Activity-dependent changes in excitability of perirhinal cortex networks in vitro.

Rat brain slices comprising the perirhinal cortex (PC) and a portion of the lateral nucleus of the amygdala (LA), in standard medium, can generate synchronous oscillatory activity that is associated with action potential discharge and reflects the activation of glutamatergic and GABAergic receptors. We report here that similar synchronous oscillatory events are recorded in the PC in response to single-shock, electrical stimuli delivered in LA. In addition, we found that the latency of these responses progressively increased when the stimulus interval was varied from 10 to 1 s; for example, the response latency during stimuli delivered at 1 Hz was more than twofold longer than that seen during stimulation at 0.1 Hz. This prolongation in latency occurred after approximately 5 stimuli, attained a steady value after 24-35 stimuli, and recovered to control values 30 s after stimulation arrest. These frequency-dependent changes in latency continued to occur during NMDA receptor antagonism but weakened following application of GABAA and/or GABAB receptor blockers. Our findings identify a new type of short-term plasticity that is mediated by GABA receptor function and may play a role in decreasing neuronal network synchronization during repeated activation. We propose that this frequency-dependent adaptive mechanism influences the excitability of limbic networks, thus potentially controlling epileptiform synchronization.

Spatial distribution of Aphis glycines (Hemiptera: Aphididae): a summary of the suction trap network.

The soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is an economically important pest of soybean, Glycine max (L.) Merrill, in the United States. Phenological information of A. glycines is limited; specifically, little is known about factors guiding migrating aphids and potential impacts of long distance flights on local population dynamics. Increasing our understanding of A. glycines population dynamics may improve predictions of A. glycines outbreaks and improve management efforts. In 2005 a suction trap network was established in seven Midwest states to monitor the occurrence of alates. By 2006, this network expanded to 10 states and consisted of 42 traps. The goal of the STN was to monitor movement of A. glycines from their overwintering host Rhamnus spp. to soybean in spring, movement among soybean fields during summer, and emigration from soybean to Rhamnus in fall. The objective of this study was to infer movement patterns of A. glycines on a regional scale based on trap captures, and determine the suitability of certain statistical methods for future analyses. Overall, alates were not commonly collected in suction traps until June. The most alates were collected during a 3-wk period in the summer (late July to mid-August), followed by the fall, with a peak capture period during the last 2 wk of September. Alate captures were positively correlated with latitude, a pattern consistent with the distribution of Rhamnus in the United States, suggesting that more southern regions are infested by immigrants from the north.

Ecology and management of the soybean aphid in North America.

The soybean aphid, Aphis glycines Matsumura, has become the single most important arthropod pest of soybeans in North America. Native to Asia, this invasive species was first discovered in North America in July 2000 and has rapidly spread throughout the northcentral United States, much of southeastern Canada, and the northeastern United States. In response, important elements of the ecology of the soybean aphid in North America have been elucidated, with economic thresholds, sampling plans, and chemical control recommendations widely adopted. Aphid-resistant soybean varieties were available to growers in 2010. The preexisting community of aphid natural enemies has been highly effective in suppressing aphid populations in many situations, and classical biological control efforts have focused on the addition of parasitoids of Asian origin. The keys to sustainable management of this pest include understanding linkages between the soybean aphid and other introduced and native species in a landscape context along with continued development of aphid-resistant varieties.

Neuropathic Nav1.3-mediated sensitization to P2X activation is regulated by protein kinase C.

