Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To try to identify the critical structures during epileptogenesis, we used the lithium-pilocarpine model that reproduces most clinical and neuropathological features of temporal lobe epilepsy (TLE). We used imaging techniques as well as a disease modifying approach and pharmacological strategy. With [14C]-2-deoxyglucose autoradiography, we assessed changes in cerebral glucose utilization. T2-weighted magnetic resonance imaging (MRI, 4.7 T) allowed follow-up of structures involved in epileptogenesis. A potential disease-modifying effect was studied using preconditioning with brief seizures (amygdala kindling, maximal electroshocks) and pharmacological strategies including vigabatrin (250 mg/kg), caffeine (0.3 g/L in drinking water), topiramate (10-60 mg/kg), pregabalin (50 mg/kg followed by 10 mg/kg), or RWJ-333369 (10-120 mg/kg). In adult and PN21 rats that became epileptic, entorhinal, and piriform cortices were the initial structures exhibiting significant signal changes on MRI scans, from 6 h after status epilepticus (SE) onset, reflecting neuronal death. In PN21 rats that did not become epileptic, no signal occurred in parahippocampal cortices. In hippocampus, MRI signal change appeared 36-48 h after SE, and progressively worsened to sclerosis. During the latent and chronic phases, the metabolic level in the hilus of adult and PN21 epileptic rats was normal although neuronal loss reached 60-75%. Protection limited to CA1 and/or CA3 (caffeine, topiramate, vigabatrin, amygdala kindling) did not affect the latency to spontaneous seizures. Protection limited to the entorhinal and piriform cortices (pregabalin) delayed epileptogenesis. The combined protection of Ammon's horn and parahippocampal cortices (RWJ-333369) prolonged the latency before the onset of seizures in a dose-dependent manner or, in some cases, prevented the epilepsy. The entorhinal and piriform cortices are critically involved in the early phase of the epileptogenesis while the hilus may initiate and/or maintain epileptic seizures. Pharmacological protection of the basal cortices is necessary for a beneficial disease-modifying effect but this must be combined with protection of the hippocampus to prevent epileptogenesis in this model of TLE.
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PMID:Pathogenesis and pharmacology of epilepsy in the lithium-pilocarpine model. 1791 May 80

Propofol (2,6-diisopropylphenol) is inadequably soluble in water and is therefore formulated as a lipid emulsion. This may have disadvantages when propofol is used to provide total intravenous anaesthesia or especially during long-term sedation. There has been considerable interest in the development of new propofol formulations or propofol prodrugs. GPI 15715 or fospropofol (Aquavan injection; Guilford Pharmaceutical, Baltimore, MD) is the first water-soluble prodrug that has been thoroughly studied in human volunteers and patients. GPI 15751 or fospropofol is cleaved by alkaline phosphatase to phosphate, formaldehyde and propofol. Formaldehyde is rapidly metabolised to formate. Although a formate accumulation is the principal pathomechanism responsible for the toxicity of methanol ingestion, so far there has been no report of toxicity due to the administration of fospropofol or other phosphate ester prodrugs, such as fosphenytoin. Fosphenytoin has been successfully introduced into the market for the treatment of status epilepticus in 1996. The main side-effects were a feeling of paraesthesia after rapid i.v. administration of GPI 15715 or fospropofol, which has also been described for fosphenytoin. The pharmacokinetics of GPI 15715 or fospropofol could be described by a combined pharmacokinetic model with a submodel of two compartments for GPI 15715 and of three compartments for propofol(G). The liberated propofol(G) compared to lipid-formulated propofol showed unexpected pharmacokinetic and pharmacodynamic differences. We found a significantly greater V(c), V(dss), significantly shorter alpha- and beta-half-life and a longer MRT (mean residence time) for propofol(G). The pharmacodynamic potency of propofol(G) appears to be higher than propofol when measured by EEG and clinical signs of hypnosis. In summary, GPI 15715 or fospropofol was well suited to provide anaesthesia or conscious sedation.
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PMID:Pharmacokinetics and pharmacodynamics of GPI 15715 or fospropofol (Aquavan injection) - a water-soluble propofol prodrug. 1817 95

Polysialylation is a post-translational modification of the neural cell adhesion molecule (NCAM), which in the adult brain promotes structural changes in regions of neurogenesis and neuroplasticity. Because a variety of plastic changes including neurogenesis have been suggested to be functionally involved in the pathophysiology of epilepsies, it is of specific interest to define the impact of the polysialic acid (PSA)-NCAM system on development of this disease and associated comorbidities. Therefore, we studied the impact of transient enzymatic depolysialylation of NCAM on the pathophysiology in an electrically induced rat post-status epilepticus (SE) model. Loss of PSA counteracted the SE-induced increase in neurogenesis in a significant manner. This effect of endoneuraminidase (endoN) treatment on hippocampal neurogenesis did not impact the subsequent development of spontaneous seizures. In contrast, transient lack of PSA during SE and in the early phase of epileptogenesis exhibited a cognition sparing effect as revealed in the Morris water maze paradigm. In conclusion, our data do not support a central role of neurogenesis in the development of a hyperexcitable epileptic network. However, in view of the cognition-sparing effect, the transient modulation of the PSA-NCAM system seems to allow beneficial long-term disease modification, which might be mediated by the partial normalization of neurogenesis.
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PMID:Targeting epileptogenesis-associated induction of neurogenesis by enzymatic depolysialylation of NCAM counteracts spatial learning dysfunction but fails to impact epilepsy development. 1819 17

