) to study alterations of LTP /DP in area dentate gyrus (DG) of the hippocampus after congenital infection. The Ca(2+) and mRNA level of calmodulin (CaM) in the hippocampus neurons of the experiment group (congenital infected by HCMV) and the control group were measured;The input/output (I/O) curves of the EPSP slope PS amplitude in area DG in experiment group were significantly depressed when compared to control group (P<0.05). LTP of the EPSP slope and PS amplitude in area DG of the hippocampus was 137±4% (EPSP) and 225±11% (PS) in control rats and 115±9% (EPSP) and 163±7% (PS) in experiment rats (EPSP: F=25.29,P<0.05;PS: F=74.33 P<0.05, two-way ANOVA with Tukey test); DP of the EPSP slope and PS amplitude was 86±3% (EPSP) and 85±2% (PS) in control rats and 94±5% (EPSP) and 93±4% (PS) in congenitally infected rats (EPSP: F=5.62, P<0.05;PS: F=4.22, P<0.05, two-way ANOVA with Tukey test) . At the same time, intracellular [Ca(2+)] and mRNA level of CaM in the hippocampus neurons of the experiment group were significantly increased than that of in the controls ([Ca(2+)]: P<0.01;CaM mRNA: P<0.01) . The results demonstrate that congenital HCMV infection could reduce the range of synaptic plasticity in the Sprague-Dawley rats, which may trigger the dysfunction of learning and memory through disrupting the calcium balance.
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Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/metabolismo , Giro Dentado/metabolismo , Giro Dentado/virología , Plasticidad Neuronal/fisiología , Animales , Calcio/metabolismo , Calmodulina/metabolismo , Infecciones por Citomegalovirus/complicaciones , Potenciales Postsinápticos Excitadores/fisiología , Inmunohistoquímica , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
With the increasing applications of titanium dioxide nanoparticles (TiO(2) NPs) in industry and daily life, an increasing number of studies showed that TiO(2) NPs may have negative effects on the respiratory or metabolic circle systems of organisms, while very few studies focused on the brain central nervous system (CNS). Synaptic plasticity in hippocampus is believed to be associated with certain high functions of CNS, such as learning and memory. Thus, in this study, we investigated the effects of developmental exposure to TiO(2) NPs on synaptic plasticity in rats' hippocampal dentate gyrus (DG) area using in vivo electrophysiological recordings. The input/output (I/O) functions, paired-pulse reaction (PPR), field excitatory postsynaptic potential, and population spike amplitude were measured. The results showed that the I/O functions, PPR, and long-term potentiation were all attenuated in lactation TiO(2) NPs-exposed offspring rats compared with those in the control group. However, in the pregnancy TiO(2) NPs exposure group, only PPR was attenuated significantly. These findings suggest that developmental exposure to TiO(2) NPs could affect synaptic plasticity in offspring's hippocampal DG area in vivo, which indicates that developmental brains, especially in lactation, are susceptible to TiO(2) NPs exposure. This study reveals the potential toxicity of TiO(2) NPs in CNS. It may give some hints on the security of TiO(2) NPs production and application and shed light on its future toxicological studies.