BACKGROUND: Increased neuronal excitability and spontaneous firing are hallmark characteristics of injured sensory neurons. Changes in expression of various voltage-gated Na+ channels (VGSCs) have been observed under neuropathic conditions and there is evidence for the involvement of protein kinase C (PKC) in sensory hyperexcitability. Here we demonstrate the contribution of PKC to P2X-evoked VGSC activation in dorsal root ganglion (DRG) neurons in neuropathic conditions. RESULTS: Using the spinal nerve ligation (SNL) model of neuropathic pain and whole-cell patch clamp recordings of dissociated DRG neurons, we examined changes in excitability of sensory neurons after nerve injury and observed that P2X3 purinoceptor-mediated currents induced by α,ß-meATP triggered activation of TTX-sensitive VGSCs in neuropathic nociceptors only. Treatment of neuropathic DRGs with the PKC blocker staurosporine or calphostin C decreased the α,ß-meATP-induced Na+ channels activity and reversed neuronal hypersensitivity. In current clamp mode, α,ß-meATP was able to evoke action-potentials more frequently in neuropathic neurons than in controls. Pretreatment with calphostin C significantly decreased the proportion of sensitized neurons that generated action potentials in response to α,ß-meATP. Recordings measuring VGSC activity in neuropathic neurons show significant change in amplitude and voltage dependence of sodium currents. In situ hybridization data indicate a dramatic increase in expression of embryonic Nav1.3 channels in neuropathic DRG neurons. In a CHO cell line stably expressing the Nav1.3 subunit, PKC inhibition caused both a significant shift in voltage-dependence of the channel in the depolarizing direction and a decrease in current amplitude. CONCLUSION: Neuropathic injury causes primary sensory neurons to become hyperexcitable to ATP-evoked P2X receptor-mediated depolarization, a phenotypic switch sensitive to PKC modulation and mediated by increased activity of TTX-sensitive VGSCs. Upregulation in VGSC activity after injury is likely mediated by increased expression of the Nav1.3 subunit, and the function of the Nav1.3 channel is regulated by PKC.

Impacts of thiamethoxam seed treatment and host plant resistance on the soybean aphid fungal pathogen, Pandora neoaphidis.

Since the introduction of soybean aphid, Aphis glycines Matsumura, from Asia, insecticide use in soybean has increased substantially in the north central United States. Insecticide seed treatments and aphid resistant soybean varieties are management tactics that may reduce reliance on foliar applications of broad-spectrum insecticides. Exploring potential nontarget impacts of these technologies will be an important step in incorporating them into aphid management programs. We investigated impacts of thiamethoxam seed treatment and Rag1 aphid resistant soybean on a fungal pathogen of soybean aphid, Pandora neoaphidis (Remaudière & Hennebert) Humber, via open plot and cage studies. We found that although thiamethoxam seed treatment did significantly lower aphid pressure in open plots compared with an untreated control, this reduction in aphid density translated into nonsignificant decreases in fungal disease prevalence in aphids. Furthermore, when aphid densities were approximately equal in seed treated and untreated soybean, no impact on aphid fungal disease was observed. In open plots, Rag1 resistant soybean experienced lower aphid pressure and aphid disease prevalence compared with a nonresistant isoline. However, in cages when aphid densities were equivalent in both resistant and susceptible soybean, resistance had no impact on aphid disease prevalence. The addition of thiamethoxam seed treatment to resistant soybean yielded aphid densities and aphid disease prevalence similar to untreated, resistant soybean. These studies provide evidence that thiamethoxam seed treatments and Rag1 resistance can impact P. neoaphidis via decreased aphid densities; however, this impact is minimal, implying use of seed treatments and host plant resistance are compatible with P. neoaphidis.

Non-target impacts of soybean rust fungicides on the fungal entomopathogens of soybean aphid.

