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1.
Permanent cognitive impairment is common following status epilepticus (SE) in both humans and animals. We examined the effect of the NMDA antagonist ketamine administered after SE onset on two forms of associative learning in the rat: conditioned taste aversion and fear-conditioned analgesia. Following the onset of lithium/pilocarpine-induced SE, rats were administered either ketamine (100 mg/kg) or acepromazine (25 mg/kg). Acepromazine-treated animals show marked deficits in both learning measures at 1 month after SE. In contrast, ketamine-treated and nonepileptic control animals did not differ in performance for either task. Although studies have shown that ketamine is ineffective at controlling electrographic seizures early in SE, these results are consistent with previous studies showing that ketamine can preserve learning proficiency if administered shortly after seizure onset. As a clinically available drug, ketamine may prove useful in the treatment of SE when combined with conventional antiepileptic strategies.  相似文献   

2.
Status epilepticus (SE) was induced in rats by administration of 3 mmol/kg lithium chloride followed 24 h later by injection of 25 mg/kg pilocarpine. Treatment with 20 mg/kg diazepam was initiated at the time each of four EEG patterns was seen: (i) discrete electrographic seizures; (ii) waxing and waning epileptiform activity; (iii) continuous, high-amplitude, rapid spiking; and (iv) periodic epileptiform discharges (PEDs) on a relatively flat background. Success of diazepam in stopping all seizure activity was predicted by the EEG pattern seen at the time of treatment. All rats treated while displaying discrete electrographic seizures had status stopped with diazepam, but only three of six with waxing and waning epileptiform activity and one of six each with continuous spiking and PEDs. Rats which continued to seize had a decrease in spike amplitude of 74.8 +/- 18.25% following diazepam injection. These data confirm the clinical impression that the longer the duration of status epilepticus, the more difficult it is to control and suggest that the EEG pattern at the time of treatment predicts the probability of success.  相似文献   

3.
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.  相似文献   

4.
目的 探讨红藻氨酸 ( KA)诱导大鼠复杂部分性癫痫发作的 EEG特点以及可能的电生理起搏点位置。方法 在立体定位指引下 ,将 EEG记录电极植入 1 2只大鼠双侧海马、额叶皮质或杏仁核中 ,其中 8只为实验组 ,4只为对照组。手术后 1周在大鼠清醒状态下 ,连续描记 KA或盐水注射后 EEG 1 2 0 min,观察 EEG波形、波幅以及频率的变化特点并记录每次电发作的起搏点位置。结果  ( 1 ) KA注射后大鼠 EEG表现出多种形式的放电波形 ,典型波形有单棘波、多棘波、多相棘波、正相棘波、棘节律、节律性慢波、棘慢波等。 ( 2 )大鼠在凝视发作以及自动症发作时海马、杏仁核和额叶皮质均有异常放电。 ( 3) KA注射后大鼠电发作起搏点不固定。 ( 4 )各导放电频率多数情况下一致 ,偶有不一致现象。 ( 5 )存在亚临床放电。结论  ( 1 ) KA注射后大鼠 EEG表现为多种形式的电发作活动 ;( 2 )大鼠在复杂部分性发作过程中不仅有边缘系统参与 ,也有边缘外额叶皮质参与 ;( 3)KA模型中 ,电发作起搏点不固定 ,KA注射后大鼠脑内可能存在一个异常的神经元网络 ,在网络中存在放电不均衡现象。  相似文献   

5.
N-methyl-D-aspartate (NMDA) receptors play a prominent role in the pathogenesis of epilepsy, yet few studies have used NMDA as a convulsant in whole animals. In developing rats, systemic NMDA induces seizures with a unique seizure phenotype ("emprosthotonic" or hyperflexion seizures) and electrographic pattern (electrodecrement). These features are not seen in kainic acid-induced seizures, suggesting that seizures activated by NMDA might cause different long-term consequences. Therefore, we investigated the effects of NMDA seizures during development on cognitive function and susceptibility to seizures in adulthood. Rat pups (P12-20) were injected with saline (n=36) or NMDA (n=64) at convulsant doses (15-30mg/kg, i.p.). After NMDA injection, a characteristic sequence of seizure activity was seen: initial behavioral arrest, followed by hyperactivity, agitation, and then emprosthotonus and generalized tonic-clonic seizures. Seizures were terminated 30min later by ketamine (50mg/kg, i.p.). On P85, rats underwent behavioral testing in the water maze. Rats that had experienced NMDA seizures as pups took significantly longer to learn the platform location over 5 days of testing, compared to controls. On P90, rats were injected with pentylenetetrazol (PTZ, 50mg/kg, i.p.) to assess their susceptibility to generalized seizures. NMDA-treated rats had decreased latency and increased duration of class V PTZ seizures. Cresyl violet-stained sections of cortex and hippocampus had no obvious cell loss or gliosis. In summary, NMDA causes a unique seizure phenotype in the developing brain, with subsequent deficits in spatial learning and an increased susceptibility to PTZ seizures in adulthood. This study provides additional evidence for long-term alterations of neuronal excitability and cognitive capacity associated with seizures during development.  相似文献   

