Interictal aggression in rats with chronic seizures after an early life episode of status epilepticus.

OBJECTIVE: In spite of anecdotal reports describing an association between chronic epilepsy and interictal aggressiveness, and of a few studies suggesting that such an association is common in temporal lobe epilepsy, this concept has not been generally accepted by epileptologists. In the course of studies of the long-term consequences of limbic status epilepticus (SE) in juvenile rats, we noticed that experimental animals, unlike littermate controls, could not be housed together because of severe fighting. We now report a study of interictal aggression in those rats. METHODS: Long-term behavioral consequences of lithium/pilocarpine SE were studied 3 months after SE had been induced with lithium and pilocarpine in male Wistar rats at age 28 days. Chronic spontaneous seizures developed in 100% of animals. We tested rats for territorial aggression under the resident-intruder paradigm. We measured the number of episodes of dominance (mounting and pinning), and agonistic behavior (attacks, boxing, and biting). RESULTS: Untreated lithium/pilocarpine SE induced a large increase in aggressive behavior, which involved all aspects of aggression in the resident-intruder paradigm when tested 3 months after SE. The experimental rats were dominant toward the controls, as residents or as intruders, and showed episodes of biting and boxing rarely displayed by controls. They also displayed increased aggressiveness compared with controls when tested against each other. SIGNIFICANCE: This robust model offers an opportunity to better understand the complex relationship between seizures, epilepsy, and aggression, and the role of age, SE vs. recurrent spontaneous seizures, and focal neuronal injury in the long-term behavioral effects of SE.

Potential impact of diphacinone application strategies on secondary exposure risk in a common rodent pest: implications for management of California ground squirrels.

Anticoagulant rodenticides are a common tool used to manage rodents in agricultural systems, but they have received increased scrutiny given concerns about secondary exposure in non-target wildlife. Rodenticide application strategy is one factor that influences exposure risk. To understand the impact of application strategy, we tested residues of a first-generation anticoagulant (diphacinone) in liver tissue of radiotransmittered California ground squirrels (Otospermophilus beecheyi) following spot treatments, broadcast applications, and bait station applications in rangelands in central California during summer and autumn 2018-2019. We also documented the amount of bait applied, the mean time from bait application until death, and the proportion of ground squirrels that died belowground. We documented the greatest amount of bait applied via bait stations and the least by broadcast applications. We did not document a difference in diphacinone residues across any application strategy, although survivors had an order of magnitude lower concentration of diphacinone than mortalities, potentially lowering secondary exposure risk. We did not observe any difference among bait delivery methods in time from bait application to death, nor did we identify any impact of seasonality on any of the factors we tested. The vast majority of mortalities occurred belowground (82-91%), likely reducing secondary exposure. Secondary exposure could be further reduced by daily carcass searches. Results from this study better define risk associated with first-generation anticoagulant rodenticide applications, ultimately assisting in development of management programs that minimize non-target exposure.

Rational polytherapy in the treatment of cholinergic seizures.

