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.

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.

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.

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.

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.

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.

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.

Crystal structure of Natratoxin, a novel snake secreted phospholipaseA2 neurotoxin from Naja atra venom inhibiting A-type K+ currents.

Snake secreted phospholipasesA2 (sPLA2s) are widely used as pharmacological tools to investigate their role in diverse pathophysiological processes. Some members of snake venom sPLA2s have been found to block voltage-activated K(+) channels (K(v) channels). However, most studies involved in their effects on ion channels were indirectly performed on motor nerve terminals while few studies were directly done on native neurons. Here, a novel snake sPLA2 peptide neurotoxin, Natratoxin, composed of 119 amino acid residues and purified from Naja atra venom was reported. It was characterized using whole-cell patch-clamp in acutely dissociated rat dorsal root ganglion (DRG) neurons. It was found to effectively inhibit A-type K(+) currents and cause alterations of channel gating characters, such as the shifts of steady-state activation and inactivation curves to hyperpolarization direction and changes of V(1/2) and slope factor. Therefore, Natratoxin was suggested to be a gating modifier of K(v) channel. In addition, this inhibitory effect was found to be independent of its enzymatic activity. These results suggested that the toxin enacted its inhibitory effect by binding to K(v) channel. To further elucidate the structural basis for this electrophysiological phenomenon, we determined the crystal structure of Natratoxin at 2.2 A resolution by molecular replacement method and refined to an R-factor of 0.190. The observed overall fold has a different structural organization from other K(+) channel inhibitors in animal toxins. Compared with other K(v) channel inhibitors, a similar putative functional surface in its C-terminal was revealed to contribute to protein-protein interaction in such a blocking effect. Our results demonstrated that the spatial distribution of key amino acid residues matters most in the recognition of this toxin towards its channel target rather than its type of fold.

Modulation of long-term potentiation by individual subtypes of muscarinic acetylcholine receptor in the rat dentate gyrus.

The roles of the muscarinic acetylcholine (ACh) receptors (mAChRs) in long-term potentiation (LTP) at many areas of the central nervous system including the hippocampus, have been extensively studied. However, not much is known about the modulation of LTP through individual subtypes of mAChR (M(1)-M(5) subtype). In this study, we investigated the involvement of each individual subtypes of mAChR in LTP induction by intrahippocampal administration of cholinergic ligands at the dentate gyrus (DG) of anesthetized rats. We found atropine, an antagonist of mAChRs, suppressed the induction of LTP. This observation confirmed that the muscarinic system is involved in LTP. We then examined the effects of M(1)AChR antagonists (pirenzepine and telenzepine), M(2/4)AChR antagonists (Methoctramine and {11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one}(AFDX-116)), and M(3/5)AChR antagonist (4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP)) on LTP. Our results showed that both M(1)AChR and M(2/4)AChR antagonists but not M(3/5)AChR antagonist suppressed the amplitude of LTP. We also examined the effects of these cholinergic ligands on basal synaptic transmission and found that only pirenzepine augmented the amplitude of population spike. This study suggests that individual mAChR subtypes play different modulation roles in LTP induction in the DG of rats.

Excitatory effects of low-level lead exposure on action potential firing of pyramidal neurons in CA1 region of rat hippocampal slices.

Lead is putatively regarded as an environmental neurotoxicant. Long-term low-level lead exposure causes cognitive deficits, but the mechanism remains to be elucidated. In the present study, the excitatory effects of low-level lead exposure on action potential (AP) firing of pyramidal neurons in CA1 region of rat hippocampal slices and the pathway through which lead induced these effects were studied with conventional whole-cell recording. Low-level lead (0.5 and 5 microM) exposure did not significantly change either voltage threshold or amplitude, duration, rise time, or rising velocity of single AP; conversely, 5 microM lead exposure significantly increased AP firing rates and reduced spike frequency adaptation. These excitatory effects of 5 microM lead were blocked by mibefradil, a selective blocker of T-type voltage-dependent calcium channels (VDCC), but not by verapamil and omega-conotoxin, selective blockers of L-type and N-type VDCC, respectively. Five micromolar lead could not change the excitability of pyramidal neurons when slices were perfused with calcium-free ACSF. In addition, the effects were abolished by inhibitors of two intracellular calcium release channels: 2-APB, an inhibitor of inositol trisphosphate receptors, and dantrolene, an inhibitor of ryanodine receptors, but not by thapsigargin, an inhibitor of endoplasmic reticulum calcium uptake. These results provide evidence for excitatory neurotoxicity of low-level lead exposure, contribution of T-type VDCC in the entrance of lead into neurons, and a possible involvement of calcium flux alteration during APs in this excitatory neurotoxicity.

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.

