Neuroprotective Effect of Ketamine Administered After Status Epilepticus Onset

Summary We investigated the neuroprotective effect of the noncompetitive N -methyl- d -asparatate (NMDA) antagonist ketamine when administered after onset of lithium-pilocarpine-induced status epilepticus (SE). Seizures were induced in Wistar rats with lithium chloride (3 mEq/kg) and pilocarpine (PC) (30–60 mg/kg intraperitoneally, i.p.). Fifteen minutes after SE onset, either ketamine 100 mg/kg or normal saline was injected i.p., and 3 h after SE onset atropine, diazepam (DZP), and phenobarbital (PB) were administered i.p. to terminate the seizures. Twentyfour hours later, rats underwent brain perfusion-fixation, with subsequent brain processing for light-microscopic examination. Rats administered saline (n = 5) had neuronal damage in 24 of 25 brain regions examined. Rats administered ketamine (n = 7) had significant neuroprotection in 22 of 24 damaged regions. Ketamine reduced the amplitude of seizure discharges, and in 3 rats EEG seizur activity ceased in 30 min; none of these rats had neuronal damage. In the other 4 rats, EEG seizure discharges persisted >90 min; in these animals, 21 of 24 damaged regions were protected. In contrast, rats with 1-h high-dose PC-induced SE (400 mg/kg i.p. without lithium chloride preadministration) had 14 damaged regions, of which 7 were significantly different from the undamaged regions of the ketamine subgroup with persistent electrographic seizures. Thus, ketamine is remarkably neuroprotective when administered after onset of SE, whether or not seizure discharges are eliminated.     

Characterization of status epilepticus induced by two organophosphates in rats

Organophosphates (OPs) inhibit the enzyme cholinesterase and cause accumulation of acetylcholine, and are known to cause seizures and status epilepticus (SE) in humans. The animal models of SE caused by organophosphate analogs of insecticides are not well characterized. SE caused by OPs paraoxon and diisopropyl fluorophosphate (DFP) in rats was characterized by electroencephalogram (EEG), behavioral observations and response to treatment with the benzodiazepine diazepam administered at various stages of SE. A method for SE induction using intrahippocampal infusion of paraoxon was also tested. Infusion of 200nmol paraoxon into the hippocampus caused electrographic seizures in 43/52 (82.7%) animals tested; and of these animals, 14/43 (30%) had self-sustaining seizures that lasted 4-18h after the end of paraoxon infusion. SE was also induced by peripheral subcutaneous injection of diisopropyl fluorophosphate (DFP, 1.25mg/kg) or paraoxon (1.00mg/kg) to rats pretreated with atropine (2mg/kg) and 2-pralidoxime (2-PAM, 50mg/kg) 30min prior to OP injection. SE occurred in 78% paraoxon-treated animals and in 79% of DFP-treated animals. Diazepam (10mg/kg) was administered 10min and 30min after the onset of continuous EEG seizures induced by paraoxon and it terminated SE in a majority of animals at both time points. DFP-induced SE was terminated in 60% animals when diazepam was administered 10min after the onset of continuous EEG seizure activity but diazepam did not terminate SE in any animal when it was administered 30min after the onset of continuous seizures. These studies demonstrate that both paraoxon and DFP can induce SE in rats but refractoriness to diazepam is a feature of DFP induced SE.     

Cognitive Functions After Pilocarpine-Induced Status Epilepticus: Changes During Silent Period Precede Appearance of Spontaneous Recurrent Seizures

