Multiple epigenetic factors predict the attention deficit/hyperactivity disorder among the Chinese Han children.

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.

Developmental lead exposure alters synaptogenesis through inhibiting canonical Wnt pathway in vivo and in vitro.

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.

Epigenetic histone modification regulates developmental lead exposure induced hyperactivity in rats.

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.

Levothyroxine rescues the lead-induced hypothyroidism and impairment of long-term potentiation in hippocampal CA1 region of the developmental rats.

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.

Galantamine rescues lead-impaired synaptic plasticity in rat dentate gyrus.

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.

Local infusion of ghrelin enhanced hippocampal synaptic plasticity and spatial memory through activation of phosphoinositide 3-kinase in the dentate gyrus of adult rats.

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.

Protective effects of omega-3 fish oil on lead-induced impairment of long-term potentiation in rat dentate gyrus in vivo.

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.

Effects of decabrominated diphenyl ether (PBDE 209) on voltage-gated sodium channels in primary cultured rat hippocampal neurons.

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.

The effect of quantum dots on synaptic transmission and plasticity in the hippocampal dentate gyrus area of anesthetized rats.

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).

Effects of decabrominated diphenyl ether (PBDE 209) exposure at different developmental periods on synaptic plasticity in the dentate gyrus of adult rats In vivo.

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.

Effects of chronic administration of melatonin on spatial learning ability and long-term potentiation in lead-exposed and control rats.

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.

Effects of sodium valproate on synaptic transmission and neuronal excitability in rat hippocampus.

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.

Protective effects of gastrodin on lead-induced synaptic plasticity deficits in rat hippocampus.

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.

Epigallocatechin-3-gallate induced primary cultures of rat hippocampal neurons death linked to calcium overload and oxidative stress.

Epigallocatechin-3-gallate (EGCG), a catechin polyphenols component, is the main ingredient of green tea extract. It has been reported that EGCG is a potent antioxidant and beneficial in oxidative stress-related diseases, but others and our previous study showed that EGCG has pro-oxidant effects at high concentration. Thus, in this study, we tried to examine the possible pathway of EGCG-induced cell death in cultures of rat hippocampal neurons. Our results showed that EGCG caused a rapid elevation of intracellular free calcium levels ([Ca(2+)](i)) in a dose-dependent way. Exposure to EGCG dose- and time-dependently increased the production of reactive oxygen species (ROS) and reduced mitochondrial membrane potential (Deltapsi(m)) as well as the Bcl-2/Bax expression ratio. Importantly, acetoxymethyl ester of 5,5'-dimethyl-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, ethylene glycol-bis-(2-aminoethyl)-N,N,N',N'-tetraacetic acid, and vitamin E could attenuate EGCG-induced apoptotic responses, including ROS generation, mitochondrial dysfunction, and finally partially prevented EGCG-induced cell death. Furthermore, treatment of hippocampal neurons with EGCG resulted in an elevation of caspase-3 and caspase-9 activities with no significant accompaniment of lactate dehydrogenase release, which provided further evidence that apoptosis was the dominant mode of EGCG-induced cell death in cultures of hippocampal neurons. Taken together, these findings indicated that EGCG induced hippocampal neuron death through the mitochondrion-dependent pathway.

Muscarinic cholinergic modulation of synaptic transmission and plasticity in rat hippocampus following chronic lead exposure.