Soybean aphid, Aphis glycines, has caused serious economic damage to soybean across the North Central US since its introduction to North America in 2000. The management of another invasive soybean pest, Asian soybean rust, Phakopsora pachyrhizi, using foliar fungicide applications has the potential to impact soybean aphid populations by suppressing beneficial fungal entomopathogens. In 2005 and 2006, we applied recommended soybean rust fungicide treatments, consisting of strobilurin and triazole fungicides, to small soybean plots in two locations to assess if such applications might suppress aphid fungal epizootics. In Lamberton, MN, in 2005, during the epizootic, fungicide-treated plots averaged 2.0+/-0.7% (mean+/-SE) disease prevalence while untreated plots averaged 14.2+/-5.6%. In 2007, we applied strobilurin and strobilurin-triazole mix fungicides to single-plant microplots either before or after release of Pandora neoaphidis, the most commonly observed aphid pathogen in 2005 and 2006. Treatments that contained a mixture of two active ingredients significantly lowered peak and cumulative aphid disease prevalence in both early and late reproductive stage soybeans indicating that fungicide mixtures used to manage soybean rust can negatively impact an aphid-specific fungal pathogen. However, no consistent soybean aphid population response was observed in these studies of low levels of aphid fungal infection.

Development and validation of node-based sample units for estimating soybean aphid (Hemiptera: Aphididae) densities in field cage experiments.

The soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is currently the most important insect threat to soybean, Clycine max (L.) Merr., production in the North Central United States. Field cage studies are a key tool in investigating the potential of natural enemies and host plant resistance to control this pest. However, a major constraint in the use of cage studies is the limited number of treatments and replicates that can be used as aphid densities frequently become so large as to limit the number of experimental units that can be quantified. One way to overcome this limitation is to develop methods that estimate whole-plant aphid densities based on a reduced sampling plan. Here, we extend an existing method, node-sampling, used for estimating aphid populations in open field conditions and apply it to caged populations. We show that parameters calculated under open field conditions are inappropriate to estimate caged populations. In contrast, using four independent data sets of caged populations and a cross-validation technique, we demonstrate that a three-node sampling unit and a weighted formula provide accurate and robust estimates of whole-plant aphid density. This method reduced the number of aphids counted per plant by and average of 60%, with greater reductions at higher aphid densities. We further demonstrate that nearly identical statistical results were obtained when whole-plant or node-sampling estimates were used in the analysis of two case studies. The reduced sample unit method developed here saves time without sacrificing efficiency so that more plants, replications, or studies can be conducted that will lead to improved soybean aphid management.

Probability of cost-effective management of soybean aphid (Hemiptera: Aphididae) in North America.

Soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is one of the most damaging pests of soybean, Glycine max (L.) Merrill, in the midwestern United States and Canada. We compared three soybean aphid management techniques in three midwestern states (Iowa, Michigan, and Minnesota) for a 3-yr period (2005-2007). Management techniques included an untreated control, an insecticidal seed treatment, an insecticide fungicide tank-mix applied at flowering (i.e., a prophylactic treatment), and an integrated pest management (IPM) treatment (i.e., an insecticide applied based on a weekly scouting and an economic threshold). In 2005 and 2007, multiple locations experienced aphid population levels that exceeded the economic threshold, resulting in the application of the IPM treatment. Regardless of the timing of the application, all insecticide treatments reduced aphid populations compared with the untreated, and all treatments protected yield as compared with the untreated. Treatment efficacy and cost data were combined to compute the probability of a positive economic return. The IPM treatment had the highest probability of cost effectiveness, compared with the prophylactic tank-mix of fungicide and insecticide. The probability of surpassing the gain threshold was highest in the IPM treatment, regardless of the scouting cost assigned to the treatment (ranging from $0.00 to $19.76/ha). Our study further confirms that a single insecticide application can enhance the profitability of soybean production at risk of a soybean aphid outbreak if used within an IPM based system.

How do mutant Nav1.1 sodium channels cause epilepsy?

