Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The specific role of endogenous glutathione in response to neuronal degeneration induced by trimethyltin (TMT) in the hippocampus was examined in rats. A single injection of TMT (8 mg/kg, i.p.) produced a rapid increase in the formation of hydroxyl radical and in the levels of malondialdehyde (MDA) and protein carbonyl. TMT-induced seizure activity significantly increased after this initial oxidative stress, and remained elevated for up to 2 weeks post-TMT. Although a significant loss of hippocampal Cornus Ammonis CA1, CA3 and CA4 neurons was observed at 3 weeks post-TMT, the elevation in the level of hydroxyl radicals, MDA, and protein carbonyl had returned to near-control levels at that time. In contrast, the ratio of reduced to oxidized glutathione remained significantly decreased at 3 weeks post-TMT, and the glutathione-like immunoreactivity of the pyramidal neurons was decreased. However glutathione-positive glia-like cells proliferated mainly in the CA1, CA3, and CA4 sectors and were intensely immunoreactive. Double labeling demonstrated the co-localization of glutathione-immunoreactive glia-like cells and reactive astrocytes, as indicated by immunostaining for glial fibrillary acidic protein. This suggests that astroglial cells were mobilized to synthesize glutathione in response to the TMT insult. The TMT-induced changes in glutathione-like immunoreactivity appear to be concurrent with changes in the expression levels of glutathione peroxidase and glutathione reductase. Ascorbate treatment significantly attenuated TMT-induced seizures, as well as the initial oxidative stress, impaired glutathione homeostasis, and neuronal degeneration in a dose-dependent manner. These results suggest that ascorbate is an effective neuroprotectant against TMT. The initial oxidative burden induced by TMT may be a causal factor in the generation of seizures, prolonged disturbance of endogenous glutathione homeostasis, and consequent neuronal degeneration.
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PMID:Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis. 1590 28

Nefiracetam is a novel pyrrolidone-type nootropic agent, and it has been reported to possess a potential for antiepileptic therapy as well as cognition-enhancing effects. We investigated the anticonvulsant and neuroprotective effects of nefiracetam in kainic acid-induced seizures of rats, compared with levetiracetam and standard antiepileptic drugs. Subcutaneous injection of kainic acid (10 mg/kg) induced typical behavioral seizures such as wet dog shakes and limbic seizures and histopathological changes in the hippocampus (degeneration and loss of pyramidal cells in CA1 to CA4 areas). Nefiracetam (25, 50 and 100 mg/kg po) had no effect on the behavioral seizures and dose-dependently inhibited the hippocampal damage. In contrast, levetiracetam, a pyrrolidone-type antiepileptic drug, inhibited neither. Valproic acid and ethosuximide prevented the hippocampal damage without attenuating the behavioral seizures as nefiracetam. Zonisamide and phenytoin did not inhibit the behavioral seizures, while zonisamide enhanced the hippocampal damage and phenytoin increased the lethality rate. Carbamazepine inhibited the behavioral seizures at 50 mg/kg and enhanced that at 100 mg/kg, and it completely inhibited the hippocampal damage at both doses. We have previously reported that anticonvulsant spectrum of nefiracetam paralleled that of zonisamide, phenytoin or carbamazepine in standard screening models. However, the pharmacological profile of nefiracetam was closer to valproic acid or ethosuximide than that of zonisamide, phenytoin or carbamazepine in this study. These results suggest that anticonvulsant spectrum and mechanism of nefiracetam are distinct from those of standard antiepileptic drugs, and nefiracetam possesses a neuroprotective effect that is unrelated to seizure inhibition.
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PMID:Anticonvulsant and neuroprotective effects of the novel nootropic agent nefiracetam on kainic acid-induced seizures in rats. 1612 14

