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 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 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.

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.