Asunto(s)
Anestesia , Giro Dentado/efectos de los fármacos , Hipocampo/efectos de los fármacos , Exposición Materna , Nanopartículas del Metal , Plasticidad Neuronal/efectos de los fármacos , Titanio/farmacología , Potenciales de Acción , Animales , Giro Dentado/fisiología , Femenino , Hipocampo/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Microscopía Electrónica de Transmisión , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Ghrelin, an orexigenic hormone, is mainly produced by the stomach and released into the circulation. Ghrelin receptors (growth hormone secretagogue receptors) are expressed throughout the brain, including the hippocampus. The activation of ghrelin receptors facilitates high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in vitro, and also improves learning and memory. Herein, we report that a single infusion of ghrelin into the hippocampus led to long-lasting potentiation of excitatory postsynaptic potentials (EPSPs) and population spikes (PSs) in the dentate gyrus of anesthetized rats. This potentiation was accompanied by a reduction in paired-pulse depression of the EPSP slope, an increase in paired-pulse facilitation of the PS amplitude, and an enhancement of EPSP-spike coupling, suggesting the involvement of both presynaptic and postsynaptic mechanisms. Meanwhile, ghrelin infusion time-dependently increased the phosphorylation of Akt-Ser473, a downstream molecule of phosphoinositide 3-kinase (PI3K). Interestingly, PI3K inhibitors, but not NMDA receptor antagonist, inhibited ghrelin-induced potentiation. Although ghrelin had no effect on the induction of HFS-induced LTP, it prolonged the expression of HFS-induced LTP through extracellular signal-regulated kinase (ERK)1/2. The Morris water maze test showed that ghrelin enhanced spatial memory, and that this was prevented by pretreatment with PI3K inhibitor. Taken together, the findings show that: (i) a single infusion of ghrelin induced a new form of synaptic plasticity by activating the PI3K signaling pathway, without HFS and NMDA receptor activation; (ii) a single infusion of ghrelin also enhanced the maintenance of HFS-induced LTP through ERK activation; and (iii) repetitive infusion of ghrelin enhanced spatial memory by activating the PI3K signaling pathway. Thus, we propose that the ghrelin signaling pathway could have therapeutic value in cognitive deficits.
Asunto(s)
Giro Dentado/enzimología , Giro Dentado/fisiología , Ghrelina/farmacología , Memoria/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Animales , Giro Dentado/efectos de los fármacos , Activación Enzimática , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/fisiología , Plasticidad Neuronal/fisiología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Ratas , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Transducción de Señal/fisiología , Conducta Espacial/efectos de los fármacos , Conducta Espacial/fisiologíaRESUMEN
In order to evaluate the effect of omega-3 fish oil supplement by gavage (0.4 mL/100 g body weight) on the chronic lead-induced (0.2% lead acetate) impairments of long-term potentiation (LTP) in rat dentate gyrus (DG) in vivo, we designed the experiments which were carried out in four groups of newborn Wistar rats (the control, the lead-exposed, the control with fish oil treatment and the lead-exposed with fish oil treatment, respectively). The excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude were measured in the DG of rats with above different treatments at the age of 80-90 d in response to stimulation applied to the lateral perforant path. The results showed (1) postnatal chronic lead-exposure impaired LTP measured on both EPSP slope and PS amplitude in DG area of the hippocampus; (2) in the control rats, omega-3 fish oil had no effect on LTP while in the lead-exposed rats, omega-3 fish oil had a protective effect on LTP. These results suggest that omega-3 fish oil supplement could protect rats from the lead-induced impairment of LTP. Omega-3 fish oil might be a preventive substance in reducing LTP deficits induced by lead.
Asunto(s)
Giro Dentado/efectos de los fármacos , Ácidos Grasos Omega-3/farmacología , Aceites de Pescado/química , Intoxicación por Plomo/fisiopatología , Potenciación a Largo Plazo/efectos de los fármacos , Animales , Animales Recién Nacidos , Potenciales Postsinápticos Excitadores , Vía Perforante , Ratas , Ratas WistarRESUMEN
Polybrominated diphenyl ethers (PBDEs) are widely used as flame-retardant additives. But the application of PBDEs has been challenged due to their toxicity, especially neurotoxicity. In this study, we investigated the effects of decabrominated diphenyl ether (PBDE 209), the major PBDEs product, on voltage-gated sodium channels (VGSCs) in primary cultured rat hippocampal neurons. Employing the whole-cell patch-clamp technique, we found that PBDE 209 could irreversibly decrease voltage-gated sodium channel currents (I(Na)) in a very low dose and in a concentration-dependent manner. We had systematically explored the effects of PBDE 209 on I(Na) and found that PBDE 209 could shift the activation and inactivation of I(Na) toward hyperpolarizing direction, slow down the recovery from inactivation of I(Na), and decrease the fraction of activated sodium channels. These results suggested that PBDE 209 could affect VGSCs, which may lead to changes in electrical activities and contribute to neurotoxicological damages. We also showed that ascorbic acid, as an antioxidant, was able to mitigate the inhibitory effects of PBDE 209 on VGSCs, which suggested that PBDE 209 might inhibit I(Na) through peroxidation. Our findings provide new insights into the mechanism for the neurological symptoms caused by PBDE 209.