PURPOSE: To study the possible relation between spontaneous recurrent seizures (SRS) and the derangement of cognitive memory. METHODS: Status epilepticus (SE) was induced in adult Long-Evans rats by pilocarpine (320 mg/kg, i.p.) and interrupted after 2 h by clonazepam (CZPs mg/kg, i.p.). In addition to the animals that were given pilocarpine and CZP (group P), two groups received ketamine (100 mg/kg, i.p.): the first group 15 minutes after SE onset (group K15), and the second immediately after the CZP (group K120). Control groups were formed from animals not treated with pilocarpine as well as animals that received pilocarpine but did not develop motor seizures. Spatial cognitive memory was tested in the Morris water maze. RESULTS: Testing was impossible for more than 6 days after SE in group P. Ketamine shortened this period for the two groups that received it. During the silent period, deteriorated cognitive memory progressively improved, but the performance of group P started to worsen before the appearance of SRS. Group K120 only expressed a tendency toward declining performance, whereas group K15 never developed SRS, and the behavior of these animals did not differ from that of the controls after the postseizure period was over. Histologically, massive hippocampal cell loss was seen in group P. Ketamine protected hippocampal cells in a time-dependent manner; group K15 did not exhibit any obvious necrosis in the hippocampus. CONCLUSIONS: There is no close relation between cognitive functions and the appearance of SRS, because ketamine, administered 120 min after the beginning of SE, prevented the derangment of cognitive functions but not the appearance of SRSs.     

Ketamine controls prolonged status epilepticus

New treatments are needed to control prolonged status epilepticus given the high failure rate of current therapies. In an animal model of status epilepticus based on electrical stimulation of the hippocampus, rats demonstrate at least 5 five-hours of seizure activity following stimulation. Phenobarbital (70 mg/kg) administered 15 min after stimulation effectively controlled seizures in 66% of animals (n=6). When phenobarbital (70 mg/kg) was administered 60 min after stimulation, seizures were controlled in 25% of animals (n=4). Ketamine (100 mg/kg) administered 15 min after stimulation did not control seizures in any animal (n=4). But when ketamine was administered one hour after stimulation it effectively controlled seizures in all animals (n=4). Increasing doses of ketamine were administered 60 min after stimulation to generate a dose-response curve. The ketamine dose response (fraction of seizure free rats) data were fit to a sigmoid curve to derive an ED(50) of 58 mg/kg. These findings suggest that prolonged status epilepticus becomes refractory to phenobarbital but can be effectively controlled by ketamine. For patients experiencing prolonged status epilepticus that is refractory to phenobarbital, ketamine may be an alternative to general anesthesia.     

A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation

PURPOSE: New treatments are needed for status epilepticus (SE) that is refractory to drugs modulating GABA(A) receptors, and NMDA receptor antagonists are candidate drugs. METHODS: Clinically available NMDA receptor antagonist ketamine was tested for effectiveness in terminating prolonged SE induced by a combination of lithium and pilocarpine. Animals were treated 10 min after first grade 5 behavioral seizure (Racine scoring scale) by intraperitoneal administration of ketamine, diazepam, or saline. Seizure termination was determined by electroencephalogram (EEG) recordings from the hippocampus and the cortex. RESULTS: Animals treated with normal saline or either 20 mg/kg diazepam, or 50 mg/kg ketamine continued in SE for the next 300 min. However, combined treatment with diazepam and ketamine rapidly terminated prolonged cholinergic stimulation-induced SE. Detailed study of dose response relationships demonstrated that diazepam enhanced efficacy and potency of ketamine in terminating SE. DISCUSSION: This study demonstrated synergistic action of diazepam and ketamine in terminating SE. It suggests that a ketamine-diazepam combination might be a clinically useful therapeutic option for the treatment of refractory SE.     

Ketamine anaesthesia has no effect on striatal dopamine metabolism in rats

Striatal levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid and homovanillic acid in rats were not altered for at least 6 h after a ketamine injection (100 mg/kg). Striatal DA turnover which was measured by giving alpha-methyl-p-tyrosine after ketamine was unchanged. Even the dose regimen of ketamine which anaesthetized animals for approximately 3.5 h (100 mg/kg + 5 maintenance injections of 50 mg/kg at 30 min intervals) produced no alteration in DA turnover for at least 9 h. These results suggest that ketamine anaesthesia will not adversely affect studies investigating central DAergic mechanisms in rats.     

