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)

Pilocarpine (PILO) induces in rats limbic seizures that become secondarily generalized and evolve to status epilepticus (SE). Spontaneous recurrent seizures are registered during the long-term period following the systemic administration of PILO in rats. EEG, behavioral, and pathological features resemble those of complex partial seizures. The antiepileptic drugs (AEDs) diazepam, phenobarbital (PB), valproic acid (VPA) and trimethadione protect against PILO-induced SE while phenytoin (PHT) and carbamazepine (CBZ) are ineffective. Studies with AEDs on spontaneous seizures (chronic period) of this model have not yet been established. We now report the effects of different AEDs on spontaneous seizures. Male Wistar rats were subjected to PILO-induced SE. Following recovery from SE animals were daily observed in order to detect spontaneous seizures and to establish the baseline seizure frequency. PB 40 mg/kg, PHT 100 mg/kg, CBZ 120 mg/kg, VPA (450 mg/kg and 600 mg/kg) and ethosuximide (ETX) 400 mg/kg were given daily to epileptic rats for two weeks during the spontaneous recurrent seizures period. PB, CBZ and PHT were effective against spontaneous seizures. VPA was also effective against spontaneous seizures at the dose of 600 mg/kg and ETX was inactive against these seizures. Such pharmacological profiles correlate well with complex partial seizures. The results indicate that spontaneous recurrent seizures after PILO-induced SE may be a useful model for finding new AEDs with better efficacy against complex partial seizures. The use of animal models that share both pharmacological and phenomenological features with human epilepsy might improve their predictive value for specific types of human epilepsy.
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PMID:Effects of conventional antiepileptic drugs in a model of spontaneous recurrent seizures in rats. 775 May 14

Pilocarpine administration to lithium chloride-pretreated rats results initially in discrete convulsive seizures, each behaviorally and electroencephalographically terminated, which then progress to convulsive activity with waxing-and-waning behavioral and electrographic severity; finally, a continuous convulsive state ensues, associated electrographically with continuous fast spiking. This stage does not last indefinitely but is followed by a dramatic electrographic change to periodic epileptiform discharges. The purpose of the present study was to determine with the 14C-2-deoxyglucose functional mapping technique what changes occur in the seizure anatomic substrate during and after this transition, in order to enable inferences about underlying mechanisms. Behavior associated with early and late continuous fast spiking consisted of head twitching; corresponding deoxyglucose autoradiographs displayed seizure-induced intense glucose utilization in most forebrain areas; extranigral brainstem was normal. At 2-3 h of status, fast spiking became interrupted by flat periods; periodic complexes soon dominated the electroencephalogram. Behaviorally, convulsive severity increased. Despite this dramatic electrographic evolution, little change in generalized forebrain metabolic hyperactivation occurred, except that the zona incerta/pretectal/superior colliculus complex displayed markedly increased activity. Deoxyglucose studies in late stages of periodic epileptiform discharges established a sequence of further changes. In late periodic discharges with clonic jerks, at 4 h after status entry, generalized forebrain hyperactivation still prevailed, but to a lesser degree than in early periodic discharges with clonic jerks. At a still later stage, late periodic discharges, subtle convulsive, autoradiographs revealed constriction of the seizure-activated anatomic substrate: hyperactivation was lost in most of neocortex and thalamus, and in caudal olfactory structures, cortical amygdala, and entorhinal areas, but retained in deep occipital cortex and many limbic areas. In the last stage, late periodic discharges, electrical, not associated with convulsive behavior, autoradiographs revealed residual activation in only Ammon's horn; in contrast, much of the forebrain displayed below-normal glucose utilization. These results demonstrate that in the later stages of status epilepticus, the transition from fast spiking to periodic complexes is not associated with a reduction in the seizure anatomic substrate. The electrographic entity of periodic epileptiform discharges is not anatomically or behaviorally homogeneous, but proceeds through successive stages characterized initially by a reduction of glucose utilization within generalized seizure-activated forebrain, then a contraction of the seizure anatomic substrate. Possible mechanisms underlying the transition to periodic complexes are discussed.
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PMID:Functional mapping of the late stages of status epilepticus in the lithium-pilocarpine model in rat: a 14C-2-deoxyglucose study. 775 76