Structural changes in neurons and oxidative stress in hippocampus were studied in rats "tolerant" (TR) and susceptible (SR) to tonic and clonic seizures in pentylenetetrazole (PTZ) kindling. The number of normal neurons was significantly decreased in CA1 subfield of TR hippocampus after 11 injections of PTZ, while in SR neuronal cell loss was evident in CA1 and fascia dentata. In both groups, neuronal cell loss was accompanied by increase in damaged neuron number in CA4 subfield. After 21 injections of PTZ, the decrease in normal neuron number was revealed in CA1 subfield of both TR and SR, while the number of damaged neurons was above the control level in hippocampal subfields CA1 and CA4 in TR only. Glutathione level was decreased in hippocampus of both TR and SR as compared with control rats. Thus, rats tolerant to PTZ-induced convulsions demonstrated oxidative stress and neurodegeneration in hippocampus. The results suggest that, in PTZ kindling model, oxidative damage of neurons resulting in neurodegeneration in hippocampus is not directly related to the convulsive activity.
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PMID:[Pentylenetetrazole kindling in rats: whether neurodegeneration is associated with manifestations of seizure activity?]. 1620 20

The disabling seizures associated with mesial temporal lobe epilepsy (TLE) are often resistant to antiepileptic drugs (AEDs). The biological basis of this refractoriness is unknown but may include alterations in AED targets in the epileptogenic brain tissue, reduced AED penetration to the seizure focus, and neuropathological brain alterations such as hippocampal sclerosis typically found in patients with refractory TLE. In the present study, we used a rat model of TLE to examine whether AED responders differ from non-responders in their structural alterations and GABA(A) receptor characteristics in the hippocampal formation. In this model, spontaneous recurrent seizures develop after a status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala. The frequency of these seizures was recorded by continuous video/EEG monitoring before, during, and after daily treatment with phenobarbital, which was given at maximum tolerated doses for 2 weeks. Based on their individual response to phenobarbital, rats were grouped into responders and non-responders. The severity or duration of the initial brain insult (the status epilepticus) did not differ between responders and non-responders, indicating that the difference between the two subgroups is genetically determined. Subsequent histological examination showed a significant loss of neurons in the CA1, CA3c/CA4, and dentate hilus of non-responders, whereas responders did not differ in this respect from non-epileptic controls. The morphological alterations in the non-responders were associated with striking alterations in autoradiographic imaging of diazepam-sensitive and diazepam-insensitive GABA(A) receptor binding in the dentate gyrus with a significant shift to enhanced diazepam-insensitive binding. The present data indicate that neurodegeneration and associated GABA(A) receptor changes in the dentate gyrus are critically involved in the mechanisms underlying refractoriness of seizures in TLE.
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PMID:Antiepileptic drug-resistant rats differ from drug-responsive rats in hippocampal neurodegeneration and GABA(A) receptor ligand binding in a model of temporal lobe epilepsy. 1625 58

Intrathecal methotrexate in children with leukemia is known to cause seizures, dementia, leukoencephalopathy and cognitive dysfunction. To investigate the role of brain amines in cognitive dysfunction, male Wistar rats were given multiple intracerebroventricular injections of methotrexate. Our earlier studies in this regard revealed disruption of brain monoamines in hippocampus with severe cytotoxic effect on CA4 hippocampal neurons. Further extending this study, the levels of brain monoamines in frontal cortex, hypothalamus and brainstem were estimated by HPLC method and histopathological study of the frontal cortex. The concentration of all three-brain amine (norepinephrine, dopamine and serotonin) levels was reduced in 2 mg/kg dose of methotrexate in frontal cortex and brain stem. Hypothalamus did not show any significant change in brain monoamine levels. No structural changes in the frontal cortex neurons were observed. Disruption of brain monoamines has been proposed as a cause of brain dysfunction from this chemotherapy. The outcome of the study may have therapeutic implications in the management of childhood lymphoblastic leukemia.
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PMID:Effect of intracerebroventricular methotrexate on brain amines. 1657 96