A comparison of three NMDA receptor antagonists in the treatment of prolonged status epilepticus

Three different classes of NMDA receptor antagonists were compared for their effectiveness in terminating prolonged status epilepticus (SE), induced by continuous hippocampal stimulation. Animals were treated after 150 min of SE by intraperitoneal administration of increasing doses of 3-((R,S)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), MK-801 (dizocilpine), ifenprodil, or saline. EEG recordings were used to determine seizure termination. The first experiment (n = 57 animals) determined the most effective anticonvulsant dose of each agent by determining its ability to terminate SE within the next 300 min. Five control rats treated with normal saline after 150 min of SE continued to exhibit continuous seizures for the next 300 min. All drugs were administered after 150 min of SE. CPP terminated seizures with an ED(50) of 6.4 mg/kg; the maximal effective dose was 15 mg/kg. MK-801 has an ED(50) of 1.4 mg/kg; the maximal effective dose was 2 mg/kg. Ifenprodil was maximally effective at 30 mg/kg. However, an ED(50) could not be calculated. In a subsequent experiment, the NMDA antagonists were compared for their ability to terminate prolonged SE within 60 min of their administration at the most effective dose. MK-801 (2.0 mg/kg) terminated SE in 6 of 10 animals within 60 min, CPP (15 mg/kg) terminated it in 1 of 9 animals; ifenprodil (30 mg/kg) did not terminate it in any of 9 animals treated. In the 300 min following administration, CPP (6/9) and MK-801 (6/10) were equally efficacious in terminating SE but ifenprodil (2/7) was less effective (P = 0.065, chi-square test). The results indicate that the non-competitive NMDA receptor antagonist MK-801 was superior to the competitive antagonist CPP and the pH-sensitive site antagonist ifenprodil, in terminating prolonged experimental SE.     

A new derivative of valproic acid amide possesses a broad-spectrum antiseizure profile and unique activity against status epilepticus and organophosphate neuronal damage

Purpose: sec‐Butyl‐propylacetamide (SPD) is a one‐carbon homolog of valnoctamide (VCD), a central nervous system (CNS)–active amide derivative of valproic acid (VPA) currently in phase II clinical trials. The study reported herein evaluated the anticonvulsant activity of SPD in a battery of rodent seizure and epilepsy models and assessed its efficacy in rat and guinea pig models of status epilepticus (SE) and neuroprotection in an organotypic hippocampal slice model of excitotoxic cell death. Methods: The anticonvulsant activity of SPD was evaluated in several rodent seizure and epilepsy models, including maximal electroshock (MES), 6‐Hz psychomotor; subcutaneous (s.c.) metrazol‐, s.c. picrotoxin, s.c. bicuculline, and audiogenic, corneal, and hippocampal kindled seizures following intraperitoneal administration. Results obtained with SPD are discussed in relationship to those obtained with VPA and VCD. SPD was also evaluated for its ability to block benzodiazepine‐resistant SE induced by pilocarpine (rats) and soman (rats and guinea pigs) following intraperitoneal administration. SPD was tested for its ability to block excitotoxic cell death induced by the glutamate agonists N‐methyl‐d ‐aspartate (NMDA) and kainic acid (KA) using organotypic hippocampal slices and SE‐induced hippocampal cell death using FluoroJade B staining. The cognitive function of SPD‐treated rats that were protected against pilocarpine‐induced convulsive SE was examined 10–14 days post‐SE using the Morris water maze (MWM). The relationship between the pharmacokinetic profile of SPD and its efficacy against soman‐induced SE was evaluated in two parallel studies following SPD (60 mg/kg, i.p.) administration in the soman SE rat model. Key Findings: SPD was highly effective and displayed a wide protective index (PI = median neurotoxic dose/median effective dose [TD₅₀/ED₅₀]) in the standardized seizure and epilepsy models employed. The wide PI values of SPD demonstrate that it is effective at doses well below those that produce behavioral impairment. Unlike VCD, SPD also displayed anticonvulsant activity in the rat pilocarpine model of SE. Thirty minutes after the induction of SE, the calculated rat ED₅₀ for SPD against convulsive SE in this model was 84 mg/kg. SPD was not neuroprotective in the organotypic hippocampal slice preparation; however, it did display hippocampal neuroprotection in both SE models and cognitive sparing in the MWM, which was associated with its antiseizure effect against pilocarpine‐induced SE. When administered 20 and 40 min after SE onset, SPD (100–174 mg/kg) produced long‐lasting efficacy (e.g., 4–8 h) against soman‐induced convulsive and electrographic SE in both rats and guinea pigs. SPD ED₅₀ values in guinea pigs were 67 and 92 mg/kg when administered at SE onset or 40 min after SE onset, respectively. Assuming linear pharmacokinetics (PK), the PK–PD (pharmacodynamic) results (rats) suggests that effective SPD plasma levels ranged between 8 and 40 mg/L (20 min after the onset of soman‐induced seizures) and 12–50 mg/L (40 min after the onset of soman‐induced seizures). The time to peak (t_max) pharmacodynamic effect (PD‐t_max) occurred after the PK‐t_max, suggesting that SPD undergoes slow distribution to extraplasmatic sites, which is likely responsible for antiseizure activity of SPD. Significance: The results demonstrate that SPD is a broad‐spectrum antiseizure compound that blocks SE induced by pilocarpine and soman and affords in vivo neuroprotection that is associated with cognitive sparing. Its activity against SE is superior to that of diazepam in terms of rapid onset, potency, and its effect on animal mortality and functional improvement.     