Pilocarpine (PILO) administered to rats acutely induces status epilepticus (acute period), which is followed by a transient seizure-free period (silent period), and finally by a chronic phase of spontaneous recurrent seizures (chronic period, SRS) that lasts for the rest of animal's life. Hippocampal neurochemical changes following PILO administration include alteration in monoamines and amino acids content during all phases of this epilepsy model. The present work was delineated to study the content of prostaglandins (PG) levels in hippocampus during the three phases of this model. The levels of PG E2, PG F2 alpha and PG D2 were measured by radioimmunoassay 1 h after PILO, 5 h after PILO, during the silent period, and interictally into the chronic period. The results show, in hippocampus of rats, increase of PG F2 alpha and PG D2 during status epilepticus, increase of PG D2 during the silent period and increase of PG E2 and PG D2 during the chronic phase, when compared with control group. These changes match previously reported alteration in monoamines and amino acid levels, showing that altered neurotransmission is accompanied by changes in second messengers and enzyme activity related to PG production during all phases of the epilepsy model.
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PMID:Profile of prostaglandin levels in the rat hippocampus in pilocarpine model of epilepsy. 857 74

Systemic administration of pilocarpine (400 mg/kg i.p.) or intrahippocampal injection of carbachol (100 micrograms/1 microliters) induced limbic motor seizures in rats, characterized by head weaving and paw treading, rearing and falling, and forepaw myoclonus, developing into status epilepticus. After being in status for 30 min, rats were killed and levels of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined in eight brain regions by high performance liquid chromatography. Pilocarpine-induced seizures significantly elevated dopamine in the striatum, and in both dorsal and ventral aspects of the hippocampus, but did not affect dopamine in substantia nigra, nucleus accumbens, olfactory tubercle, cingulate cortex or amygdala. Metabolite levels were increased in striatum, substantia, nigra, nucleus accumbens and cingulate cortex, and fell in the hippocampus, but remained unchanged in the olfactory tubercle and amygdala. Intrahippocampal carbachol significantly raised the dopamine contents of striatum and nigra, and in both ventral and dorsal aspects of the hippocampus, but not elsewhere. DOPAC and/or HVA were elevated in all brain regions tested, save for amygdala and dorsal hippocampus. These changes translated into seizure-induced increases in dopamine utilization in the nucleus accumbens, olfactory tubercle and cingulate cortex, and to a fall in dopamine utilisation in the hippocampus, with no net change in amygdala. In addition pilocarpine (but not carbachol) increased dopamine utilization in the nigrostriatal axis, possibly through a seizure-unrelated mechanism. The relevance of these findings to seizure development are discussed.
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PMID:Regional changes in brain dopamine utilization during status epilepticus in the rat induced by systemic pilocarpine and intrahippocampal carbachol. 873 84

Pilocarpine injection into rodents leads to the development of chronic limbic seizures that follow an initial status epilepticus and a seizure-free interval. It has been proposed that a decreased efficacy of the mechanisms that buffer the extracellular concentration of K+ ([K+]o) leads to an increase in seizure susceptibility. Therefore, we analyzed the changes in [K+]o associated with the synchronous activity induced by 4-aminopyridine (4AP) in hippocampal slices obtained from control and pilocarpine-treated rats. At all recording sites (i.e. stratum radiatum of the CA1 and CA3 subfields, and hilus of the dentate gyrus), the amplitude of GABA-mediated synchronous field potentials induced by 4AP, as well as the associated [K+]o increases, were significantly reduced in slices obtained from the pilocarpine-treated rats. In the control group, the field-potential amplitudes reached 1 mV (i.e. 1.7 +/- 0.3 mV in CA1, 0.93 +/- 0.2 mV in CA3, and 1.03 +/- 0.12 mV in the hilus; mean +/- SEM), while the accompanying rises in [K+]o exceeded 4 mM (i.e. 4.17 +/- 0.15 mM in CA1, 4.04 +/- 0.12 mM in CA3, 4.04 +/- 0.11 mM in the hilus) from a baseline of 3.25 mM. The corresponding values in slices from the pilocarpine-treated group were rarely greater than 0.4 mV (i.e. 0.3 +/- 0.09 mV in CA1, 0.27 +/- 0.03 mV in CA3 and 0.38 +/- 0.06 mV in the hilus), and larger than 3.6 mM (i.e. 3.63 +/- 0.04 mM in CA1, 3.64 +/- 0.03 mM in CA3 and 3.60 +/- 0.04 mM in the hilus) from a similar baseline value. With pilocarpine, the rate of occurrence of the GABA-mediated potential significantly decreased from 0.035 to 0.016 s-1. Since the rises in [K+]o decreased rather than increased and their overall duration was unchanged (possibly reflecting cell loss), we conclude that a modification of [K+]o buffering capacity is unlikely to account for the appearance of in vivo seizures in the pilocarpine model of epilepsy.
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PMID:Extracellular potassium elevations in the hippocampus of rats with long-term pilocarpine seizures. 883 Mar 21