The initiation and maintenance phases of cholinergic status epilepticus (SE) are associated with maladaptive trafficking of synaptic GABAA and glutamate receptors. The resulting pharmacoresistance reflects a decrease in synaptic GABAA receptors and increase in NMDA and AMPA receptors, which tilt the balance between inhibition and excitation in favor of the latter. If these changes are important to the pathophysiology of SE, both should be treated, and blocking their consequences should have therapeutic potential. We used a model of benzodiazepine-refractory SE (RSE) (Tetz et al., 2006) and a model of soman-induced SE to test this hypothesis. Treatment of RSE with combinations of the GABAAR agonists midazolam or diazepam and the NMDAR antagonists MK-801 or ketamine terminated RSE unresponsive to high-dose monotherapy with benzodiazepines, ketamine or other antiepileptic drugs (AEDs). It also reduced RSE-associated neuronal injury, spatial memory deficits and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of sc soman-induced SE similarly showed much greater reduction of EEG power by a combination of midazolam with ketamine, compared to midazolam monotherapy. When treating late (40 min after seizure onset), there may not be enough synaptic GABAAR left to be able to restore inhibition with maximal GABAAR stimulation, and further benefit is derived from the addition of an AED which increases inhibition or reduces excitation by a non-GABAergic mechanism. The midazolam-ketamine-valproate combination is effective in terminating RSE. 3-D isobolograms demonstrate positive cooperativity between midazolam, ketamine and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index is increased by combination therapy between GABAAR agonist, NMDAR antagonist and selective AEDs. We compared this drug combination based on the receptor trafficking hypothesis to treatments based on clinical practice. The midazolam-ketamine-valproate combination is far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines. Furthermore, sequential administration of midazolam, ketamine and valproate is far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that we should re-evaluate our traditional treatment of RSE, and that treatment should be based on pathophysiology. The search for a better drug has to deal with the fact that most monotherapy leaves half the problem untreated. The search for a better benzodiazepine should acknowledge the main cause of pharmacoresistance, which is loss of synaptic GABAAR. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm.

Early polytherapy for benzodiazepine-refractory status epilepticus.

The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABAA) and glutamate receptors. The receptor trafficking hypothesis proposes that these changes are key events in the development of pharmacoresistance to antiepileptic drugs (AEDs) during SE, and that blocking their expression will help control drug-refractory SE (RSE). We tested this hypothesis in a model of SE induced by very high-dose lithium and pilocarpine (RSE), and in a model of SE induced by sc soman. Both models are refractory to benzodiazepines when treated 40 min after seizure onset. Our treatments aimed to correct the loss of inhibition because of SE-associated internalization of synaptic GABAA receptors (GABAAR), using an allosteric GABAAR modulator, sometimes supplemented by an AED acting at a nonbenzodiazepine site. At the same time, we reduced excitation because of increased synaptic localization of NMDA and AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate) receptors (NMDAR, AMPAR (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, N-methyl-D-aspartate receptors)) with an NMDAR channel blocker, since AMPAR changes are NMDAR-dependent. Treatment of RSE with combinations of the GABAAR allosteric modulators midazolam or diazepam and the NMDAR antagonists dizocilpine or ketamine terminated RSE unresponsive to high-dose monotherapy. It also reduced RSE-associated neuronal injury, spatial memory deficits, and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of soman-induced SE also reduced seizures, behavioral deficits, and epileptogenesis. Addition of an AED further improved seizure outcome in both models. Three-dimensional isobolograms demonstrated positive cooperativity between midazolam, ketamine, and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index was increased by combination therapy. The midazolam-ketamine-valproate combination based on the receptor trafficking hypothesis was far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines for the treatment of SE. Furthermore, sequential administration of midazolam, ketamine, and valproate was far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that treatment of RSE should be based at least in part on its pathophysiology. The search for a better treatment should focus on the cause of pharmacoresistance, which is loss of synaptic GABAAR and gain of synaptic glutamate receptors. Both need to be treated. Monotherapy addresses only half the problem. Improved pharmacokinetics will not help pharmacoresistance because of loss of receptors. Waiting for one drug to fail before giving the second drugs gives pharmacoresistance time to develop. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

An assessment of vegetation management practices and burrow fumigation with aluminum phosphide as tools for managing voles within perennial crop fields in California, USA.