Effect of folic acid on oxidative stress and behavioral changes in the animal model of schizophrenia induced by ketamine

Recent studies have shown benefits for the supplementation of folic acid in schizophrenic patients. The aim of this study was to evaluate the effects of folic acid addition on adult rats, over a period of 7 or 14 days. It also sets out to verify any potential protective action using an animal model of schizophrenia induced by ketamine, in behavioral and biochemical parameters. This study used two protocols (acute and chronic) for the administration of ketamine at a dose of 25 mg/kg (i.p.). The folic acid was given by oral route in doses of 5, 10 and 50 mg/kg, once daily, for 7 and/or 14 days in order to compare the protective effects of folic acid. Thirty minutes after the last administration of ketamine, the locomotor and social interaction activities were evaluated, and immediately the brain structure were removed for biochemical analysis. In this study, ketamine was administered in a single dose or in doses over the course of 7 days increasing the animal’s locomotion. This study showed that the administration of folic acid over 7 days was unable to prevent hyper locomotion. In contrast, folic acid (10 and 50 mg/kg) administrated over a period of 14 days, was able to partially prevent the hyper locomotion. Our data indicates that both acute and chronic administrations of ketamine increased the time to first contact between the animals, while the increased latency for social contact was completely prevented by folic acid (5, 10 and 50 mg/kg). Chronic and acute administrations of ketamine also increased lipid peroxidation and protein carbonylation in brain. Folic acid (10 and 50 mg/kg) supplements showed protective effects on the oxidative damage found in the different brain structures evaluated. All together, the results indicate that nutritional supplementation with folic acid provides promising results in an animal model of schizophrenia induced by ketamine.     

Suppression of Methamphetamine Self-Administration by Ketamine Pre-treatment Is Absent in the Methylazoxymethanol (MAM) Rat Model of Schizophrenia

Ketamine may prove to be a potential candidate in treating the widespread drug addiction/substance abuse epidemic among patients with schizophrenia. Clinical studies have shown ketamine to reduce cocaine and heroin cravings. However, the use of ketamine remains controversial as it may exacerbate the symptoms of schizophrenia. Therefore, the aim of this study is to characterize the effects of ketamine on drug addiction in schizophrenia using the methylazoxymethanol (MAM) acetate rat model on operant IV methamphetamine (METH) self-administration. MAM was administered intraperitoneally (22 mg/kg) on gestational day 17. Locomotor activity test and later IV self-administration (IVSA) were then performed in the male offspring followed by a period of forced abstinence and relapse of METH taking. After reaching stable intakes in the relapse phase, ketamine (5 mg/kg) was administered intraperitoneally 30 min prior to the self-administration session. As documented previously, the MAM rats showed a lack of habituation in the locomotor activity test but developed stable maintenance of METH self-administration with no difference in operant behaviour to control animals. Results show that ketamine treatment significantly reduced the METH intake in the control animals but not in MAM animals. Ketamine effect on METH self-administration may be explained by increased glutamatergic signalling in the prefrontal cortex caused by the N-methyl-D-aspartate antagonism and disinhibition of GABA interneurons which was shown to be impaired in the MAM rats. This mechanism may at least partly explain the clinically proven anti-craving potential of ketamine and allow development of more specific anti-craving medications with fewer risks.     