1. The authors examined the anticonvulsant effects of MK-801 on the pilocarpine-induced seizure model. Intraperitoneal injection of pilocarpine (400 mg/kg) induced tonic and clonic seizure. Scopolamine (10 mg/kg) and pentobarbital (5 mg/kg) prevented development of pilocarpine-induced behavioral seizure but MK-801 (0.5 mg/kg) did not. 2. An electrical seizure measured with hippocampal EEG appeared in the pilocarpine-treated group. Scopolamine and pentobarbital blocked the pilocarpine-induced electrographic seizure, MK-801 treatment augmented the electrographic seizure induced by pilocarpine. 3. Brain damage was assessed by examining the hippocampus microscopically. Pilocarpine produced neuronal death in the hippocampus, which showed pyknotic changes. Pentobarbital, scopolamine and MK-801 protected the brain damage by pilocarpine, though in the MK-801-treated group, the pyramidal cells of hippocampus appeared darker than normal. In all treatments, granule cells of the dentate gyrus were not affected. 4. These results indicate that status epilepticus induced by pilocarpine is initiated by cholinergic overstimulation and propagated by glutamatergic transmission, the elevation of which may cause brain damage through an excitatory NMDA receptor-mediated mechanism.
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PMID:MK-801 augments pilocarpine-induced electrographic seizure but protects against brain damage in rats. 906 77

The dentate granule cell layer of the rodent hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. In both human temporal lobe epilepsy and rodent models of limbic epilepsy, this same neuronal population undergoes extensive remodeling, including reorganization of mossy fibers, dispersion of the granule cell layer, and the appearance of granule cells in ectopic locations within the dentate gyrus. The mechanistic basis of these abnormalities, as well as their potential relationship to dentate granule cell neurogenesis, is unknown. We used a systemic chemoconvulsant model of temporal lobe epilepsy and bromodeoxyuridine (BrdU) labeling to investigate the effects of prolonged seizures on dentate granule cell neurogenesis in adult rats, and to examine the contribution of newly differentiated dentate granule cells to the network changes seen in this model. Pilocarpine-induced status epilepticus caused a dramatic and prolonged increase in cell proliferation in the dentate subgranular proliferative zone (SGZ), an area known to contain neuronal precursor cells. Colocalization of BrdU-immunolabeled cells with the neuron-specific markers turned on after division, 64 kDa, class III beta-tubulin, or microtubule-associated protein-2 showed that the vast majority of these mitotically active cells differentiated into neurons in the granule cell layer. Newly generated dentate granule cells also appeared in ectopic locations in the hilus and inner molecular layer of the dentate gyrus. Furthermore, developing granule cells projected axons aberrantly to both the CA3 pyramidal cell region and the dentate inner molecular layer. Induction of hippocampal seizure activity by perforant path stimulation resulted in an increase in SGZ mitotic activity similar to that seen with pilocarpine administration. These observations indicate that prolonged seizure discharges stimulate dentate granule cell neurogenesis, and that hippocampal network plasticity associated with epileptogenesis may arise from aberrant connections formed by newly born dentate granule cells.
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PMID:Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. 913 93

Pilocarpine (PILO), a muscarinic agonist, produces status epilepticus when administered to rats in vivo and induces interictal or ictal patterns of epileptiform activity in rat hippocampal slices. We investigated the effects of PILO (10 microM) on paired pulse inhibition (PPI) in the CA3 region of rat hippocampal slices. PPI was assessed by stimulating either the alveus or str. radiatum and recording the extracellular response from str. pyramidale of CA3. The evoked population spike following the second stimulus was compared to the first. PILO was bath applied for 1 h and then washed out to assess acute and long lasting effects. PILO decreased the amplitude of evoked population spikes measured in CA3. PPI following alveus stimulation was not affected by PILO; however, a significant loss of PPI at 15 and 30 ms interpulse intervals occurred following str. radiatum stimulation in the presence of PILO and 5 mM [K+]o artificial cerebrospinal fluid (ACSF). The decrease in PPI at the 15 ms interval persisted following wash-out of PILO. PILO in 7.5 mM [K+]o ACSF produced epileptiform activity and a resultant long lasting loss of PPI that followed str. radiatum stimulation. This effect was not observed following epileptiform activity produced by 7.5 mM [K+]o alone, suggesting that the loss of PPI was due to PILO. Because str. radiatum-evoked PPI was selectively impaired, PILO appears to preferentially decreased feed-forward inhibition. The more dramatic loss of PPI following exposure to PILO and high [K+]o may represent the first steps in the development of chronic seizures that results from PILO-induced status epilepticus in rats.
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PMID:Effects of pilocarpine on paired pulse inhibition in the CA3 region of the rat hippocampus. 920 42