The cholinergic system is believed to be associated with learning and memory functions. Lead (Pb2+) is a well-known neurotoxic metal that causes irreversible damage to the central nervous system (CNS). To investigate whether Pb2+ interferes with cholinergic modulation, we examined the effects of carbachol (CCh), a muscarinic cholinergic agonist, on synaptic transmission and plasticity in the CA1 area of the hippocampus of developmentally Pb2+-exposed rats. The results showed that: (1) In both control and Pb2+-exposed rats, 0.1 microM CCh significantly enhanced tetanus-induced long-term potentiation (LTP), while 5 microM CCh induced a reversible depression of field excitatory postsynaptic potentials (fEPSPs). However, both the enhancement of LTP and depression of fEPSPs were significantly smaller in Pb2+-exposed rats than in controls, suggesting that the extent of the effect of CCh on the cholinergic system was depressed by Pb2+. (2) In Pb2+-exposed rats, the enhancement of LTP induced by 0.1 microM CCh was attenuated by pirenzepine, a M1AChR antagonist, but was not affected by methoctramine tetrahydrochloride (M-105), a M2/4AChR antagonist. The depression of fEPSPs induced by 5 microM CCh was reduced by either pirenzepine or M-105. (3) Furthermore, paired-pulse facilitation (PPF) was not affected by 0.1 microM CCh in control and Pb2+-exposed rats but was increased by 5 microM CCh in either group; the increase in PPF was less pronounced in Pb2+-treated when compared to control rats. These results suggested that cholinergic modulation could be impaired by Pb2+, and this kind of impairment might occur via different mAChR subtypes. Our study delineated the effects of Pb2+ on muscarinic modulation, and this might be one of the underlying mechanisms by which Pb2+ impairs learning and memory.

Monosialoanglioside (GM1) prevents lead-induced neurotoxicity on long-term potentiation, SOD activity, MDA levels, and intracellular calcium levels of hippocampus in rats.

Lead (Pb(2+)) is one of the most common neurotoxic metals present in our environment. Chronic or acute exposure to Pb(2+) causes impairment to the central nervous system (CNS). As one potent useful tool in the attempt to protect against impairment and promote functional recovery of the CNS, gangliosides are hopeful for recovering Pb(2+) neurotoxicity. The aim of this study is to investigate the effects of monosialoganglioside (GM1) on the Pb(2+)-induced impairments of synaptic plasticity, antioxidant system function, and intracellular calcium levels in the hippocampus of acute Pb(2+)-exposed rats. Our study showed that: (1) Acute Pb(2+) exposure impaired synaptic transmission and plasticity in the hippocampus and GM1 preconditioning rescued to some extent this impairment in urethane-anesthetized rats. (2) Superoxide dismutase activities and malondialdehyde levels were significantly increased in the acute Pb(2+)-exposed hippocampus which could be reduced by GM1 preconditioning. (3) Further, acute Pb(2+) exposure caused the internal free Ca(2+) fluctuation in the cultured hippocampal neurons and GM1 preconditioning could abate this fluctuation. Taken together, our results illustrated the possible mechanisms underlying the protective effects of GM1 against Pb(2+) neurotoxicity and might shed light on protection against Pb(2+) toxicity and its treatment.

Case-control study of blood lead levels and attention deficit hyperactivity disorder in Chinese children.

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) and lead exposure are high-prevalence conditions among children. OBJECTIVE: Our goal was to investigate the association between ADHD and blood lead levels (BLLs) in Chinese children, adjusting for known ADHD risk factors and potential confounding variables. METHODS: We conducted a pair-matching case-control study with 630 ADHD cases and 630 non-ADHD controls 4-12 years of age, matched on the same age, sex, and socioeconomic status. The case and control children were systematically evaluated via structured diagnostic interviews, including caregiver interviews, based on the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., revised criteria (DSM-IV-R). We evaluated the association between BLLs and ADHD using the Pearson chi-square test for categorical variables and the Student t-test for continuous data. We then performed conditional multiple variables logistic regression analyses with backward stepwise selection to predict risk factors for ADHD. RESULTS: There was a significant difference in BLLs between ADHD cases and controls. ADHD cases were more likely to have been exposed to lead during childhood than the non-ADHD control subjects, with adjustment for other known risk factors [children with BLLs >or= 10 microg/dL vs.

[Protection effects of S-adenosyl-L-methionine on lead-exposed rats during development and its mechanism of long-term potentiation].