Asunto(s)
Éteres Difenilos Halogenados/toxicidad , Hipocampo/efectos de los fármacos , Activación del Canal Iónico , Neuronas/efectos de los fármacos , Canales de Sodio/efectos de los fármacos , Animales , Hipocampo/citología , Hipocampo/metabolismo , Neuronas/metabolismo , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , Canales de Sodio/metabolismo , Técnicas de Cultivo de TejidosRESUMEN
Recently, quantum dots (QDs) have attracted widespread interest in biology and medicine. They are rapidly being used as new tools for both diagnostic and therapeutic purposes. Critical issues for further applications of QDs include the assessment of biocompatibility and biosafety of QDs. Most of previous researches concerning QD cytotoxicity focused on in vitro studies. In the present study, the impairments of acute exposure to well-modified and unmodified QDs (streptavidin-CdSe/ZnS and CdSe QDs, respectively) on synaptic transmission and plasticity were examined in adult rat hippocampal dentate gyrus (DG) area in vivo. The input/output (I/O) functions, paired-pulse ratio (PPR), field excitatory postsynaptic potential (fEPSP) and population spike (PS) amplitude were measured. The results showed that PPR and long-term potentiation (LTP) were all significantly decreased in these two types of QD-exposed rats compared to those in control rats. While the I/O functions and the amplitudes of fEPSP slope and PS amplitude of the baseline were significantly increased under QD exposure. These findings suggest that exposure to QDs, no matter whether they are well modified or not, could impair synaptic transmission and plasticity in the rat DG area in vivo and reveal the potential risks of QD applications in biology and medicine, especially in the toxin-susceptible central nervous system (CNS).
Asunto(s)
Giro Dentado/metabolismo , Plasticidad Neuronal , Puntos Cuánticos , Transmisión Sináptica , Animales , Compuestos de Cadmio/química , Giro Dentado/ultraestructura , Estrés Oxidativo , Ratas , Ratas Wistar , Compuestos de Selenio/química , Estreptavidina/química , Sulfuros/química , Compuestos de Zinc/químicaRESUMEN
Polybromininated diphenyl ethers (PBDEs) are widely used as flame-retardant additives. Previous studies have demonstrated that PBDEs exposure can lead to neurotoxicity. However, little is known about the effects of PBDE 209 on synaptic plasticity. This study investigated the effect of decabrominated diphenyl ether (PBDE 209), a major PBDEs product, on synaptic plasticity in the dentate gyrus of rats at different developmental periods. We examined the input/output functions, paired-pulse reactions, and the long-term potentiation of the field excitatory postsynaptic potential slope and the population spike amplitude in vivo. Rats were exposed to PBDE 209 during five different developmental periods: pregnancy, lactation via mother's milk, lactation via intragastric administration, after weaning, and prenatal to life. We found that exposed to PBDE 209 during different developmental periods could impair the synaptic plasticity of adult rats in different degrees. The results also showed that PBDE 209 might cause more serious effects on the postsynaptic cell excitability in synaptic plasticity, and the lactation period was the most sensitive time of development towards PBDE 209.
