Nonlinear two-level dynamics of quantum time crystals.

A time crystal is a macroscopic quantum system in periodic motion in its ground state. In our experiments, two coupled time crystals consisting of spin-wave quasiparticles (magnons) form a macroscopic two-level system. The two levels evolve in time as determined intrinsically by a nonlinear feedback, allowing us to construct spontaneous two-level dynamics. In the course of a level crossing, magnons move from the ground level to the excited level driven by the Landau-Zener effect, combined with Rabi population oscillations. We demonstrate that magnon time crystals allow access to every aspect and detail of quantum-coherent interactions in a single run of the experiment. Our work opens an outlook for the detection of surface-bound Majorana fermions in the underlying superfluid system, and invites technological exploitation of coherent magnon phenomena - potentially even at room temperature.

Half-quantum vortices and walls bounded by strings in the polar-distorted phases of topological superfluid 3He.

Symmetries of the physical world have guided formulation of fundamental laws, including relativistic quantum field theory and understanding of possible states of matter. Topological defects (TDs) often control the universal behavior of macroscopic quantum systems, while topology and broken symmetries determine allowed TDs. Taking advantage of the symmetry-breaking patterns in the phase diagram of nanoconfined superfluid 3He, we show that half-quantum vortices (HQVs)-linear topological defects carrying half quantum of circulation-survive transitions from the polar phase to other superfluid phases with polar distortion. In the polar-distorted A phase, HQV cores in 2D systems should harbor non-Abelian Majorana modes. In the polar-distorted B phase, HQVs form composite defects-walls bounded by strings hypothesized decades ago in cosmology. Our experiments establish the superfluid phases of 3He in nanostructured confinement as a promising topological media for further investigations ranging from topological quantum computing to cosmology and grand unification scenarios.

Effect of lacosamide on structural damage and functional recovery after traumatic brain injury in rats.

In a subgroup of patients, traumatic brain injury (TBI) results in the occurrence of acute epileptic seizures or even status epilepticus, which are treated with antiepileptic drugs (AEDs). Recent experimental data, however, suggest that administration of AEDs at the early post-injury phase can compromise the recovery process. The present study was designed to assess the profile of a novel anticonvulsant, lacosamide (Vimpat) on post-TBI structural, motor and cognitive outcomes. Moderate TBI was induced by lateral fluid-percussion injury in adult rats. Treatment with 0.9% saline or lacosamide (30 mg/kg, i.p.) was started at 30 min post-injury and continued at 8h intervals for 3d (total daily dose 90 mg/kg/d). Rats were randomly assigned to 4 treatment groups: sham-operated controls treated with vehicle (Sham-Veh) or lacosamide (Sham-LCM) and injured animals treated with vehicle (TBI-Veh) or lacosamide (TBI-LCM). As functional outcomes we tested motor recovery with composite neuroscore and beam-walking at 2, 7, and 15 d post-injury. Cognitive recovery was tested with the Morris water-maze at 12-14 d post-TBI. To assess the structural outcome, animals underwent magnetic resonance imaging (MRI) at 2 d post-TBI. At 16d post-TBI, rats were perfused for histology to analyze cortical and hippocampal neurodegeneration and axonal damage. Our data show that at 2 d post-TBI, both the TBI-Veh and TBI-LCM groups were equally impaired in neuroscore. Thereafter, motor recovery occurred similarly during the first week. At 2 wk post-TBI, recovery of the TBI-LCM group lagged behind that in the TBI-VEH group (p<0.05). Performance in beam-walking did not differ between the TBI-Veh and TBI-LCM groups. Both TBI groups were similarly impaired in the Morris water-maze at 2 wk post-TBI. MRI and histology did not reveal any differences in the cortical or hippocampal damage between the TBI-Veh and TBI-LCM groups. Taken together, acute treatment with LCM had no protective effects on post-TBI structural or functional impairment. Composite neuroscore in the TBI-LCM group lagged behind that in the TBI-Veh group at 15 d post-injury, but no compromise was found in other indices of post-TBI recovery in the LCM treated animals.

Intraoperative pressure measurement in radial artery harvest. A tool with additional value?