The neuroprotective effects of pentoxifylline (PTX) against lithium-pilocarpine (Li-Pc)-induced status epilepticus (SE) in young rats are described. Animals treated with PTX (0, 20, 40, and 60 mg/kg) before induction of SE were examined for latency to and frequency of SE, behavioral changes, oxidative stress, neurochemical alterations in the hippocampus and striatum, and histological abnormalities in the hippocampus. Treatment with PTX significantly ameliorated the frequency and severity of epileptic seizures in a dose-dependent manner. Our behavioral studies using the elevated plus-maze, rotarod, and water maze tests suggested a significant reduction in anxiety, enhanced motor performance, and improved learning and memory in PTX-treated rats. Li-Pc-induced neuronal cell loss and sprouting of mossy fibers in the hippocampus were also attenuated by PTX. The neuroprotective activity of PTX was accompanied by reduction in oxidative stress and reversal of SE-induced depletion of dopamine and 5-hydroxytryptamine in hippocampus and striatum. The results of this study provide a good rationale to explore the prophylactic/therapeutic potential of PTX in SE.
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PMID:Pentoxifylline ameliorates lithium-pilocarpine induced status epilepticus in young rats. 1820 64

Mossy fiber sprouting (MFS) is the main characteristic of temporal lobe epilepsy (TLE), which is highly correlated with the frequencies of recurrent seizures as well as degrees of severity of TLE. A recent MRI technique, referred to as diffusion spectrum imaging (DSI), can resolve crossing fibers and investigate the intravoxel heterogeneity of water molecular diffusion. Being able to achieve higher accuracy in depicting the complex fiber architecture, DSI may help improve localization of the seizure-induced epileptic foci. In this study, two indices of DSI, which represented the mean diffusivity (MSL) and diffusion anisotropy (DA), were proposed. A correlative study between diffusion characteristics and the severity of MFS was investigated in the pilocarpine-induced status epilepticus (SE) rat model. Nine SE rats and five control rats were studied with MRI and histological Timm's staining. For MSL, no significant correlation was found in the dentate gyrus (DG), r=-0.36; p=0.2017, and positive correlation was found in cornu ammonis (CA3), r=0.62; p=0.0174. The correlation between DA and Timm's score showed positive correlation in DG, r=0.71; p=0.0047, and negative correlation in CA3, r=-0.63; p=0.0151. Our results were compatible with the previous reports on fiber architecture alterations in DG and CA3 subregions. In conclusion, the histological correspondence of DSI indices was demonstrated. With DSI indices, longitudinal follow-up of hippocampal fiber architecture can be achieved to elucidate the pathophysiology of TLE, which might be helpful in disease localization.
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PMID:Mossy fiber sprouting in pilocarpine-induced status epilepticus rat hippocampus: a correlative study of diffusion spectrum imaging and histology. 1844 34

In the hippocampus, pyramidal cells encode information in two major ways: rate coding and temporal coding. Rate coding, in which information is coded through firing frequency, is exemplarily illustrated by place cells, characterized by their location-specific firing. In addition, the precise temporal organization of firing of multiple place cells provides information, in a compressed time window, about the temporal sequence of the locations visited by the animal. This encoding is accomplished through phase precession, a phenomenon whereby unit firing is linked to theta rhythm, one of the major hippocampal EEG oscillations. Although it is likely that this type of processing is critical for normal brain function, its involvement in pathologies associated with cognitive disorders is unknown. In this experiment, we determined whether the temporal organization of place cell firing is affected in an animal model of mesial temporal lobe epilepsy (MTLE), a disease accompanied with cognitive impairment. We investigated hippocampal coding and its relationship to theta rhythm in rats after status epilepticus (SE), a condition that leads to MTLE. We found a great proportion of SE place cells had aberrant phase/precession pattern and temporal organization of firing among pairs of neurons, which constitutes the compression of temporal sequences, was altered in SE rats. The same animals were also markedly impaired in the water maze task, a measure of spatial memory. We propose that the synaptic and cellular alterations observed in MTLE induce aberrant temporal coding in the hippocampus, contributing in turn to cognitive dysfunction.
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PMID:Altered phase precession and compression of temporal sequences by place cells in epileptic rats. 1846 58