Voles (Cricetidae) cause extensive damage to a variety of crops throughout much of the Northern Hemisphere. The removal of vegetation from crop fields at the end of the growing season, combined with a subsequent burrow fumigant application of aluminum phosphide, has the potential to substantially curtail vole activity but has not been thoroughly examined. We set up a study to test the impact of these management tools in perennial globe artichoke (Cynara cardunculus var. scolymus) fields in Monterey County, CA, during 2010 and 2011, to determine their potential utility as part of an integrated pest management (IPM) program for managing California voles (Microtus californicus). We used both chewing indices and mortality estimates derived via radiotelemetry to assess the efficacy of aboveground vegetation removal and aluminum phosphide applications on vole abundance. We determined the impact of plowing artichoke fields on vole activity as well. Both removal of vegetation and applications of aluminum phosphide substantially reduced vole presence within treated fields. Plowing also reduced vole abundance to the point of little residual activity following treatment. These management practices appear to be effective at eliminating voles from crop fields. Combining these tools with management practices designed to slow down reinvasion by neighboring vole populations (e.g., barriers, repellents, traps) has the potential to substantially reduce farmer reliance on rodenticides for vole management, although rodenticides will still be needed to curtail populations that reestablish within crop fields. Such an IPM approach should substantially benefit both farmers and agro-ecosystems.

Pursuing Age-Friendly University (AFU) principles at a major university: Lessons in grassroots organizing.

Population aging presents challenges and opportunities that Michigan State University (MSU) is now taking on in a strategic way, but it has been a long road to reach a major milestone of establishing a program called AgeAlive. AgeAlive builds on fifty years of advocacy for coordinated aging-related programming and a more current grassroots effort that has led to a commitment to building an aging network connecting research, education, and outreach efforts based on Age-Friendly University principles. This case study describes AgeAlive's path from inception to a recognized program with a clear vision and strategic plan. Concrete goals include a complete inventory of aging-related activity on campus, a virtual hub for networking and information exchange, educational opportunities for students and elders, and building new retirement pathways. The MSU experience may benefit others interested in developing similar programs by offering strategies for moving forward amidst challenges inherent in large-scale, research-intensive institutions.

Efficacy and nontarget impact of zinc phosphide-coated cabbage as a ground squirrel management tool.

BACKGROUND: Effective management of ground squirrels relies on an integrated pest management (IPM) approach. Rodenticides may be included in an IPM program, but they must be efficacious with minimal impact on nontarget species. A zinc phosphide-coated green bait may meet these requirements. We established a study in northeastern California to test zinc phosphide-coated cabbage as a management tool for Belding's ground squirrels (Urocitellus beldingi). We specifically addressed factors that would influence the efficacy of a baiting program, as well as potential exposure risk to nontarget species. RESULTS: We found that prebaiting was an important application strategy, and efficacy increased as ground squirrel abundance increased. Efficacy was also greater in western portions of the study area, likely due to greater bait consumption at western sites. Belding's ground squirrels fed most heavily on cabbage during mid-morning and late afternoon; bait applications shortly before these time periods would increase bait consumption while minimizing nontarget risk. Bait uptake was greatest around burrow entrances. The only nontarget species observed feeding on cabbage was the California kangaroo rat (Dipodomys californicus), although they were never observed feeding on treated cabbage. CONCLUSION: Zinc phosphide-coated cabbage can be an efficacious tool for managing ground squirrels, but there will be limitations on where and how it can be used effectively. It posed a low risk to nontarget species present in our study area, but nontarget risk could vary regionally. The use of a zinc phosphide-coated green bait should only be one part of an IPM strategy for managing ground squirrels. © 2019 Society of Chemical Industry.

Simultaneous triple therapy for the treatment of status epilepticus.

Early maladaptive internalization of synaptic GABAA receptors (GABAAR) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABAAR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAAR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE-induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABAAR and NMDAR trafficking can reduce the severity of SE and its long-term consequences.

Treatment of experimental status epilepticus with synergistic drug combinations.