Pilocarpine, a muscarinic agonist, produces status epilepticus that is associated with the later development of chronic recurrent seizures. When applied to rat hippocampal slices, pilocarpine (10 microM) produced brief (<200 ms) epileptiform discharges that resembled interictal activity that occurs between seizures, as well as more prolonged synchronous neuronal activation that lasted seconds (3-20 s), and was comparable to ictal or seizures-like discharges. We assessed the factors that favored ictal patterns of activity and determined the biophysical properties of the ictal discharge. The probability of observing ictal discharges was increased when extracellular potassium ([K+]o) was increased from 5 to 7.5 mM. Raising [K+]o to 10 mM resulted in loss of ictal patterns and, in 20 of 34 slices, desynchronization of epileptiform activity. Making the artificial cerebrospinal fluid (ACSF) hyposmotic favored ictal discharges at 5 mM [K+]o, but shifted 7.5 mM [K+]o ACSF patterns to interictal discharges or desynchronized activity. Conversely, increasing osmolality suppressed ictal patterns. The pilocarpine-induced ictal discharges were blocked by atropine (1 microM, n = 5), a muscarinic antagonist, and pirenzepine (1 microM, n = 6), a selective M1 receptor antagonist. Kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor blockade stopped all epileptiform activity (n = 8). The N-methyl--aspartate antagonist ,-2-amino-5-phosphonovaleric acid (100 microM, n = 34) did not change the pattern of epileptiform activity but significantly increased the rate of interictal discharges and prolonged the duration of ictal discharges. The ictal discharge was characterized intracellularly by a depolarization that was associated with action potential generation and persisted as a membrane oscillation of 4-10 Hz. The ictal oscillations reversed in polarity at -22.7 +/- 2.2 mV (n = 11) with current-clamp recordings and -20.9 +/- 3.1 mV (n = 7) with voltage-clamp recordings. The reversal potential of the ictal discharge in the presence of the gamma-aminobutyric acid-A blocker bicuculline (10 microM, n = 6) was -2.2 +/- 2.6 mV and was significantly different from that measured without bicuculline. Bicuculline added to 7.5 mM [K+]o and 10 microM pilocarpine did not cause epileptiform activity to change pattern but significantly increased the rate of interictal discharges and prolonged the ictal discharge duration. Both synaptic and nonsynaptic mechanisms are important for the generation of ictal patterns of epileptiform activity. Although the synchronous epileptiform activity produced by pilocarpine required fast glutamate-mediated synaptic transmission, the transition from an interictal to ictal pattern of activity depended on [K+]o and could be influenced by extracellular space.
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PMID:Ictal epileptiform activity in the CA3 region of hippocampal slices produced by pilocarpine. 963 5

Neuroplasticity has been investigated considering the neuronal growth-associated phosphoprotein as a marker of neuronal adaptive capabilities. In the present work, studying the hippocampal reorganization observed in the epilepsy model induced by pilocarpine, we carried out quantitative western blotting associated with immunohistochemistry to determine the distribution of growth-associated phosphoprotein in the hippocampus of rats in acute, silent and chronic periods of this epilepsy model. The fibers and punctate elements from the inner molecular layer of the dentate gyrus were strongly immunostained in animals killed 5 h after status epilepticus, compared with the same region in control animals. Rats presenting partial seizures showed no alterations in the immunostaining pattern compared with saline-treated animals. The hippocampal dentate gyrus of animals during the seizure-free period and presenting spontaneous recurrent seizures was also characterized by strong growth-associated phosphoprotein immunostaining of fibers and punctate elements in the inner molecular layer, contrasting with the control group. As determined by western blotting analysis, growth-associated phosphoprotein levels increased following status epilepticus and remained elevated at the later time-points, both during the silent period and during the period of chronic recurring seizures. Pilocarpine-treated animals, which did not develop status epilepticus, showed no change in growth-associated phosphoprotein levels, indicating that status epilepticus is important to induce growth-associated phosphoprotein overexpression. The measurement of this overexpression could represent one of the early signals of hippocampal reorganization due to status epilepticus-induced damage.
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PMID:Growth-associated phosphoprotein expression is increased in the supragranular regions of the dentate gyrus following pilocarpine-induced seizures in rats. 1036 5


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