Asunto(s)
Giro Dentado/efectos de los fármacos , Retardadores de Llama/toxicidad , Éteres Difenilos Halogenados/toxicidad , Lactancia , Potenciación a Largo Plazo/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Transmisión Sináptica/efectos de los fármacos , Envejecimiento , Animales , Giro Dentado/crecimiento & desarrollo , Giro Dentado/metabolismo , Giro Dentado/fisiopatología , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores , Femenino , Retardadores de Llama/metabolismo , Edad Gestacional , Éteres Difenilos Halogenados/metabolismo , Síndromes de Neurotoxicidad/fisiopatología , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
1. Valproate (VPA) has long been used in the treatment of both generalized and partial seizures. However, its cellular mechanisms of action remain unclear. 2. In the present study, the effects of VPA on synaptic transmission and neuronal excitability were examined in the hippocampal CA1 region using whole-cell patch clamp recordings. 3. Perfusion with VPA, at therapeutically attainable concentrations (i.e. 0.3 and 0.6 mmol/L), significantly increased the frequency (112 +/- 2 and 133 +/- 2% of control, respectively; n = 5; both P < 0.05), but not the average amplitude, of miniature inhibitory post-synaptic currents (mIPSCs). Perfusion with VPA had no effect on either the amplitude or the frequency of miniature excitatory post-synaptic currents (mEPSCs). 4. In acutely dissociated CA1 pyramidal neurons, VPA had no effect on 10 micromol/L GABA-induced currents. Furthermore, following the administration of 0.3 and 0.6 mmol/L VPA, the frequency of action potential firing was significantly reduced from 18.0 +/- 1.1 to 15.3 +/- 0.9 and from 18.6 +/- 0.9 to 12.6 +/- 0.6, respectively (n = 8; both P < 0.05). In contrast, 0.3 and 0.6 mmol/L VPA significantly increased spike frequency adaptation from 4.02 +/- 0.47 to 4.72 +/- 0.55 and from 3.47 +/- 0.41 to 4.48 +/- 0.58, respectively (n = 8; P < 0.05). 5. The results of the present study suggest that VPA presynaptically increases inhibitory synaptic activity without modifying excitatory synaptic transmission and reduces neuronal excitability. Any or all of these effects may contribute to its anticonvulsant action.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Región CA1 Hipocampal/efectos de los fármacos , Alcamidas Poliinsaturadas/farmacología , Propionatos/farmacología , Células Piramidales/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Ácido Valproico/farmacología , Animales , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Técnicas de Placa-Clamp , Células Piramidales/fisiología , Ratas , Ratas Wistar , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
OBJECTIVE: To explore the changes in spatial learning performance and long-term potentiation (LTP) which is recognized as a component of the cellular basis of learning and memory in normal and lead-exposed rats after administration of melatonin (MT) for two months. METHODS: Experiment was performed in adult male Wistar rats (12 controls, 12 exposed to melatonin treatment, 10 exposed to lead and 10 exposed to lead and melatonin treatment). The lead-exposed rats received 0.2% lead acetate solution from their birth day while the control rats drank tap water. Melatonin (3 mg/kg) or vehicle was administered to the control and lead-exposed rats from the time of their weaning by gastric gavage each day for 60 days, depending on their groups. At the age of 81-90 days, all the animals were subjected to Morris water maze test and then used for extracellular recording of LTP in the dentate gyrus (DG) area of the hippocampus in vivo. RESULTS: Low dose of melatonin given from weaning for two months impaired LTP in the DG area of hippocampus and induced learning and memory deficit in the control rats. When melatonin was administered over a prolonged period to the lead-exposed rats, it exacerbated LTP impairment, learning and memory deficit induced by lead. CONCLUSION: Melatonin is not suitable for normal and lead-exposed children.
Asunto(s)
Plomo/toxicidad , Aprendizaje/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Melatonina/toxicidad , Conducta Espacial/efectos de los fármacos , Animales , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Melatonina/administración & dosificación , RatasRESUMEN
Lead is a well-known toxin in the environment that causes severe damage to the nervous system. Gastrodin is the main bioactive component of Tian ma ( GASTRODIA ELATA Bl.), which is a traditional herbal medicine widely used in eastern Asia. Increasing lines of evidence show that gastrodin has diverse effects, especially neuroprotective effects. In the present study, we investigated whether gastrodin supplementation can rescue impairments of synaptic plasticity produced by developmental lead exposure. We examined three electrophysiological parameters of synaptic plasticity: input/output (I/O) function, paired-pulse facilitation (PPF), and long-term potentiation (LTP) of field excitatory postsynaptic potential (fEPSP) in the hippocampal CA1 region of rats on postnatal day 22 (P22). Our results showed that lead exposure significantly impaired synaptic plasticity in the hippocampal CA1 region and that gastrodin can effectively rescue these lead-induced impairments. Therefore, gastrodin may have potential therapeutic value for lead-induced impairments during human developmental stages.