Unmodified CdSe quantum dots induce elevation of cytoplasmic calcium levels and impairment of functional properties of sodium channels in rat primary cultured hippocampal neurons.

BACKGROUND: The growing applications of nanotechnologic products, such as quantum dots (QDs), increase the likelihood of exposure. Furthermore, their accumulation in the bioenvironment and retention in cells and tissues are arousing increasing worries about the potentially harmful side effects of these nanotechnologic products. Previous studies concerning QD cytotoxicity focused on the reactive oxygen species produced by QDs. Cellular calcium homeostasis dysregulation caused by QDs may be also responsible for QD cytotoxicity. Meanwhile the interference of QDs with voltage-gated sodium channel (VGSC) current (I(Na)) may lead to changes in electrical activity and worsen neurotoxicologic damage. OBJECTIVE: We aimed to investigate the potential for neurotoxicity of cadmium selenium QDs in a hippocampal neuronal culture model, focusing on cytoplasmic calcium levels and VGSCs function. METHODS: We used confocal laser scanning and standard whole-cell patch clamp techniques. RESULTS: We found that a) QDs induced neuron death dose dependently; b) cytoplasmic calcium levels were elevated for an extended period by QD treatment, which was due to both extracellular calcium influx and internal calcium release from endoplasmic reticulum; and c) QD treatment enhanced activation and inactivation of I(Na), prolonged the time course of activation, slowed I(Na) recovery, and reduced the fraction of available VGSCs. CONCLUSION: Results in this study provide new insights into QD toxicology and reveal potential risks of their future applications in biology and medicine.

Mechanisms of unmodified CdSe quantum dot-induced elevation of cytoplasmic calcium levels in primary cultures of rat hippocampal neurons.

Quantum dots (QDs) have shown great promise for applications in biology and medicine, which is being challenged by their potential nanotoxicity. Reactive oxygen species (ROS) produced by QDs are believed to be partially responsible for QD cytotoxicity. Cytoplasmic Ca(2+) plays an important role in the development of ROS injury. Here we found unmodified cadmium selenium (CdSe) QDs could elevate cytoplasmic calcium levels ([Ca(2+)](i)) in primary cultures of hippocampal neurons, involved both extracellular Ca(2+) influx and internal Ca(2+) release. More specifically, verapamil and mibefradil (L-type and T-type calcium channels antagonists, respectively) failed to prevent extracellular Ca(2+) influx under QD insult, while omega-conotoxin (N-type antagonist) could partially block this Ca(2+) influx. Surprisingly, this Ca(2+) influx could be well blocked by voltage-gated sodium channels (VGSCs) antagonist, tetrodotoxin (TTX). QD-induced internal Ca(2+) release could be avoided by clonazepam, a specific inhibitor of mitochondrial sodium-calcium exchangers (MNCX), and also by TTX. Furthermore, dantrolene, an antagonist of ryanodine (Ry) receptors in endoplasmic reticulum (ER), almost abolished internal Ca(2+) release, while 2-APB [inositol triphosphate (IP(3)) receptors antagonist] failed to block this Ca(2+) release, indicating that released Ca(2+) from mitochondria, which was induced by extracellular Na(+) influx, further triggered much more Ca(2+) release from ER. Our results imply that more research on the biocompatibility and biosafety of QD is both warranted and necessary.

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 Cd2+ on transient outward and delayed rectifier potassium currents in acutely isolated rat hippocampal CA1 neurons.

The effects of cadmium (Cd(2+)) on the transient outward potassium current (I(A)) and delayed rectifier potassium current (I(K)) were investigated in acutely dissociated rat hippocampal CA1 neurons using the whole-cell patch-clamp technique. The results showed that Cd(2+) inhibited the amplitudes of I(A) and I (K) in a reversible and concentration-dependent manner, with half-maximal inhibitive concentration (IC(50)) values of 546+/-59 and 749+/-53 microM, and the inhibitory effect of Cd(2+) was voltage dependent. Cd(2+) significantly shifted the steady-state activation and inactivation curve of I(A) to more positive potentials. In contrast, Cd(2+) caused a relatively less but still significant positive shift in the activation of I(K) without effect on the inactivation curve. Cd(2+) significantly slowed the recovery from inactivation of I(K) but had no effect on the recovery time course of I(A). The results suggest that the modulation of I(A) and I(K) was most likely mediated by the interaction of Cd(2+) with a specific site on the potassium-channel protein rather than by screening of bulk surface-negative charge. The effects of Cd(2+) on the voltage-gated potassium currents may be a possible contributing mechanism for the Cd(2+)-induced neurotoxic damage. In addition, the effects of Cd(2+) on the potassium currents at concentrations that overlap with its effects on calcium currents raise concerns about its use in pharmacological or physiological studies.