OBJECTIVE: To explore the effects of S-adenosyl-L-methionine (SAM) on blood lead concentration and oxidative stress of tissue in prenatal and postnatal lead-exposed rats, and evaluate the potential reparation exerted by SAM on paired-pulse facilitation (PPF) and long-term potentiation (LTP) in lead-exposed rat. METHODS: Pregnant Wistar rats were randomly divided into three groups: control, lead-exposed and lead-exposed with SAM treatment groups. Lead-exposed rats drank 1.5 g/L lead acetate solution through pregnancy until weaning and then the pups received 20 mg/kg SAM or saline daily intraperitoneally depending on their group. Control group rats drank tap water throughout the experiment. At the postnatal 44-60 days, all the pup rats were given an extracellular recording measured in dentate gyrus (DG) area of hippocampus. The blood lead concentration and oxidative stress in liver, brain and hippocampus were also detected. RESULTS: The blood lead concentration in lead-exposed group was higher (159. 3 +/- 10. 9 microg/L) in comparing with those of control group (27.5 +/-3.8 microg/L) and lead +SAM group (33.1 +/-9.5 microg/L) (F=213.5, P<0.01). A significant recovery of liver, brain glutathione (GSH) and malondialdehyde (MDA) level was clearly produced in lead-exposed rats after SAM treatment (P <0.05). Chronic lead exposure during development impaired LTP measured on field excitatory postsynaptic potential (EPSP) [(112 +/-2.1)%] compared with control rats [(131+/-4.5)%] and the impaired LTP could be significantly increased by SAM treatment [(120 +/- 2.6)%] (F = 26. 1, P <0. 05). CONCLUSION: SAM might be beneficial for treatment of lead intoxication, especially in the rescue of learning and memory impairment induced by lead and should deserve more detailed research.

S-adenosyl-L-methionine improves impaired hippocampal long-term potentiation and water maze performance induced by developmental lead exposure in rats.

Lead (Pb(2+)) exposure in children can induce long-lasting deficits in cognitive function and has been modeled in experimental animals. Based on previous studies which demonstrated that S-adenosyl-l-methionine (SAM) is beneficial in the treatment of lead intoxication, here, we asked the question if SAM treatment could rescue the impaired cognition and synaptic plasticity induced by lead. Rats drank 1500 ppm lead acetate (PbAc) solution or distilled water throughout gestation and lactation. After weaning at postnatal day 22, one half of the control and lead-exposed male offspring were intraperitoneally injected 20 mg SAM/kg daily over a period of 20-22 days. Electrophysiological and Morris water maze test were performed at 44-54 days of age. The result showed that the impaired learning ability induced by lead could be improved significantly by SAM. Furthermore, our results revealed that long-term potentiation (LTP) of excitatory postsynaptic potential and population spike impairments induced by lead were also ameliorated by SAM treatment.

Effects of EGCG on voltage-gated sodium channels in primary cultures of rat hippocampal CA1 neurons.

(-)-Epigallocatechin-3-gallate (EGCG), the main active component of green tea, is commonly known for its beneficial properties at low doses. On the other hand, little is known about the adverse effects of EGCG. Voltage-gated sodium channel (VGSC) is responsible for both initiation and propagation of action potentials of the neurons in the hippocampus and throughout the central nervous system (CNS). In this study, the effects of EGCG on voltage-gated sodium channel currents (I(Na)) were investigated in rat primary cultures of hippocampal CA1 neurons via the conventional whole-cell patch-clamp technique. We found that I(Na) was not affected by EGCG at the concentration of 0.1microM, but was completely blocked by EGCG at the concentration of 400microM and higher, and EGCG reduced the amplitudes of I(Na) in a concentration-dependent manner in the range of 0.1-400microM. Furthermore, our results also showed that at the concentration of 100microM, EGCG was known to have the following performances: (1) it decreased the activation threshold and the voltage at which the maximum I(Na) current was evoked, caused negative shifts of I(Na) steady-state activation curve. (2) It enlarged I(Na) tail-currents. (3) It induced a left shift of the steady-state inactivation. (4) It reduced fraction of available sodium channels. (5) It delayed the activation of I(Na) in a voltage-dependent manner. (6) It prolonged the time course of the fast inactivation of sodium channels. (7) It accelerated the activity-dependent attenuation of I(Na). On the basis of these findings, we propose that EGCG could impair certain physiological functions of VGSCs, which may contribute, directly or indirectly, to EGCG's effects in CNS.