During status epilepticus (SE), synaptic γ-aminobutyric acid A receptors (GABAA Rs) become internalized and inactive, whereas spare N-methyl-d-aspartate receptors (NMDARs) assemble, move to the membrane, and become synaptically active. When treatment of SE is delayed, the number of synaptic GABAA Rs is drastically reduced, and a GABAA agonist cannot fully restore inhibition. We used a combination of low-dose diazepam (to stimulate the remaining GABAA Rs), ketamine (to mitigate the effect of the NMDAR increase), and valproate (to enhance inhibition at a nonbenzodiazepine site) to treat seizures in a model of severe cholinergic SE. High doses of diazepam failed to stop electrographic SE, showing that benzodiazepine pharmacoresistance had developed. The diazepam-ketamine-valproate combination was far more effective in stopping SE than triple-dose monotherapy using the same individual drugs. Isobolograms showed that this drug combination's therapeutic actions were synergistic, with positive cooperativity between drugs, whereas drug toxicity was simply additive, without positive or negative cooperativity. As a result, the therapeutic index was improved by this drug combination compared to monotherapy. These results suggest that synergistic drug combinations that target receptor changes can control benzodiazepine-refractory SE.

Novel and current rodenticides for pocket gopher Thomomys spp. management in vineyards: what works?

BACKGROUND: Rodenticides are often included as part of an integrated pest management approach for managing pocket gophers (Thomomys spp.) given that they are relatively quick and inexpensive to apply. Strychnine has historically been the most effective toxicant for pocket gophers, but its use is currently limited in the United States; alternative registered toxicants have not proven effective. Recent research with baits containing cholecalciferol plus anticoagulant toxicants proved effective against pocket gophers in a lab setting. Therefore, we established a field study to compare cholecalciferol plus anticoagulant combinations [0.03% cholecalciferol plus 0.005% diphacinone (C + D), 0.015% cholecalciferol plus 0.0025% brodifacoum (C + B1), 0.03% cholecalciferol plus 0.0025% brodifacoum (C + B2)] with strychnine (0.5%) for pocket gopher management. RESULTS: Strychnine treatments resulted in 100% efficacy after two treatment periods. Both C + D and C + B2 resulted in efficacy significantly greater than 70% after two treatment periods (83 and 75% respectively). Efficacy from C + B1 (85%) was not significantly greater than 70%, but did yield high overall efficacy as well. CONCLUSION: Although strychnine remains the most effective rodenticide for pocket gopher control, the cholecalciferol plus anticoagulant baits tested would be a good alternative when strychnine is unavailable. C + D may be the best option given that it uses a first-generation anticoagulant as the synergist. © 2016 Society of Chemical Industry.

Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits.

OBJECTIVE: Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic γ-aminobutyric acid A (GABAA ) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences. METHODS: A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits. RESULTS: Midazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits. SIGNIFICANCE: This study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.

Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment.

Cholinergic status epilepticus (CSE) quickly becomes self-sustaining, independent of its initial trigger, and resistant to benzodiazepines and other antiepileptic drugs. We review a few of the many physiological changes associated with CSE, with an emphasis on receptor trafficking. Time-dependent internalization of synaptic γ-aminobutyric acid (GABA)A receptors explains, in part, the loss of inhibition and the loss of response to benzodiazepines in the early stages of CSE. The increase in N-methyl-d-aspartate receptors may contribute to the runaway excitation and excitotoxicity of CSE. These changes have therapeutic implications. The time-dependent increase in maladaptive changes points to the importance of early treatment. The involvement of both inhibitory and excitatory systems challenges current therapeutic guidelines, which recommend treating only one system, and questions the rationale for monotherapy. It suggests that polytherapy may be needed, especially when treatment is delayed, so that drugs can only reach a much reduced number of GABAA receptors. Finally, it raises the possibility that the current practice of waiting for one treatment to fail before starting the next drug may need to be reevaluated.

Deep hypothermia for the treatment of refractory status epilepticus.

In a rat model of status epilepticus (SE) induced by lithium and pilocarpine and refractory to midazolam, deep hypothermia (20 °C for 30 min) reduced EEG power over 50-fold, stopped SE within 12 min, and reduced EEG spikes by 87%. Hypothermia deserves further investigation as a treatment of last resort for refractory SE. This article is part of a Special Issue entitled "Status Epilepticus".