Opposite effects of alpha-lipoic acid on antioxidation and long-term potentiation in control and chronically lead-exposed rats.

Among the developmental changes identified in rats exposed to lead are impairments in long-term potentiation (LTP) in the hippocampus and changes in the levels of reactive oxygen species (ROS) in cells and some soft tissues. alpha-Lipoic acid (LA) has been reported to be highly effective in improving the thiol capacity of the cells and in reducing lead-induced oxidative stress. To explore the effects of LA on LTP in chronically lead-exposed rats and the relationship between ROS and LTP in both control and lead-exposed rats, we have compared LTP and oxidative stress parameters in groups of lead-exposed and control rats with or without LA treatment (10, 25, 50, and 100 mg/kg through intraperitoneal injection). The capacity of LA to decrease hippocampal lead levels in lead-exposed rats was examined. We found that LA had no effects in decreasing the level of lead in the hippocampus, but it did appear to have both antioxidant properties and a reparatory effect on LTP amplitude in rats developmentally exposed to lead for 2 weeks following birth. Interestingly, bell-shaped dose-response curves emerged. In the lower LA dosage groups (10, 25 mg/kg LA), there was an increasing LTP amplitude. The strongest protective effect in terms of the induction and amplitude of LTP in the lead-exposed group with at 25 mg/kg LA; when higher dosages were applied (50, 100 mg/kg LA), the LTP amplitude decreased as compared to the 25 mg/kg LA treatment group. The administration of LA to control animals resulted in a significant impairment of LTP amplitude, with the 100 mg/kg LA treatment having harmful effects on the oxidative parameters. These differential effects of LA on LTP in control and lead-exposed rats may be due to the different redox status of the control and lead-exposed rats.

Quercetin relieves chronic lead exposure-induced impairment of synaptic plasticity in rat dentate gyrus in vivo.

Increasing evidence suggests that lead (Pb) produces impairments partly through oxidative stress. Though many researchers have investigated protective effect of some antioxidant nutrients against Pb toxicity, little information is available about the effect of antioxidants on Pb-induced impairment of synaptic plasticity. Quercetin, a strong antioxidant and radical scavenger, is the representative natural flavonoid molecule abundant in fruits and vegetables. Previous studies have found that quercetin was neuroprotective in many cases. This study was designed to evaluate the effect of quercetin on chronic Pb exposure-induced impairment of synaptic plasticity in adult rat dentate gyrus (DG) area in vivo. The input/output (I/O) functions, paired-pulse reactions (PPR), excitatory postsynaptic potential (EPSP), and population spike (PS) amplitude were measured in the DG area of different groups of rats in response to stimulation applied to the lateral perforant path. The results showed that the depressed I/O, PPR, and long-term potentiation (LTP) of Pb-exposed group were significantly increased by quercetin treatment. In addition, hippocampal Pb concentration was partially reduced after quercetin treatment. These findings suggest that quercetin treatment could relieve chronic Pb exposure-induced impairment of synaptic plasticity and might be a potential therapeutic intervention to cure cognitive deficits induced by Pb.

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.

Effects of Epigallocatechin-3-gallate on lead-induced oxidative damage.

Recent studies have shown that lead (Pb) could disrupt the prooxidant/antioxidant balance of tissue which leads to biochemical and physiological dysfunction. Epigallocatechin-3-gallate (EGCG), a catechin polyphenols component, is found to be an effective antioxidant. The present study investigated whether EGCG administration could reverse the changes on redox states in rat hippocampus caused by lead exposure. The association between redox status changes and long-term potentiation (LTP) in CA1 area of hippocampus were also examined. Wistar rats exposed to lead from postnatal day 1 were followed by 10 days of EGCG (10, 25 and 50 mg/kg) administration through intraperitoneally (ip), and the rats were sacrificed for experiments at the age of 21-23 days. The experimental results showed that glutathione (GSH) and superoxide dismutase (SOD) activity decreased accompanied with LTP amplitude decrease in CA1 area of hippocampus in the lead-exposed group. EGCG supplementation following lead intoxication resulted in increases in the GSH and SOD levels and increases in the LTP amplitude. Malondialdehyde (MDA) levels, a major lipid peroxidation byproduct, increased following lead exposure and decreased following EGCG treatment. In hippocampal neuron culture model, lead exposure (20 microM) significantly inhibited the viability of neurons which was followed by an accumulation of ROS and a decrease of mitochondrial membrane potential (delta Psi m). Treatment by EGCG (10-50 microM) effectively increased cell viability, decreased ROS formation and improved delta Psi m in hippocampal neurons exposed to lead. These observations suggest that EGCG is a potential complementary agent in the treatment of chronic lead intoxication through its antioxidative character.