OBJECTIVES: The radial artery is widely used as a graft in coronary artery bypass surgery (CABG). Due to its location and function it should be screened prior to harvesting to avoid ischaemic complications of the hand. In acute situations the Allen test is often the only preoperative screening method available. As has been noted earlier, a negative Allen test does not mean a non-harvestable radial artery. We endeavoured to find out whether intraoperative pressure measurement could be used as a complement while screening the radial artery. DESIGN: Ninety patients planned for elective CABG with radial artery as a conduit were examined preoperatively with the Allen test, handheld Doppler and pletysmography of the second and fourth digits. Radial artery pressure was measured intraoperatively. Symptom scale was recorded pre- and postoperatively. RESULTS: There were ten patients with a positive Allen test. The intraoperative index of radial artery pressures was 0.868 in the Allen positive group and 0.885 in the Allen negative group with no statistically significant difference (P value .68). Tolerance of exercise and cold was significantly impaired postoperatively, P values .002 and .001 respectively. No ischaemic complications occurred. CONCLUSIONS: Intraoperative pressure measurement can be used when screening radial arteries are to be harvested and no metric preoperative screening methods are available.

Pulmonary function and immediate and late outcome after coronary artery bypass surgery.

AIM: The aim of this study was to evaluate whether pulmonary function as assessed by spirometry affects the immediate and late outcome after isolated coronary artery bypass surgery (CABG). METHODS: Data on preoperative percentages of the predicted forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were retrieved from a series of 1848 patients who underwent isolated CABG. Pulmonary disease was defined according to EuroSCORE criteria. RESULTS: Logistic regression showed that percentage of predicted FVC was an independent predictor of in-hospital mortality along with estimated glomerular filtration rate, age and extracardiac arteriopathy. Cox regression analysis showed that pulmonary disease and percentages of predicted FVC were independent predictors of late overall mortality. Percentage of predicted FVC < 70% (at 10-year: 63.8% vs. 74.3%, Cox regression analysis: P = 0.014, RR 1.50, 95%C.I. 1.08-2.08) and pulmonary disease (at 10-year: 58.0% vs. 76%, Cox regression analysis: P < 0.0001, RR 1.75, 95%C.I. 1.29-2.39), but not percentage of predicted FEV1 < 70%, were associated with a marked decrease in late survival. CONCLUSION: This study confirmed the significant, negative prognostic impact of pulmonary disease on the immediate and long-term survival after isolated CABG.

Outcome after coronary artery bypass surgery with miniaturized versus conventional cardiopulmonary bypass.

We have reviewed the results of our experience with the use of miniaturized (Mini-CPB) versus conventional (C-CPB) cardiopulmonary bypass in coronary artery bypass surgery (CABG). This study included 365 patients who underwent CABG with C-CPB and 101 patients with Mini-CPB. In-hospital mortality was lower in the C-CPB group (1.4% vs. 3.0%, P = 0.38). A better, but not statistically significant, immediate outcome was observed in the C-CPB group as indicated by a shorter length of stay in the intensive care unit as well as a lower incidence of combined adverse end-point. However, this was probably due to significantly higher operative risk in the Mini-CPB group (logistic EuroSCORE: 8.5 +/- 10.0 vs. 4.6 +/- 7.1, P < 0.0001). Seventy-seven propensity score-matched pairs had similar immediate postoperative results after Mini-CPB and C-CPB (30-day mortality: 1.3% vs. 1.3%; stroke: 0% vs. 0%; intensive care unit stay > or = 5 days: 6.5% vs. 9.1%; combined adverse events: 14.3% vs. 11.7%). Mini-CPB achieves similar results to C-CPB in patients undergoing isolated CABG. The potential efficacy of Mini-CPB is expected to be more evident in high-risk patients or in complex cardiac surgery requiring much longer cardiopulmonary perfusion.

Epileptogenesis after cortical photothrombotic brain lesion in rats.

We investigated epileptogenesis after cortical photothrombotic stroke induced with Rose Bengal dye in adult Sprague-Dawley rats. To detect spontaneous seizures, video-electroencephalograms were recorded at 2, 4, 6, 8, and 10 months for 7-14 days (24 h/day). At the end, spatial and emotional learning and memory were assessed using the Morris water-maze and fear-conditioning test, respectively, and the brains were processed for histologic analysis. Seizures were detected in 18% of rats that received photothrombosis. The average seizure frequency was 0.39 seizures per recording day and mean seizure duration was 117 s. Over 60% of seizures occurred during the dark hours. Rats with photothrombotic lesions were impaired in the water-maze (P<0.05) but not in the fear-conditioning test as compared with controls. Histology revealed that lesion depth varied from cortical layers I to VI in photothrombotic rats with epilepsy. Epileptic rats had light mossy fiber sprouting in the inner molecular layer of the dentate gyrus both ipsilateral and contralateral to the lesion. This study extends the current understanding of epileptogenesis and functional impairment after cortical lesions induced by photothrombosis. Our observations support the hypothesis that photothrombotic stroke in rats is a useful animal model for investigating the mechanisms of post-stroke epileptogenesis.