Structural changes in neurons and measures of oxidative stress were studied in the hippocampus of rats tolerant (ST) and sensitive (SS) to developing clonic-tonic seizures in conditions of pentylenetetrazol kindling. Sequences of 11 injections of pentylenetetrazol significantly decreased the number of normal neurons in hippocampal field CA1 in SS rats, this effect being seen in both hippocampal field CA1 and the dentate fascia in ST rats. Decreases in the numbers of normal neurons were accompanied by increases in the numbers of damaged cells in field CA4 in rats of both groups. After 21 injections, decreases in the numbers of normal neurons were seen in field CA1 in both SS and ST rats, while the numbers of damaged neurons were significantly greater than control only in ST rats in fields CA1 and CA4. The glutathione level was significantly lower in the hippocampus in both groups of rats than in controls. Thus, rats " tolerant" to developing convulsions show signs of oxidative stress and neurodegenerative changes in the hippocampus. This suggests that oxidative neuron damage leading to neurodegeneration in the pentylenetetrazol kindling model is not directly associated with convulsive activity.
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PMID:Pentylenetetrazol kindling in rats: Is neurodegeneration associated with manifestations of convulsive activity? 1684 Nov 55

We propose a histopathological classification system for hippocampal cell loss in patients suffering from mesial temporal lobe epilepsies (MTLE). One hundred and seventy-eight surgically resected specimens were microscopically examined with respect to neuronal cell loss in hippocampal subfields CA1-CA4 and dentate gyrus. Five distinct patterns were recognized within a consecutive cohort of anatomically well-preserved surgical specimens. The first group comprised hippocampi with neuronal cell densities not significantly different from age matched autopsy controls [no mesial temporal sclerosis (no MTS); n = 34, 19%]. A classical pattern with severe cell loss in CA1 and moderate neuronal loss in all other subfields excluding CA2 was observed in 33 cases (19%), whereas the vast majority of cases showed extensive neuronal cell loss in all hippocampal subfields (n = 94, 53%). Due to considerable similarities of neuronal cell loss patterns and clinical histories, we designated these two groups as MTS type 1a and 1b, respectively. We further distinguished two atypical variants characterized either by severe neuronal loss restricted to sector CA1 (MTS type 2; n = 10, 6%) or to the hilar region (MTS type 3, n = 7, 4%). Correlation with clinical data pointed to an early age of initial precipitating injury (IPI < 3 years) as important predictor of hippocampal pathology, i.e. MTS type 1a and 1b. In MTS type 2, IPIs were documented at a later age (mean 6 years), whereas in MTS type 3 and normal appearing hippocampus (no MTS) the first event appeared beyond the age of 13 and 16 years, respectively. In addition, postsurgical outcome was significantly worse in atypical MTS, especially MTS type 3 with only 28% of patients having seizure relief after 1-year follow-up period, compared to successful seizure control in MTS types 1a and 1b (72 and 73%). Our classification system appears suitable for stratifying the clinically heterogeneous group of MTLE patients also with respect to postsurgical outcome studies.
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PMID:A new clinico-pathological classification system for mesial temporal sclerosis. 1722 Dec 3