Neuroprotective Effect of Felbamate After Kainic Acid-Induced Status Epilepticus

Summary: Felbamate (FBM), a newly developed antiepileptic drug (AED), was previously shown to offer some neuroprotective effects against hypoxic injury in both in vivo and in vitro studies. We administered FBM (100 or 300 mg/kg) to 30-day-old rats 1 h after they received a convulsant dosage of kainic acid (KA). Animals were then tested at age 80 days in the water maze, open field, and handling tests. Seizure latency was then tested by flurothyl inhalation. Animals that received 300 mg/kg FBM performed better in all three tests and had longer latencies to flurothyl-induced seizures than did animals that received vehicle. This study suggests that FBM may have some neuroprotective effects after KA-induced status epilepticus (SE).     

Comparison of neuroprotective effects induced by alpha-phenyl-N-tert-butyl nitrone (PBN) and N-tert-butyl-alpha-(2 sulfophenyl) nitrone (S-PBN) in lithium-pilocarpine status epilepticus

The status epilepticus (SE) induced in rats by lithium-pilocarpine (Li-pilo) shares many common features with soman-induced SE including extensive limbic neuropathology. Reactive oxygen species are hypothesized to play a role in the SE induced neuropathology and we propose that the free radical scavengers alpha-phenyl-N-tert-butyl nitrone (PBN) and N-tert-butyl-alpha-(2 sulfophenyl) nitrone (S-PBN) may be neuroprotective. PBN or S-PBN were administered either immediately following pilocarpine (exposure treatment) or 5 min after the onset of SE as determined by ECoG activity. SE was allowed to continue for 3 h before termination with propofol. The rats were sacrified 24 h following pilocarpine administration. S-PBN induced minor effects to reduce SE duration and improve neurological deficit 24 h following pilocarpine administration. One hundred and fifty milligrams per kilograms PBN administered 5 min after SE onset produced significant neuroprotection in the parietal, occipital, perirhinal and piriform cortices as well as the lateral amygdala. One hundred and fifty milligrams per kilograms S-PBN was neuroprotective only in the occipital and perirhinal cortex while 300 mg/kg S-PBN exacerbated cortical neuropathology. S-PBN administered 5 min after SE onset exacerbated neuropathology in thalamic regions. In contrast, PBN and S-PBN administered as exposure treatment exacerbated neuropathology in thalamic and CA3 regions. The differential neuroprotective effects of PBN and S-PBN may be the result of the poor brain penetration by S-PBN. The results suggest that free radical scavenger activity is neuroprotective in cortical regions during cholinergic convulsions. Regional variations in drug-induced neuroprotectant activity in Li-pilo SE are common and suggest multiple mechanisms of neuropathology.     

Outcome of Status Epilepticus in Immature Rats Varies According to the Paraldehyde Treatment

Summary:  Purpose: To test effects of paraldehyde on behavioral outcome of status epilepticus (SE) in developing rats.
Methods: Motor SE was induced by LiCl-pilocarpine in rats on postnatal (P) day 12 or 25. Two hours after SE onset, animals were injected with a single dose of paraldehyde (0.07 and 0.3 ml/kg in the P12 group and 0.3 and 0.6 ml/kg in the P25 group). Effects on seizure severity and mortality were evaluated. Growth of animals and their motor abilities were monitored until the adulthood. Three months after SE, cognitive abilities were tested by using the Morris water maze.
Results: Both tested doses of paraldehyde equally affected motor seizures. Convulsions continued until the paraldehyde administration, but then they quickly subsided in all groups. During the subsequent 24 h, occasional clonic seizures occurred in P25 animals treated with the lower dose of paraldehyde. Only hyperactivity and/or automatisms were observed in the other experimental groups. Mortality was not affected by the dosage of paraldehyde. The higher dosage of paraldehyde improved recovery after SE in both age groups. No difference was found in motor abilities between controls and SE animals, except shortening of time spent on the rod in the rotarod test in the P12 group. In P25 rats, treatment with a higher dosage of paraldehyde improved learning abilities compared with the lower dosage. In the P12 group, animals treated with the lower dosage exhibited slightly impaired learning compared with controls and animals receiving the higher dosage.
Conclusions: Paraldehyde injected 2 h after SE onset modulates long-term outcome in immature rats in a dose-related manner.     

Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration

The early postnatal brain development, when many potentially sensitive processes occur, has been shown to be vulnerable to different pharmacological and environmental compounds. In the present investigation, four groups of neonatal NMRI male mice were administered the glutamate NMDA receptor antagonist ketamine (50 mg/kg, s.c.), or the GABA(A) receptor agonist diazepam (5 mg/kg, s.c.), or co-administered ketamine (50 mg/kg, s.c.) and diazepam (5 mg/kg, s.c.), or vehicle (0.9% saline, s.c.) on day 10 after birth. On day 11, mice from each treatment group were sacrificed and brains were taken for analysis of neuronal cell degeneration, using Fluoro-Jade staining technique. Ketamine, but not diazepam, induced a severe degeneration of cells in the parietal cortex. The opposite was observed for diazepam in the laterodorsal thalamus. The most pronounced cell degeneration was seen in parietal cortex of mice exposed to both ketamine and diazepam. At 2 months of age each treatment group was tested for motor activity and learning performance. Ketamine and ketamine + diazepam treated mice displayed severe deficits of habituation to the test chamber in the spontaneous motor activity test, marked deficits of acquisition learning and retention memory in the radial arm maze-learning task and less shift learning in the circular swim maze-learning task. This study indicates that the observed functional deficits can be related to cell degeneration induced during a critical stage of neonatal brain development. The potentiated apoptosis induced by ketamine and diazepam may have implications for the selection of drugs used in neonatal paediatric anaesthesia.     

Effects of NMDA receptor antagonists on visceromotor reflexes and on intestinal motility, in vivo

Antagonists of NMDA receptors can inhibit both the transmission of pain signals from the intestine and enteric reflexes. However, it is unknown whether doses of the NMDA antagonist, ketamine, that are used in anaesthetic mixtures suppress motility reflexes and visceromotor responses (VMRs). In fact, whether intestinal motility is affected by NMDA receptor blockers in vivo has been little investigated. We studied the effects of ketamine and memantine, administered intravenously or intrathecally. Rats were maintained under alpha-chloralose plus xylazine or pentobarbitone anaesthesia; VMR and jejunal motility were measured. Under alpha-chloralose/xylazine anaesthesia, i.v. ketamine inhibited VMRs at 6 mg kg h(-1), but not at 3 mg kg h(-1). It did not inhibit propulsive reflexes in the jejunum at 10 mg kg h(-1), but reduced them by 30% at 20 mg kg h(-1). Under alpha-chloralose/pentobarbitone anaesthesia, i.v. ketamine reduced propulsive reflexes at 40 mg kg h(-1) and VMR at 10 mg kg h(-1). Memantine inhibited VMRs at 20 mg kg h(-1) and propulsion at 2 mg kg h(-1). Ketamine and memantine, intrathecally, prevented VMRs, but not jejunal propulsion. We conclude that peripherally administered ketamine reduces both VMR and motility reflexes, but not at doses used in anaesthetic mixes (1.8-2.4 mg kg h(-1)). Effects on motility reflexes are likely to be due to non-NMDA receptor actions, possibly on nicotinic receptors.     

Effect of novel AMPA antagonist, NS1209, on status epilepticus. An experimental study in rat