A model of posttraumatic epilepsy induced by lateral fluid-percussion brain injury in rats.

Although traumatic brain injury is a major cause of symptomatic epilepsy, the mechanism by which it leads to recurrent seizures is unknown. An animal model of posttraumatic epilepsy that reliably reproduces the clinical sequelae of human traumatic brain injury is essential to identify the molecular and cellular substrates of posttraumatic epileptogenesis, and perform preclinical screening of new antiepileptogenic compounds. We studied the electrophysiologic, behavioral, and structural features of posttraumatic epilepsy induced by severe, non-penetrating lateral fluid-percussion brain injury in rats. Data from two independent experiments indicated that 43% to 50% of injured animals developed epilepsy, with a latency period between 7 weeks to 1 year. Mean seizure frequency was 0.3+/-0.2 seizures per day and mean seizure duration was 113+/-46 s. Behavioral seizure severity increased over time in the majority of animals. Secondarily-generalized seizures comprised an average of 66+/-37% of all seizures. Mossy fiber sprouting was increased in the ipsilateral hippocampus of animals with posttraumatic epilepsy compared with those subjected to traumatic brain injury without epilepsy. Stereologic cell counts indicated a loss of dentate hilar neurons ipsilaterally following traumatic brain injury. Our data suggest that posttraumatic epilepsy occurs with a frequency of 40% to 50% after severe non-penetrating fluid-percussion brain injury in rats, and that the lateral fluid percussion model can serve as a clinically-relevant tool for pathophysiologic and preclinical studies.

Electrophysiologic changes in the lateral and basal amygdaloid nuclei in temporal lobe epilepsy: an in vitro study in epileptic rats.

The functional consequences of neuronal loss during epileptogenesis in the lateral and basal amygdaloid nuclei are poorly understood. The present study tested the hypothesis that electrical responsiveness varies in different amygdaloid nuclei in the chronically epileptic amygdala. Further, we examined the amygdaloid region most prone to seizure initiation. Epileptogenesis was triggered in 20 rats by inducing status epilepticus (SE) with electrical stimulation of the lateral nucleus of the amygdala. Electrode-implanted non-stimulated rats served as controls. The occurrence and duration of spontaneous seizures were monitored with video-electroencephalography (EEG) at 8-9 weeks after SE. Thereafter, animals were killed and extracellular recordings were made from slices of both amygdalas. In the lateral nucleus of epileptic animals, the frequency of spontaneous responses was reduced compared with controls (P < 0.05). The amplitudes of evoked field responses were reduced (P < 0.01), whereas paired pulse (PP) facilitation was enhanced (P < or = 0.05). In the basal nucleus of the epileptic animals, PP facilitation was enhanced (P < 0.05) and sensitivity to 4-aminopyridine (4-AP)-induced epileptiform activity was increased compared with controls (P < 0.05). In the epileptic animals, the basal nucleus was also more sensitive than the lateral nucleus to 4-AP-induced epileptiform activity (P < 0.05). Correlation analysis indicated that longer SE duration was associated with longer half widths (P = 0.001) and smaller slopes (P < 0.05) of evoked responses as well as with attenuated PP facilitation (P<0.01). Moreover, a higher frequency of spontaneous seizures was associated with longer half widths (P < 0.05) and smaller slopes (P < 0.05) of evoked responses as well as with enhanced PP facilitation (P < 0.05). These data suggest that there is a reduced release of glutamate and reduced inhibition in the lateral and basal amygdaloid nuclei in epileptic animals. Further, the basal nucleus is more prone to epileptic activity than the lateral nucleus. Finally, the severity of SE and spontaneous seizures in vivo is associated with electrophysiologic alterations in vitro.

Perioperative stroke in coronary artery bypass patients.