Neuroprotective effects of deep hypothermia in refractory status epilepticus.

OBJECTIVE: Pharmacoresistance develops quickly during repetitive seizures, and refractory status epilepticus (RSE) remains a therapeutic challenge. The outcome of RSE is poor, with high mortality and morbidity. New treatments are needed. Deep hypothermia (20°C) is used clinically during reconstructive cardiac surgery and neurosurgery, and has proved safe and effective in those indications. We tested the hypothesis that deep hypothermia reduces RSE and its long-term consequences. METHODS: We used a model of SE induced by lithium and pilocarpine and refractory to midazolam. Several EEG measures were recorded in both hypothermic (n = 17) and normothermic (n = 20) animals. Neuronal injury (by Fluoro-Jade B), cell-mediated inflammation, and breakdown of the blood-brain barrier (BBB) (by immunohistochemistry) were studied 48 h following SE onset. RESULTS: Normothermic rats in RSE seized for 4.1 ± 1.1 h, and at 48 h they displayed extensive neuronal injury in many brain regions, including hippocampus, dentate gyrus, amygdala, entorhinal and pyriform cortices, thalamus, caudate/putamen, and the frontoparietal neocortex. Deep hypothermia (20°C) of 30 min duration terminated RSE within 12 min of initiation of hypothermia, reduced EEG power and seizure activity upon rewarming, and eliminated SE-induced neuronal injury in most animals. Normothermic rats showed widespread breakdown of the BBB, and extensive macrophage infiltration in areas of neuronal injury, which were completely absent in animals treated with hypothermia. INTERPRETATION: These results suggest that deep hypothermia may open a new therapeutic avenue for the treatment of RSE and for the prevention of its long-term consequences.

Perceived damage and areas of needed research for wildlife pests of California agriculture.

Many wildlife species cause extensive damage to a variety of agricultural commodities in California, with estimates of damage in the hundreds of millions annually. Given the limited availability of resources to solve all human-wildlife conflicts, we should focus management efforts on issues that provide the greatest benefit to agricultural commodities in California. This survey provides quantitative data on research needs to better guide future efforts in developing more effective, practical and appropriate methods for managing these species. We found that ground squirrels, pocket gophers, birds, wild pigs, coyotes and voles were the most common agricultural wildlife pest species in California. The damage caused by these species could be quite high, but varied by agricultural commodity. For most species, common forms of damage included loss of crop production and direct death of the plant, although livestock depredation was the greatest concern for coyotes. Control methods used most frequently and those deemed most effective varied by pest species, although greater advancements in control methods were listed as a top research priority for all species. Collectively, the use of toxicants, biocontrol and trapping were the most preferred methods for control, but this varied by species. In general, integrated pest management practices were used to control wildlife pests, with a special preference for those approaches that were efficacious and quick and inexpensive to apply. This information and survey design should be useful in establishing research and management priorities for wildlife pest species in California and other similar regions.

Effectiveness of rodenticides for managing invasive roof rats and native deer mice in orchards.

Roof rats (Rattus rattus) and deer mice (Peromyscus maniculatus) are occasional pests of nut and tree fruit orchards throughout California and in many other parts of the USA and beyond. In general, the most practical and cost-effective control method for rodents in many agricultural environments is the use of rodenticides (toxic baits), but little or no information exists on the efficacy of current rodenticides in controlling roof rats and deer mice in orchards. Therefore, our goals were to develop an index of rodent activity to monitor efficacy of rodenticides and to subsequently test the efficacy of three California Department of Food and Agriculture rodenticide baits (0.005 % chlorophacinone treated oats, 0.005 % diphacinone treated oats, and 0.005 % diphacinone wax block) to determine their utility for controlling roof rats and deer mice in agricultural orchards. We determined that a general index using the number of roof rat photos taken at a minimum of a 5-min interval was strongly correlated to the minimum number known estimate of roof rats; this approach was used to monitor roof rat and deer mouse populations pre- and post-treatment. Of the baits tested, the 0.005 % diphacinone treated oats was most effective for both species; 0.005 % chlorophacinone grain was completely ineffective against roof rats. Our use of elevated bait stations proved effective at providing bait to target species and should substantially limit access to rodenticides by many non-target species.