Mesial temporal sclerosis (MTS) is the most common cause of medically intractable temporal lobe epilepsy. Histologic findings include hippocampal atrophy with neuronal loss in the dentate, CA1, and CA3/CA4 regions with gliosis. The conventional treatment of patients with intractable epilepsy secondary to MTS has been surgical excision. Gamma knife radiotherapy (GKR) has recently been suggested as a less invasive alternative to surgery. To date, the histologic changes that occur in this setting after GKR have not been well described. The clinicopathologic features of 4 patients with MTS who received GKR and underwent subsequent surgical resection or autopsy were retrospectively reviewed. The study group is composed of 4 patients (3 women, 1 men) with ages 55, 48, 22, and 20 years, respectively, at the time of GKR. There were 2 patients who had a history of infantile febrile seizures, and 2 who had a central nervous infection during infancy. All 4 patients had a long-standing (13-36 years) history of temporal lobe seizures resistant to medical management. Imaging studies, electroencephalogram, and surgical specimens all confirmed the diagnosis of MTS. The oldest of the 4 patients died 1 month after receiving GKR, presumably because of post-gamma knife persistent seizure complications. The postmortem neuropathology on this patient was unremarkable for any radiation effect changes but showed evidence of MTS. The remaining 3 patients underwent surgical resection for persistent seizures at 18, 22, and 20 months, respectively, post-gamma knife. These 3 surgical specimens showed variable degrees of radiation effect changes in the temporal lobe, hippocampus, and amygdala, including chronic (lymphocytes and macrophages) perivascular inflammation (3/3), vascular sclerosis (3/3), foci of edema with necrosis (3/3; extensive in 2 patients), reactive astrocytosis (3/3), microglial proliferation (1/3), and microcalcifications (1/3). Patients with MTS who underwent GKR can develop typical radiation changes over time. Treatment of individuals with MTS via GKR may not always be adequate in controlling seizures. Radiation therapy effect may contribute to persistent seizures after GKR in some patients with MTS.
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PMID:Clinicopathologic findings in mesial temporal sclerosis treated with gamma knife radiotherapy. 1724 Mar 3

Because magnesium has antiseizure effects in some animal models of epilepsy, and possible neuroprotective effects in some models of neuronal injury, we aimed to investigate its effects in the kainic acid (KA) model of status epilepticus (SE) in prepubescent rats. This age was chosen because it is a common age for onset of epilepsy and of SE in humans. Three groups of P35 rats were studied: Group I (MgKA) received magnesium sulfate MgSO4 (270 mg/kg then 27 mg/kg every 20 minutes for 5 hours) and 10 mg/kg KA. Group II (KA) received saline instead of MgSO4 and 10 mg/kg KA. Group III (control) received saline injections only. The dose we used has been shown previously to have anticonvulsant activity in another seizure model. Rats were recorded for their acute behavioral seizures directly after KA, and underwent the handling and Morris Water Maze (MWM) tests on P96-97 and P102-106 respectively. The MgKA and the KA groups did not differ in their acute seizures and both showed similar histologic lesions in CA3/CA4 and CA1 hippocampal subfields, and were more aggressive on the handling test than control rats. The MgKA group took more time to reach the platform in MWM than controls, while the KA group scores were intermediate between the two groups. Using the dose of 540 mg/kg MgSO4 and 54 mg/kg every 20 min showed the similar result of lack of protection against impairment in long-term memory. We conclude that (1) Magnesium did not manifest acute behavioral antiseizure effects in the KA P35 model of SE. (2) Magnesium did not prevent the tested long-term behavioral and histological consequences of SE in this model.
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PMID:Effects of magnesium sulfate in kainic acid-induced status epilepticus. 1733 Mar 72

Marked hippocampal changes in response to excitatory amino acid agonists occur during pregnancy (e.g. decreased frequency in spontaneous recurrent seizures in rats with KA lesions of the hippocampus) and lactation (e.g. reduced c-Fos expression in response to N-methyl-d,l-aspartic acid but not to kainic acid). In this study, the possibility that lactation protects against the excitotoxic damage induced by KA in hippocampal areas was explored. We compared cell damage induced 24 h after a single systemic administration of KA (5 or 7.5 mg/kg bw) in regions CA1, CA3, and CA4 of the dorsal hippocampus of rats in the final week of lactation to that in diestrus phase. To determine cellular damage in a rostro-caudal segment of the dorsal hippocampus, we used NISSL and Fluorojade staining, immunohistochemistry for active caspase-3 and TUNEL, and we observed that the KA treatment provoked a significant loss of neurons in diestrus rats, principally in the pyramidal cells of CA1 region. In contrast, in lactating rats, pyramidal neurons from CA1, CA3, and CA4 in the dorsal hippocampus were significantly protected against KA-induced neuronal damage, indicating that lactation may be a natural model of neuroprotection.
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PMID:Neuroprotective effects of lactation against kainic acid treatment in the dorsal hippocampus of the rat. 1796 58


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