BACKGROUND AND AIMS: Stroke has remained one of the most frustrating complications in coronary artery bypass surgery (CABG). The purpose of this study was to describe the incidence and correlates of stroke in CABG patients operated on in a hospital with low annual volume of open-heart surgery procedures. The aim was moreover to clarify subsequent outcome and self-reported satisfaction-based quality of life of patients who had experienced a stroke. MATERIAL AND METHODS: The material was a cohort of 1318 consecutive CABG patients operated on over a 6-year period. Data was collected prospectively but the final analysis was retrospective. Questionnaires supplemented the estimation of survival and subsequent functional status. RESULTS: The incidence of stroke was 2.6 %. Age > 70 years, chronic obstructive pulmonary disease (COPD), peripheral vascular disease (PVD), cerebral vascular disease (CVD), number of aortic anastomoses and significant atherosclerosis of the ascending aorta were univariate predictors of stroke. Postoperative stroke was experienced in 55.9% of cases delayed appearing from 2nd postoperative day on. Stroke patients had a higher rate of mortality (14.7% vs. 1.0%, p = 0.001) and poorer survival than no-stroke patients (82.4% and 97.4% at one year and 61.2% and 89.7% at six years, p < 0.001). CONCLUSIONS: The incidence of stroke seems to be on the same level in CABG patients from a low volume hospital as in reports from centres with a high volume of annual procedures. Stroke predicts higher mortality, longer intensive care unit (ICU) stay, longer hospitalisation and poorer survival. A relatively high number of stroke patients need permanent institutional care. Satisfaction-based quality of life in CABG patients also remains on a lower level in comparison to patients without neurological complications.

Administration of caspase 3 inhibitor during and after status epilepticus in rat: effect on neuronal damage and epileptogenesis.

Symptomatic temporal lobe epilepsy typically develops in three phases: brain damage --> epileptogenesis --> spontaneous seizures (epilepsy). The challenge is to prevent epileptogenesis after injury. We hypothesized that alleviation of damage by caspase inhibitors will reduce epileptogenesis or at least have disease-modifying effects (less severe epilepsy, milder cognitive decline). Epileptogenesis was triggered by amygdala stimulation-induced status epilepticus (SE) in rats and spontaneous seizures were monitored with video-electroencephalography (EEG). First, we tested the neuroprotective effect of a 1-week treatment with caspase 1, 3 or 9 inhibitors (3 micro g/d/i.c.v., started 3 h after the beginning of SE). The least damage to the hippocampus was observed in animals treated with the caspase 3 inhibitor (z-DEVD-fmk) which reduced the enzyme activity to 6% of that in the vehicle group. Thus, z-DEVD-fmk was chosen for long-term studies, in which the treatment regime remained the same except the dose was doubled (6 micro g/d/i.c.v.). Video-EEG monitoring was performed for 3 to 4 weeks, starting either 8 or 14 weeks after SE. One group of animals was tested in water-maze and fear-conditioning tests, and all animals were perfused for histological analysis. Treatment with the caspase 3 inhibitor neither prevented the development of epilepsy, nor had any disease-modifying effects. Mossy fibre sprouting, however, was reduced. The present data indicate that administration of z-DEVD-fmk monotherapy was not antiepileptogenic despite its short-term neuroprotective effects. These findings challenge the idea that prevention of cell death is the primary target for the development of antiepileptogenic compounds.

Peripheral vascular disease as predictor of outcome after coronary artery bypass grafting.

BACKGROUND AND AIMS: Understanding and objective assessment of risks is crucial in cardiac surgery. The aim of this study was to assess the influence of peripheral vascular disease (PVD) on morbidity, mortality and outcome in coronary artery bypass grafting (CABG) patients. MATERIAL AND METHODS: The ankle-brachial pressure index (ABPI) was used as indicator of PVD and was measured in 178 CABG patients. Two groups were established: 1. normal ABPI (0.9-1.3) (n = 136) and 2. lowered ABPI (< 0.9) (n = 35). The mean follow-up was 26 months. RESULTS: The presence of PVD was 20.5 %. Patients with PVD were older (p < 0.05), more often of female sex (p < 0.05), had higher Higgins's risk score (p = 0.001) and more often intermittent claudication (IC) (p < 0.001). PVD significantly predicted atrial fibrillation (FA) (p < 0.05) and relatively postoperative myocardial infarction (MI) (p = 0.058). CONCLUSIONS: The presence of PVD is relatively high in CABG patients and increases with age. PVD predicts some morbidity but seems to have fairly little influence on short-term or middle-term outcome of CABG patients. ABPI may be of only limited value in identifying patients with high operative risk in CABG.