Trafficking of NMDA receptors during status epilepticus: therapeutic implications.

We used two models of status epilepticus (SE) to study trafficking of N-methyl-d-aspartate (NMDA) receptors. SE is associated with increased surface expression of NR1 subunits of NMDA receptors, and with an increase of NMDA synaptic and extrasynaptic currents suggesting an increase in number of functional NMDA receptors on dentate granule cells. The therapeutic implications of these results are discussed.

Rational polytherapy in the treatment of acute seizures and status epilepticus.

We used a model of severe cholinergic status epilepticus (SE) to study polytherapy aimed at reversing the effects of seizure-induced loss of synaptic GABA(A) receptors and seizure-induced gain of synaptic NMDA receptors. Combinations of a benzodiazepine with ketamine and valproate, or with ketamine and brivaracetam, were more effective and less toxic than benzodiazepine monotherapy in this model of SE.

GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models.

Galanin receptors type 1 (GalR1) and/or type 2 (GalR2) represent unique pharmacological targets for treatment of seizures and epilepsy. Previous studies have shown that the endogenous peptide ligand galanin exerts powerful anticonvulsant effect through activation of these two G protein-coupled receptors, which are highly expressed in the temporal lobe of rodent brain. Here we report the characterization of a putative GalR2-positive allosteric modulator CYM2503. CYM2503 potentiated the galanin-stimulated IP1 accumulation in HEK293 cells stably expressing GalR2 receptor, whereas it exhibited no detectable affinity for the (125)I galanin-binding site of GalR2 receptor, an effect consistent with that of a positive allosteric modulator. In the rat Li-pilocarpine status epilepticus model, CYM2503, injected intraperitoneally, increased the latency to first electrographic seizure and the latency to first stage 3 behavioral seizure, decreased the latency to the establishment of status epilepticus, and dramatically decreased the mortality. In a Li-pilocarpine seizure model in mice, CYM2503 increased the latency to first electrographic seizure and decreased the total time in seizure. CYM2503 also attenuated electroshock-induced seizures in mice. Thus, CYM2503 provides a starting point for the development of anticonvulsant therapy using the galanin R2 receptor as target.

Anticonvulsant effects of Searsia dentata (Anacardiaceae) leaf extract in rats.

Searsia species are used in South Africa to treat epilepsy. Previous studies have demonstrated an in vitro N-methyl-D-aspartic acid (NMDA) receptor antagonistic effect of the ethanolic leaf extract. The aim of this study was to evaluate the potential anticonvulsant properties of the ethanolic extract of S. dentata in various animal models of epilepsy. The extract was submitted to a screening in anticonvulsant assays including NMDA-, kainic acid (KA)-, pentylenetetrazol (PTZ)- and bicuculline (BIC)-induced seizures in rats. The extract protected 47% of the PN 18 Wistar pups (postnatal day 18, date of birth PN 0) (p < 0.05, n > 10) against NMDA-induced seizures and significantly delayed the onset of PTZ-induced seizures (p < 0.05, n > 8) at a dose of 250 mg/kg. A dose optimum was detected at 500 mg/kg for protection against KA-(63% protection, p < 0.05, n > 8) and BIC-induced seizures (50% protection, p < 0.05, n > 8) in young adult and PN 18 rats, respectively. The ethanolic extract of S. dentata showed anticonvulsive properties in several models of epilepsy. These results are compatible with previous findings of NMDA receptor antagonism. Due to the complex composition of the extract, the effect might be caused by more than one compound.