Voltage-gated sodium channels comprise pore-forming alpha subunits and auxiliary beta subunits. Nine different alpha subtypes, designated Nav1.1-Nav1.9 have been identified in excitable cells. Nav1.1, 1.2 and 1.6 are major subtypes in the adult mammalian brain. More than 200 mutations in the Nav1.1 alpha subtype have been linked to inherited epilepsy syndromes, ranging in severity from the comparatively mild disorder Generalized Epilepsy with Febrile Seizures Plus to the epileptic encephalopathy Severe Myoclonic Epilepsy of Infancy. Studies using heterologous expression and functional analysis of recombinant Nav1.1 channels suggest that epilepsy mutations in Nav1.1 may cause either gain-of-function or loss-of-function effects that are consistent with either increased or decreased neuronal excitability. How these diverse effects lead to epilepsy is poorly understood. This review summarizes the data on sodium channel mutations and epilepsy and builds a case for the hypothesis that most Nav1.1 mutations have their ultimate epileptogenic effects by reducing Nav1.1-mediated whole cell sodium currents in GABAergic neurons, resulting in widespread loss of brain inhibition, an ideal background for the genesis of epileptic seizures.

Evolving Mechanistic Concepts of Epileptiform Synchronization and their Relevance in Curing Focal Epileptic Disorders.

The synchronized activity of neuronal networks under physiological conditions is mirrored by specific oscillatory patterns of the EEG that are associated with different behavioral states and cognitive functions. Excessive synchronization can, however, lead to focal epileptiform activity characterized by interictal and ictal discharges in epileptic patients and animal models. This review focusses on studies that have addressed epileptiform synchronization in temporal lobe regions by employing in vitro and in vivo recording techniques. First, we consider the role of ionotropic and metabotropic excitatory glutamatergic transmission in seizure generation as well as the paradoxical role of GABAA signaling in initiating and perhaps maintaining focal seizure activity. Second, we address non-synaptic mechanisms (which include voltage-gated ionic currents and gap junctions) in the generation of epileptiform synchronization. For each mechanism, we discuss the actions of antiepileptic drugs that are presumably modulating excitatory or inhibitory signaling and voltage-gated currents to prevent seizures in epileptic patients. These findings provide insights into the mechanisms of seizure initiation and maintenance, thus leading to the development of specific pharmacological treatments for focal epileptic disorders.

Proepileptic influence of a focal vascular lesion affecting entorhinal cortex-CA3 connections after status epilepticus.

In limbic seizures, neuronal excitation is conveyed from the entorhinal cortex directly to CA1 and subicular regions. This phenomenon is associated with a reduced ability of CA3 to respond to entorhinal cortex inputs. Here, we describe a lesion that destroys the perforant path in CA3 after status epilepticus (SE) induced by pilocarpine injection in 8-week-old rats. Using magnetic resonance imaging, immunohistochemical, and ultrastructural analyses, we determined that this lesion develops after 30 minutes of SE and is characterized by microhemorrhages and ischemia. After a longer period of SE, the lesion invariably involves the upper blade of the dentate gyrus. Adult rats treated with subcutaneous diazepam (20 mg kg for 3 days) did not develop the dentate gyrus lesion and had less frequent spontaneous recurrent seizures (p < 0.01). Young (3-week-old) rats rarely (20%) developed the CA3 lesion, and their spontaneous seizures were delayed (p < 0.01). To investigate the role of the damaged CA3 in seizure activity, we reinduced SE in adult and young epileptic rats. Using FosB/DeltaFosB markers, we found induction of FosB/DeltaFosB immunopositivity in CA3 neurons of young but not in adult rats. These experiments indicate that SE can produce a focal lesion in the perforant path that may affect the roles of the hippocampus in epileptic rats.

Functional and biochemical analysis of a sodium channel beta1 subunit mutation responsible for generalized epilepsy with febrile seizures plus type 1.