6.
Summary: Adult male Wistar rats were subjected to intense sound stimulation from an electric bell (100 dB and 12 KHz for 60 s) after a single intraperitoneal (i.p. 50 mg/kg) injection of metaphit [l-(l-/3 isothiocyanatophenyl-cyclohexyl) piperidine]. EEG recordings demonstrated appearance of paroxysmal activity and spike-wave complexes from cortical electrodes, with frequency and amplitude increasing with time. Metaphit-induced audiogenic seizures in the rats were tested 24 h after metaphit administration. The seizures consisted of wild running followed by clonic and tonic convulsions, and the seizure pattern could be elicited at hourly intervals for the next 24 h in all tested animals. Forty-eight hours after metaphit administration, susceptibility to sound stimulation began to decrease gradually. The first component of seizure response to disappear was tonic extension, followed by disappearance of clonic convulsion; the last component to disappear was running behavior. Each behavioral seizure response had a characteristic EEG correlate. After ~50 h, no animal responded to sound stimulation. The noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, MK-801 [5-methyl-10, ll-dihydro-5H-dibenzo (a, d) cyclohepten-5,10-imine maleate] was evaluated as an anticonvulsant against metaphit-induced audiogenic seizures in two experiments. In the first experiment, MK-801 was administered in a single dose of 0.5 mg/kg i.p. 23.5 h after metaphit injection and 30 min before sound stimulation, which completely blocked both the EEG and the behavioral response to sound stimulation for 37 h. After that time, seizure susceptibility began to appear and within 7 h reached a maximum, at which time all animals responded with a complete pattern of a severe seizure. During the next 5 h, seizure susceptibility began to abate gradually and disappeared completely 76 h after metaphit administration. The EEG and behavioral responses did not differ from those elicited in animals treated with metaphit alone. In the second experiment, MK-801 (0.5 mg/kg i.p.) administered 30 min before metaphit did not protect the animals from the effects of metaphit but significantly reduced the incidence of clonic-tonic seizures. EEG signs of seizure susceptibility and progressive increase in epileptic discharges were not suppressed by MK-801. Results suggest that MK-801 is an anticonvulsant rather than an antiepileptic agent in the metaphit-induced audiogenic seizure model.  相似文献   

7.
Purpose: Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models of temporal lobe epilepsy. Because rapamycin is also known for its immunosuppressant properties we hypothesized that one of the mechanisms by which it exerts this effect could be via suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy. Methods: Rats were treated with rapamycin or vehicle once daily for 7 days (6 mg/kg/day, i.p.) starting 4 h after the induction of SE, which was evoked by electrical stimulation of the angular bundle. Hereafter rapamycin was administered every other day until rats were sacrificed, 6 weeks after SE. Video‐electroencephalography was used to monitor the occurrence of seizures. Neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistologic staining. Fluorescein was administered to quantify blood–brain barrier leakage. Key Findings: Rapamycin treatment did not alter SE severity and duration compared to vehicle treatment rats. Rapamycin‐treated rats developed hardly (n = 9) or no (n = 3) seizures during the 6‐week treatment, whereas vehicle‐treated rats showed a progressive increase of seizures starting 1 week after SE (mean 8 ± 2 seizures per day during the sixth week). Cell loss and sprouting that normally occur after SE were prominent but on average significantly less in rapamycin‐treated rats versus vehicle‐treated rats. Nevertheless, various inflammation markers (CD11b/c and CD68) were dramatically upregulated and not significantly different between post‐SE groups. Of interest, blood–brain barrier leakage was barely detected in the rapamycin‐treated group, whereas it was prominent in the vehicle‐treated group. Significance: mTOR inhibition led to strong reduction of seizure development despite the presence of microglia activation, suggesting that effects of rapamycin on seizure development are not due to a control of inflammation. Whether the effects on blood–brain barrier leakage in rapamycin‐treated rats are a consequence of seizure suppressing properties of the drug, or contribute to a real antiepileptogenic effect still needs to be determined.  相似文献   