The current first line treatment of status epilepticus (SE) is based on the use of compounds that enhance GABAergic transmission or block sodium channels. These treatments discontinue SE in only two-thirds of patients, and therefore new therapeutic approaches are needed. We investigated whether a novel water-soluble AMPA antagonist, NS1209, discontinues SE in adult rats. SE was induced by electrical stimulation of the amygdala or subcutaneous administration of kainic acid. Animals were monitored continuously with video-electroencephalography during SE and drug treatment. We found that NS1209 could be safely administered to rats undergoing electrically induced SE at doses up to 50mg/kg followed by intravenous infusion of 5mg/kg for up to 24h. NS1209 administered as a bolus dose of 10-50mg/kg (i.p. or i.v.) followed by infusion of 4 or 5mg/kg h (i.v.) for 2-24h effectively discontinued electrically induced SE in all animals within 30-60 min, and there was no recurrence of SE after a 24-h infusion. Kainate-induced SE was similarly blocked by 10 or 30 mg/kg NS1209 (i.v.). To compare the efficacy and neuroprotective effects of NS1209 with those of diazepam (DZP), one group of rats received DZP (20mg/kg, i.p. and another dose of 10 mg/kg 6h later). By using the administration protocols described, the anticonvulsant effect of NS1209 was faster and more complete than that of DZP. NS1209 treatment (20 mg/kg bolus followed by 5mg/kg h infusion for 24 h) was neuroprotective against SE-induced hippocampal neurodegeneration, but to a lesser extent than DZP. These findings suggest that AMPA receptor blockade by NS1209 provides a novel and mechanistically complimentary addition to the armamentarium of drugs used to treat SE in humans.     

Modeling epileptogenesis and temporal lobe epilepsy in a non-human primate

Here we describe a new non-human primate model of temporal lobe epilepsy (TLE) to better investigate the cause/effect relationships of human TLE. Status epilepticus (SE) was induced in adult marmosets by pilocarpine injection (250mg/kg; i.p.). The animals were divided in 2 groups: acute (8h post-SE) and chronic (3 and 5 months post-SE). To manage the severity of SE, animals received diazepam 5min after the SE onset (acute group: 2.5 or 1.25mg/kg; i.p.; chronic group/; 1.25mg/kg; i.p). All animals were monitored by video and electrocorticography to assess SE and subsequent spontaneous recurrent seizures (SRS). To evaluate brain injury produced by SE or SRS we used argyrophil III, Nissl and neo-Timm staining techniques. Magnetic resonance image was also performed in the chronic group. We observed that pilocarpine was able to induce SE followed by SRS after a variable period of time. Prolonged SE episodes were associated with brain damage, mostly confined to the hippocampus and limbic structures. Similar to human TLE, anatomical disruption of dentate gyrus was observed after SRS. Our data suggest that pilocarpine marmoset model of epilepsy has great resemblance to human TLE, and could provide new tools to further evaluate the subtle changes associated with human epilepsy.     

Enhanced efficacy of anticonvulsants when combined with levetiracetam in soman-exposed rats

Results from studies based on microinfusions into seizure controlling brain sites (area tempestas, medial septum, perirhinal cortex, posterior piriform cortex) have shown that procyclidine, muscimol, caramiphen, and NBQX, but not ketamine, exert anticonvulsant effects against soman-induced seizures. The purpose of the present study was to examine whether levetiracetam (Keppra(?)) may enhance the anticonvulsant potency of the above drugs to become optimally effective when used systemically. Levetiracetam has a unique profile in preclinical models of epilepsy and has been shown to increase the potency of other antiepileptic drugs. The rats were pretreated with pyridostigmine (0.1mg/kg) to enhance survival and received anticonvulsants 20 min after onset of seizures evoked by soman (1.15 × LD(50)). The results showed that no single drug was able to terminate seizure activity. However, when levetiracetam (LEV; 50mg/kg) was combined with either procyclidine (PCD; 10mg/kg) or caramiphen (CMP; 10mg/kg) complete cessation of seizures was achieved, but the nicotinic antagonist mecamylamine was needed to induce full motor rest in some rats. In a subsequent experiment, rats were pretreated with HI-6 (125 mg/kg) to enhance survival and treatment started 40 min following seizure onset of a soman dose of 1.6 × LD(50). LEV (50mg/kg) combined with either PCD (20mg/kg) or CMP (20mg/kg) terminated seizure activity, but the survival rate was considerably higher for LEV+PCD than LEV+CMP. Both therapies could also save the lives of rats that were about to die 5-10 min after seizure onset. Thus, the combination of LEV and PCD or CMP may make up a model of a future autoinjector being effective regardless of the time of application.