Generalized epilepsy with febrile seizures plus type 1 is an inherited human epileptic syndrome, associated with a cysteine-to-tryptophan (C121W) mutation in the extracellular immunoglobin domain of the auxiliary beta1 subunit of the voltage-gated sodium channel. The mutation disrupts beta1 function, but how this leads to epilepsy is not understood. In this study, we make several observations that may be relevant for understanding why this beta1 mutation results in seizures. First, using electrophysiological recordings from mammalian cell lines, coexpressing sodium channel alpha subunits and either wild-type beta1 or C121Wbeta1, we show that loss of beta1 functional modulation, caused by the C121W mutation, leads to increased sodium channel availability at hyperpolarized membrane potentials and reduced sodium channel rundown during high-frequency channel activity, compared with channels coexpressed with wild-type beta1. In contrast, neither wild-type beta1 nor C121Wbeta1 significantly affected sodium current time course or the voltage dependence of channel activation. We also show, using a Drosophila S2 cell adhesion assay, that the C121W mutation disrupts beta1-beta1 homophilic cell adhesion, suggesting that the mutation may alter the ability of beta1 to mediate protein-protein interactions critical for sodium channel localization. Finally, we demonstrate that neither functional modulation nor cell adhesion mediated by wild-type beta1 is occluded by coexpression of C121Wbeta1, arguing against the idea that the mutant beta1 acts as a dominant-negative subunit. Together, these data suggest that C121Wbeta1 causes subtle effects on channel function and subcellular distribution that bias neurons toward hyperexcitabity and epileptogenesis.

An epilepsy mutation in the beta1 subunit of the voltage-gated sodium channel results in reduced channel sensitivity to phenytoin.

The antiepileptic drug phenytoin inhibits voltage-gated sodium channels. Phenytoin block is enhanced at depolarized membrane potentials and during high frequency channel activation. These properties, which are important for the clinical efficacy of the drug, depend on voltage-dependent channel gating. In this study, we examined the action of phenytoin on sodium channels, comprising a mutant auxiliary beta1 subunit (mutation C121Wbeta1), which causes the inherited epilepsy syndrome, generalized epilepsy with febrile seizures plus (GEFS+). Whole cell sodium currents in Chinese hamster ovary (CHO) cells coexpressing human Na(v)1.3 sodium channels and C121Wbeta1 exhibited altered gating properties, compared to currents in cells coexpressing Na(v)1.3 and wild type beta1. In addition mutant channels were less sensitive to inhibition by phenytoin, showing reduced tonic block at -70mV (EC(50)=26microM for C121Wbeta1 versus 11microM for wild type beta1) and less frequency-dependent inhibition in response to a 20Hz pulse train ( approximately 40% inhibition for C121Wbeta1 versus approximately 70% inhibition for wild type beta1, with 50microM phenytoin). Mutant and wild type channels did not differ in inactivated state affinity for phenytoin, suggesting that their pharmacological differences were secondary to their differences in voltage-dependent gating, rather than being caused by direct effects of the mutation on the drug receptor. Together, these data show that a sodium channel mutation responsible for epilepsy can also alter channel response to antiepileptic drugs.

Lacosamide modulates interictal spiking and high-frequency oscillations in a model of mesial temporal lobe epilepsy.

OBJECTIVE: Nearly one third of patients presenting with mesial temporal lobe epilepsy (MTLE), the most prevalent lesion-related epileptic disorder in adulthood, do not respond to currently available antiepileptic medications. Thus, there is a need to identify and characterize new antiepileptic drugs. In this study, we used the pilocarpine model of MTLE to establish the effects of a third generation drug, lacosamide (LCM), on seizures, interictal spikes and high-frequency oscillations (HFOs, ripples: 80-200 Hz, fast ripples: 250-500 Hz). METHODS: Sprague-Dawley rats (250-300 g) were injected with pilocarpine to induce a status epilepticus (SE) that was pharmacologically terminated after 1h. Eight pilocarpine-treated rats were then injected with LCM (30 mg/kg, i.p.) 4h after SE and daily for 14 days. Eight pilocarpine-treated rats were used as controls and treated with saline. Three days after SE, all rats were implanted with bipolar electrodes in the hippocampal CA3 region, entorhinal cortex (EC), dentate gyrus (DG) and subiculum and EEG-video monitored from day 4 to day 14 after SE. RESULTS: LCM-treated animals showed lower rates of seizures (0.21 (± 0.11) seizures/day) than controls (2.6 (±0.57), p<0.05), and a longer latent period (LCM: 11 (± 1) days, controls: 6.25 (± 1), p<0.05). Rates of interictal spikes in LCM-treated rats were significantly lower than in controls in CA3 and subiculum (p<0.05). Rates of ripples and fast ripples associated with interictal spikes in CA3 and subiculum as well as rates of fast ripples occurring outside of interictal spikes in CA3 were also significantly lower in LCM-treated animals. In controls, interictal spikes and associated HFOs correlated to seizure clustering, while this was not the case for isolated HFOs. SIGNIFICANCE: Our findings show that early treatment with LCM has powerful anti-ictogenic properties in the pilocarpine model of MTLE. These effects are accompanied by decreased rates of interictal spikes and associated HFOs. Isolated HFOs were also modulated by LCM, in a manner that appeared to be unrelated to its antiictogenic effects. These results thus suggest that distinct mechanisms may underlie interictal-associated and isolated HFOs in the pilocarpine model of MTLE.