Effect of lamotrigine treatment on status epilepticus-induced neuronal damage and memory impairment in rat.

Status epilepticus causes neuronal damage that is associated with cognitive impairment. The present study examined whether a novel antiepileptic drug, lamotrigine (LTG), alleviates status epilepticus-induced temporal lobe damage and memory impairment, and compared its efficacy with carbamazepine. Status epilepticus was induced by electric stimulation of the perforant pathway (PP) in rats. Treatment with LTG (12.5 mg/kg, twice a day) was started either 3 days before (preLTG group) or 1 h after (postLTG group) a 60 min PP stimulation. Treatment with carbamazepine (CBZ; 30 mg/kg, twice a day) was started 3 days before (CBZ group) a 60 min PP stimulation. All treatments were continued for 2 weeks. Thereafter, the severity of seizures, seizure-induced neuronal damage, quantitative electroencephalogram (EEG), and memory impairment were compared between vehicle-treated unstimulated and stimulated controls, LTG-treated rats, and CBZ-pretreated rats. Both in the preLTG and postLTG groups, damage to hilar somatostatin-immunoreactive neurons, hippocampal CA3b and CA3a pyramidal cells, and the piriform cortex was mild and did not differ from that in unstimulated controls. Furthermore, CA3c damage in the preLTG group did not differ from that in unstimulated controls. Vehicle-treated stimulated controls and CBZ-pretreated rats, however, had significant damage in the hilus, CA3 subregions, and piriform cortex compared with unstimulated controls (P<0.05 for the stimulated side, contralateral side, or both). Treatment with LTG or CBZ had no effect on the number or duration of behavioral seizures during PP stimulation. They did not affect the baseline EEG or status epilepticus-induced slowing of the EEG. Also, the status epilepticus-induced spatial memory impairment in the Morris water-maze was not attenuated by treatment with LTG or CBZ. Our data demonstrate that treatment with LTG has a mild neuroprotective effect on status epilepticus-induced neuronal damage in rats even when administered after the beginning of status epilepticus.

Chronic elevation of brain GABA levels beginning two days after status epilepticus does not prevent epileptogenesis in rats.

Vigabatrin (VGB) treatment is neuroprotective in various models of status epilepticus (SE) and delays the development of kindling via mechanisms that are assumed to relate to the elevation of GABA levels in the brain. Here, we tested the hypothesis that a chronic elevation of brain GABA levels obtained by VGB treatment prevents the development of spontaneous seizures (i.e. epilepsy) following SE in rats. Self-sustained SE (SSSE) was induced by stimulating the lateral nucleus of the amygdala. Two days later, chronic VGB (75 mg/kg/day) or saline treatment was started via subcutaneous osmotic minipumps. The development of spontaneous seizures was monitored once a week (24 h at a time) using video-EEG recording. Rats were perfused for histology either at the end of the 10-week drug treatment, or later at the end of an 8-week drug-free follow-up period. Before perfusion for histology, spatial learning and memory perform was tested in the Morris water-maze. Spontaneous seizures were observed in 55% (6/11) of the saline-treated and 73% (8/11) of the VGB-treated rats during the 10-week treatment period. Seizure frequency, severity, and duration were similar in VGB-treated rats and controls during and after the drug-treatment period. VGB treatment did not decrease neuronal damage in various temporal lobe regions or mossy fiber sprouting. VGB treatment also did not attenuate spatial learning or memory impairments. These findings indicate that the augmentation of GABAergic neurotransmission by VGB does not prevent the development of epilepsy when treatment is started 2 days after SE.

Is mossy fiber sprouting present at the time of the first spontaneous seizures in rat experimental temporal lobe epilepsy?