8.
Searching for new therapeutic strategies through modulation of glutamatergic transmission using effective neuroprotective agents is essential. Glutamatergic excitotoxicity is a common factor to neurodegenerative diseases and acute events such as cerebral ischemia, traumatic brain injury, and epilepsy. This study aimed to evaluate behavioral and electroencephalographic (EEG) responses of mice cerebral cortex and hippocampus to subconvulsant and convulsant application of NMDA and quinolinic acid (QA), respectively. Moreover, it aimed to evaluate if EEG responses may be related to the neuroprotective effects of NMDA. Mice were preconditioned with NMDA (75 mg/kg, i.p.) and EEG recordings were performed for 30 min. One day later, QA was injected (36.8 nmol/site) and EEG recordings were performed during 10 min. EEG analysis demonstrated NMDA preconditioning promotes spike-wave discharges (SWDs), but it does not display behavioral manifestation of seizures. Animals that were protected by NMDA preconditioning against QA-induced behavioral seizures, presented higher number of SWD after NMDA administration, in comparison to animals preconditioned with NMDA that did display behavioral seizures after QA infusion. No differences were observed in latency for the first seizure or duration of seizures. EEG recordings after QA infusion demonstrated there were no differences in the number of SWD, latency for the first seizure or duration of seizures in animals pretreated with saline or in animals preconditioned by NMDA that received QA. A negative correlation was identified between the number of NMDA-induced SWD and QA-induced seizures severity. These results suggest a higher activation during NMDA preconditioning diminishes mice probability to display behavioral seizures after QA infusion.  相似文献   

9.
Purpose: To evaluate the effects of high‐frequency electrical stimulation (HFS) in both ventral hippocampi, alone and combined with a subeffective dose of antiepileptic drugs, during the status epilepticus (SE) induced by lithium‐pilocarpine (LP). Methods: Male Wistar rats, stereotactically implanted in both ventral hippocampi, were injected with pilocarpine (30 mg/kg, i.p.) 24 h after lithium (3 mEq/kg) administration. One minute following pilocarpine injection, HFS (pulses of 60 μs width at 130 Hz at subthreshold intensities and applied during 3 h) was applied alone or combined with subeffective doses of antiepileptic drugs. Results: HFS alone reduced the incidence of severe generalized seizures. This effect was not evident when HFS was combined with phenytoin (33.3 mg/kg, i.p.). HFS combined with diazepam (0.41 mg/kg, i.p.) or phenobarbital (10 mg/kg, i.p.) reduced the incidence of severe generalized seizures and mortality rate, and augmented the latency to first forelimb clonus, generalized seizure, and status epilepticus (SE). When combined with gabapentin (46 mg/kg, i.p.), HFS reduced the incidence of severe generalized seizures, enhanced latency to SE, and decreased mortality rate. Discussion: Subeffective doses of antiepileptic drugs that increase the γ‐aminobutyric acid (GABA)ergic neurotransmission may represent a therapeutic tool to augment the HFS‐induced anticonvulsant effects.  相似文献   

10.
OBJECTIVES: It is unknown how generalised discharges in primary generalised epilepsy (PGE) develop from background brain electrical activity or how widespread these discharged are throughout the brain. Here we address this by determining which neural structures and rhythms lead to and participate in generalised discharges in the picrotoxin rat model of PGE. METHODS: Rats with chronically implanted electrodes were infused with picrotoxin until a seizure occurred. This process we refer to as acute epileptogenesis. The electroencephalogram (EEG) was recorded and spectral analysis applied off-line to determine changes in the spectral power of contributing frequencies in 13 brain regions. RESULTS: Two types of generalised discharge occurred, spindles and seizure, which were present in all brain regions studied. None of the frequencies (1-100 Hz) were significantly increased in background EEG before either spindles or seizure. Within the generalised discharges, power changes revealed significant increases in 6-8 Hz, most powerful in ventrolateral thalamus and neocortex. Gamma frequencies were increased significantly in neocortical structures during spindles with further increases in most structures at seizure onset. 1 Hz was significantly increased in parietal cortex during spindles with differential increases at seizure onset. CONCLUSIONS: We conclude that gamma, 1 and 6-8 Hz frequencies do not appear to contribute to picrotoxin epileptogenesis but do play a role in generalised seizures. The distribution of these frequencies during discharges suggests that the spindles are thalamocortical events and that the seizure is a cortical event with downstream effects on other brain regions.  相似文献   

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