State-dependent access to the batrachotoxin receptor on the sodium channel.

Batrachotoxin causes sustained opening of voltage-gated sodium channels. Toxin binds irreversibly to wild type channels; however, it dissociates rapidly from channels with mutation F1710C in transmembrane segment IVS6. This dissociation requires channel activation, suggesting that the activation gate guards the toxin-binding site. Here we show that activity-dependent toxin dissociation was not affected by external sodium, arguing against a binding site within the pore, and demonstrate that dissociation occurred only during the first few milliseconds after membrane depolarization, as if the toxin leaves its binding site during closed states that precede the final open state in the activation pathway. Toxin interaction with preopen states may facilitate subsequent channel opening, thus accounting for the batrachotoxin-induced negative shift in channel activation.

Functional characterization of the D188V mutation in neuronal voltage-gated sodium channel causing generalized epilepsy with febrile seizures plus (GEFS).

Mutations in the alpha 1 subunit of the voltage-gated sodium channel (SCN1A) have been increasingly recognized as an important cause of familial epilepsy in humans. However, the functional consequences of these mutations remain largely unknown. We identified a mutation (D188V) in SCN1A segregating with generalized epilepsy with febrile seizures (GEFS) in a large kindred. Compared to wild-type sodium channels, in vitro expression of channels harboring the D188V mutation were found to be more resistant to the decline in amplitude that is normally observed over the course of high frequency pulse trains. This small change on a single aspect of channel function is compatible with an increase in membrane excitability, such as during sustained and uncontrolled neuronal discharges. These data suggest that this specific effect on sodium channel function could be a general mechanism in the pathophysiology of epilepsies caused by mutations in sodium channels in humans.

Within-plant bottom-up effects mediate non-consumptive impacts of top-down control of soybean aphids.

There is increasing evidence that top-down controls have strong non-consumptive effects on herbivore populations. However, little is known about how these non-consumptive effects relate to bottom-up influences. Using a series of field trials, we tested how changes in top-down and bottom-up controls at the within-plant scale interact to increase herbivore suppression. In the first experiment, we manipulated access of natural populations of predators (primarily lady beetles) to controlled numbers of A. glycines on upper (i.e. vigorous-growing) versus lower (i.e. slow-growing) soybean nodes and under contrasting plant ages. In a second experiment, we measured aphid dispersion in response to predation. Bottom-up and top-down controls had additive effects on A. glycines population growth. Plant age and within-plant quality had significant bottom-up effects on aphid size and population growth. However, top-down control was the dominant force suppressing aphid population growth, and completely counteracted bottom-up effects at the plant and within-plant scales. The intensity of predation was higher on upper than lower soybean nodes, and resulted in a non-consumptive reduction in aphid population growth because most of the surviving aphids were located on lower plant nodes, where rates of increase were reduced. No effects of predation on aphid dispersal among plants were detected, suggesting an absence of predator avoidance behavior by A. glycines. Our results revealed significant non-consumptive predator impacts on aphids due to the asymmetric intensity of predation at the within-plant scale, suggesting that low numbers of predators are highly effective at suppressing aphid populations.