The contribution of mossy fiber sprouting to the generation of spontaneous seizures in the epileptic brain is under dispute. The present study addressed this question by examining whether sprouting of mossy fibers is present at the time of appearance of the first spontaneous seizures in rats, and whether all animals with increased sprouting have spontaneous seizures. Epileptogenesis was induced in 16 rats by electrically stimulating the lateral nucleus of the amygdala for 20-30 min until the rats developed self-sustained status epilepticus (SSSE). During and after SSSE, rats were monitored in long-term by continuous video-electroencephalography until they developed a second spontaneous seizure (8-54 days). Thereafter, monitoring was continued for 11 days to follow seizure frequency. The density of mossy fiber sprouting was analyzed from Timm-stained preparations. The density of hilar neurons was assessed from thionin-stained sections. Of 16 rats, 14 developed epilepsy. In epileptic rats, the density of mossy fiber sprouting did not correlate with the severity or duration (115-620 min) of SSSE, delay from SSSE to occurrence of first (8-51 days) or second (8-54 days) spontaneous seizure, or time from SSSE to perfusion (20-63 days). In the temporal end of the hippocampus, the sprouting correlated with the severity of neuronal damage (ipsilateral: r = -0.852, P < 0.01 contralateral: r = -0.748, P < 0.01). The two animals without spontaneous seizures also had sprouting. Increased density of sprouting in animals without seizures, and its association with the severity of neuronal loss was confirmed in another series of 30 stimulated rats that were followed-up with video-EEG monitoring for 60 d. Our data indicate that although mossy fiber sprouting is present in all animals with spontaneous seizures, its presence is not necessarily associated with the occurrence of spontaneous seizures.

Association between the density of mossy fiber sprouting and seizure frequency in experimental and human temporal lobe epilepsy.

PURPOSE: If the sprouting of granule cell axons or mossy fibers in the dentate gyrus is critical for the generation of spontaneous seizures in temporal lobe epilepsy (TLE), one could hypothesize that epileptic animals or humans with increased sprouting would have more frequent seizures. This hypothesis was tested by analyzing the data gathered from experimental and human epilepsy. METHODS: In experiment I (rats with "newly diagnosed" TLE), self-sustained status epilepticus was induced in rats by electrically stimulating the amygdala. Thereafter, the appearance of spontaneous seizures was monitored by continuous video-electroencephalography (EEG) until the animal developed two spontaneous seizures and for 11 d thereafter. Rats were perfused for histology, and mossy fibers were stained using the Timm method. In experiment II (rats with "recently diagnosed" TLE), status epilepticus was induced in rats and the development of seizures was monitored by video-EEG for 24 h/d every other day for 60 days. All animals were then perfused for histology. In experiment III (rats with "chronic" TLE), animals were monitored by video-EEG for 24 h/d every other day for 6 months before histologic analysis. To assess mossy fiber sprouting in human TLE, hippocampal sections from 31 patients who had undergone surgery for drug-refractory TLE were stained with an antibody raised against dynorphin. RESULTS AND CONCLUSIONS: Our data indicate that the density of mossy fiber sprouting is not associated with the total number of lifetime seizures or the seizure frequency in experimental or human TLE.

A new model of chronic temporal lobe epilepsy induced by electrical stimulation of the amygdala in rat.

Spontaneous seizures are the hallmark of human epilepsy but they do not occur in most of the epilepsy models that are used to investigate the mechanisms of epilepsy or to test new antiepileptic compounds. This study was designed to develop a new focal epilepsy model that mimics different aspects of human temporal lobe epilepsy (TLE), including the occurrence of spontaneous seizures. Self-sustained status epilepticus (SSSE) lasting for 6-20 h was induced by a 20-30 min stimulation of the lateral nucleus of the amygdala (100 ms train of 1 ms, 60 Hz bipolar pulses, 400 microA, every 0.5 s). Stimulated rats (n = 16) were monitored with a video-EEG recording system every other day (24 h/day) for 6 months, and every other video-EEG recording was analyzed. Spontaneous epileptic seizures (total number 3698) were detected in 13 of the 15 animals (88%) after a latency period of 6 to 85 days (median 33 days). Four animals (31%) had frequent (697-1317) seizures and 9 animals (69%) had occasional seizures (1-107) during the 6-months follow-up period. Fifty-seven percent of the seizures occurred during daytime (lights on 07:00-19:00 h). At the end of the follow-up period, epileptic animals demonstrated impaired spatial memory in the Morris water-maze. Histologic analysis indicated neuronal loss in the amygdala, hippocampus, and surrounding cortical areas, and mossy fiber sprouting in the dentate gyrus. The present data indicate that focal stimulation of the amygdala initiates a cascade of events that lead to the development of spontaneous seizures in rats. This model provides a new tool to better mimic different aspects of human TLE for investigation of the pathogenesis of TLE or the effects of new antiepileptic compounds on status epilepticus, epileptogenesis, and spontaneous seizures.