Quantitation of High Resolution Magic Angle Spinning (HRMAS) Nuclear Magnetic Resonance (NMR) signals enables establishing reference metabolite profiles of ex vivo tissues. Signals are often contaminated by a background signal originating mainly from macromolecules and lipids and by residual water which hampers proper quantitation. We show that automatic quantitation of HRMAS signals, even in the presence of a background, can be achieved by the semi-parametric algorithm QUEST based on prior knowledge of a metabolite basis-set. The latter was quantum-mechanically simulated with NMR-SCOPE and requires accurate spin parameters. The region of interest of spectra is a small part of the full spectral bandwidth. Reducing the computation time inherent to the large number of data-points is possible by using ER-Filter in a preprocessing step. Through Monte-Carlo studies, we analyze the performances of quantitation without and with ER-Filtering. Applications of QUEST to quantitation of 1H ex vivo HRMAS-NMR data of mouse brains after intoxication with soman, are demonstrated. Metabolic profiles obtained during status epilepticus and later when neuronal lesions are installed, are established. Acetate, Alanine, Choline and gamma-amino-butyric acid concentrations increase in the piriform cortex during the initial status epilepticus, when seizures are maximum; Lactate and Glutamine concentrations increase while myo-Inositol and N-acetylaspartate concentrations decrease when neuronal lesions are clearly installed.
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PMID:Quantitation with QUEST of brain HRMAS-NMR signals: application to metabolic disorders in experimental epileptic seizures. 1850 44

Diffusion-weighted magnetic resonance imaging (DW-MRI) is a novel noninvasive technique probing the Brownian motion of water molecules. It has already proved very useful in the early identification of cerebral ischemia in human patients. Although a wide spectrum of peri-ictal, postictal or interictal DW-MRI abnormalities are recently being increasingly identified, clinicians are often in a dilemma about their significance in epilepsy. This article briefly reviews the whole dynamic ADC fluctuations and the implications of hypothetical pathophysiological evolution of effected zones in prolonged seizures or status epilepticus (SE) and their potential clinical applications in epilepsy.
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PMID:Diffusion-weighted magnetic resonance imaging demonstrates parenchymal pathophysiological changes in epilepsy. 1851 17

Intense seizure activity associated with status epilepticus and excitatory amino acid (EAA) imbalance initiates oxidative damage and neuronal injury in CA1 of the ventral hippocampus. We tested the hypothesis that dendritic degeneration of pyramidal neurons in the CA1 hippocampal area resulting from seizure-induced neurotoxicity is modulated by cerebral oxidative damage. Kainic acid (KA, 1 nmol/5 microl) was injected intracerebroventricularly to C57Bl/6 mice. F2-isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NeuroPs) were used as surrogate measures of in vivo oxidative stress and biomarkers of lipid peroxidation. Nitric oxide synthase (NOS) activity was quantified by evaluating citrulline level and pyramidal neuron dendrites and spines were evaluated using rapid Golgi stains and a Neurolucida system. KA produced severe seizures in mice immediately after its administration and a significant (p<0.001) increase in F2-IsoPs, F4-NeuroPs and citrulline levels were seen 30 min following treatment. At the same time, hippocampal pyramidal neurons showed significant (p<0.001) reduction in dendritic length and spine density. In contrast, no significant change in neuronal dendrite and spine density or F2-IsoP, F4-NeuroPs and citrulline levels were found in mice pretreated with vitamin E (alpha-tocopherol, 100mg/kg, i.p.) for 3 days, or with N-tert-butyl-alpha-phenylnitrone (PBN, 200mg/kg, i.p.) or ibuprofen (inhibitors of cyclooxygenase, COX, 14 microg/ml of drinking water) for 2 weeks prior to KA treatment. These findings indicate novel interactions among free radical-induced generation of F2-IsoPs and F4-NeuroPs, nitric oxide and dendritic degeneration, closely associate oxidative damage to neuronal membranes with degeneration of the dendritic system, and point to possible interventions to limit severe damage in acute neurological disorders.
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PMID:Pharmacologic suppression of oxidative damage and dendritic degeneration following kainic acid-induced excitotoxicity in mouse cerebrum. 1855 69

Patients with temporal lobe epilepsy are frequently afflicted with psychiatric comorbidity and deficits in spatial and other forms of declarative memory. The relationship between epilepsy and psychopathology is poorly understood, so that systematic research in this area is important. In the present study, we characterized various behaviors and learning and memory in a mouse model in which major aspects of mesial temporal lobe epilepsy can be reproduced. In this model, a single unilateral injection of kainate into the dorsal hippocampus induces a nonconvulsive status epilepticus, followed by development of spontaneous recurrent seizures and ipsilateral lesions of CA1, CA3c and dentate hilus neurons. Unexpectedly, the epileptic mice exhibited only few alterations in a behavioral test battery used to investigate locomotor activity and function, emotionality, depression-related behavior and learning and memory. In contrast to recent experiments with the same test battery in epileptic mice generated by systemic administration of pilocarpine, mice with focal kainate administration did not exhibit reduced explorative behavior or increases of anxiety-related behavior. However, similar to pilocarpine-treated mice, a decrease in depression-like behavior was observed in the forced swimming test. In the Morris water maze test, kainate-treated animals exhibited retarded acquisition and impaired retention of visual-spatial information. Our data suggest that the focal kainate model of mesial temporal lobe epilepsy may contribute to understanding the neurobiological mechanisms underlying the association between epilepsy and behavioral or cognitive alterations.
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PMID:Behavioral alterations in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainate. 1858 9


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