Environmental consequences of invasive species: greenhouse gas emissions of insecticide use and the role of biological control in reducing emissions.

Greenhouse gas emissions associated with pesticide applications against invasive species constitute an environmental cost of species invasions that has remained largely unrecognized. Here we calculate greenhouse gas emissions associated with the invasion of an agricultural pest from Asia to North America. The soybean aphid, Aphis glycines, was first discovered in North America in 2000, and has led to a substantial increase in insecticide use in soybeans. We estimate that the manufacture, transport, and application of insecticides against soybean aphid results in approximately 10.6 kg of carbon dioxide (CO2) equivalent greenhouse gasses being emitted per hectare of soybeans treated. Given the acreage sprayed, this has led to annual emissions of between 6 and 40 million kg of CO2 equivalent greenhouse gasses in the United States since the invasion of soybean aphid, depending on pest population size. Emissions would be higher were it not for the development of a threshold aphid density below which farmers are advised not to spray. Without a threshold, farmers tend to spray preemptively and the threshold allows farmers to take advantage of naturally occurring biological control of the soybean aphid, which can be substantial. We find that adoption of the soybean aphid economic threshold can lead to emission reductions of approximately 300 million kg of CO2 equivalent greenhouse gases per year in the United States. Previous studies have documented that biological control agents such as lady beetles are capable of suppressing aphid densities below this threshold in over half of the soybean acreage in the U.S. Given the acreages involved this suggests that biological control results in annual emission reductions of over 200 million kg of CO2 equivalents. These analyses show how interactions between invasive species and organisms that suppress them can interact to affect greenhouse gas emissions.

Novel and viable acetylcholinesterase target site for developing effective and environmentally safe insecticides.

Insect pests are responsible for human suffering and financial losses worldwide. New and environmentally safe insecticides are urgently needed to cope with these serious problems. Resistance to current insecticides has resulted in a resurgence of insect pests, and growing concerns about insecticide toxicity to humans discourage the use of insecticides for pest control. The small market for insecticides has hampered insecticide development; however, advances in genomics and structural genomics offer new opportunities to develop insecticides that are less dependent on the insecticide market. This review summarizes the literature data that support the hypothesis that an insect-specific cysteine residue located at the opening of the acetylcholinesterase active site is a promising target site for developing new insecticides with reduced off-target toxicity and low propensity for insect resistance. These data are used to discuss the differences between targeting the insect-specific cysteine residue and targeting the ubiquitous catalytic serine residue of acetylcholinesterase from the perspective of reducing off-target toxicity and insect resistance. Also discussed is the prospect of developing cysteine-targeting anticholinesterases as effective and environmentally safe insecticides for control of disease vectors, crop damage, and residential insect pests within the financial confines of the present insecticide market.

Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders.

Voltage-gated sodium channels (VGSCs) are key mediators of intrinsic neuronal and muscle excitability. Abnormal VGSC activity is central to the pathophysiology of epileptic seizures, and many of the most widely used antiepileptic drugs, including phenytoin, carbamazepine, and lamotrigine, are inhibitors of VGSC function. These antiepileptic drugs might also be efficacious in the treatment of other nervous system disorders, such as migraine, multiple sclerosis, neurodegenerative diseases, and neuropathic pain. In this Review, we summarise the structure and function of VGSCs and their involvement in the pathophysiology of several neurological disorders. We also describe the biophysical and molecular bases for the mechanisms of action of antiepileptic VGSC blockers and discuss the efficacy of these drugs in the treatment of epileptic and non-epileptic disorders. Overall, clinical and experimental data indicate that these drugs are efficacious for a range of diseases, and that the development of drugs with enhanced selectivity for specific VGSC isoforms might be an effective and novel approach for the treatment of several neurological diseases.