Neuroprotective effect of remacemide hydrochloride in a perforant pathway stimulation model of status epilepticus in the rat.

Previous studies have demonstrated that remacemide and its desglycinyl metabolite, AR-R 2495AA, reduce neuronal damage in animal models of ischemia, subarachnoid hemorrhage, and traumatic brain injury. The aim of the present study was to investigate whether remacemide hydrochloride also alleviates seizure-induced neuronal damage in a model of status epilepticus induced by the stimulation of the perforant pathway (PP) in the rat. Chronic oral remacemide treatment (3 x 25 mg/kg/day) was started either 2 days before or 2 h after the beginning of PP stimulation (2 mA, 20 Hz, 0.1 ms pulse duration for 60 min). The effects of remacemide treatment on the severity of seizures, electroencephalogram (EEG) parameters, seizure-induced neuronal damage in the temporal lobe regions, and memory impairment were compared to unstimulated and stimulated vehicle-treated controls, and carbamazepine-pre-treated (3 x 40 mg/kg/day) rats. Both remacemide and carbamazepine pretreatments, but not remacemide posttreatment, decreased pyramidal cell damage in the CA3 and CA1 subregions of the hippocampus (P < 0.05). In addition, overall neuronal damage in the extrahippocampal temporal lobe regions (the piriform cortex, entorhinal cortex, and the amygdaloid complex) was milder in remacemide-pretreated rats compared to stimulated control rats (P < 0.01). The neuroprotective effect was most evident on the side contralateral to stimulation. Remacemide or carbamazepine pretreatment had no evident effect on the number or duration of behavioral seizures during PP stimulation. Neither drug altered the spectral parameters of the baseline EEG or prevented status epilepticus-induced EEG slowing observed 2 weeks after PP stimulation. Nor did remacemide or carbamazepine treatment alleviate spatial memory impairment determined in a Morris water-maze task 2 weeks after PP stimulation. Our data provide evidence that pretreatment with remacemide has a moderate neuroprotective effect against status epilepticus-induced neuronal damage.

Effects of vigabatrin treatment on status epilepticus-induced neuronal damage and mossy fiber sprouting in the rat hippocampus.

Selective neuronal damage and mossy fiber sprouting may underlie epileptogenesis and spontaneous seizure generation in the epileptic hippocampus. It may be beneficial to prevent their development after cerebral insults that are known to be associated with a high risk of epilepsy later in life in humans. In the present study, we investigated whether chronic treatment with an anticonvulsant, vigabatrin (gamma-vinyl GABA), would prevent the damage to hilar neurons and the development of mossy fiber sprouting. Vigabatrin treatment was started either 1 h, or 2 or 7 days after the beginning of kainic acid-induced (9 mg/kg, i.p.) status epilepticus and continued via subcutaneous osmotic minipumps for 2 months (75 mg/kg per day). Thereafter, rats were perfused for histological analyses. One series of horizontal sections was stained with thionine to estimate the total number of hilar neurons by unbiased stereology. One series was prepared for somatostatin immunohistochemistry and another for Timm histochemistry to detect mossy fiber sprouting. Our data show that vigabatrin treatment did not prevent the decrease in the total number of hilar cells, nor the decrease in hilar somatostatin-immunoreactive (SOM-ir) neurons when SOM-ir neuronal numbers were averaged from all septotemporal levels. However, when vigabatrin was administered 2 days after the onset of status epilepticus, we found a mild neuroprotective effect on SOM-ir neurons in the septal end of the hippocampus (92% SOM-ir neurons remaining; P < 0.05 compared to the vehicle group). Vigabatrin did not prevent mossy fiber sprouting regardless of when treatment was started. Rather, sprouting actually increased in the septal end of the hippocampus when vigabatrin treatment began 1 h after the onset of status epilepticus (P < 0.05 compared to the vehicle group). Our data show that chronic elevation of brain GABA levels after status epilepticus does not have any substantial effects on neuronal loss or mossy fiber sprouting in the rat hippocampus.