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

The behavioral and electroencephalographic effects of N-methyl-D-aspartate (NMDA, 25 nmol/1 microliter) injection into the massa intermedia (MI) was examined in rats. The injection caused violent running/jumping and shrill vocalization without evidence of EEG seizure in the hippocampus (HP) and amygdala (AM). Animals with the injection site located in the reuniens nucleus subsequently developed generalized tonic and then clonic seizure, leading to fatal status epilepticus in some animals. Intermittent or continuous EEG discharge in the limbic system was found during clonic seizures. These findings suggest that the NMDA receptor in the reuniens nucleus in the MI participates in the generation and expression of convulsive seizure in rats.
 ...
PMID:Convulsive seizures in rats induced by N-methyl-D-aspartate injection into the massa intermedia. 152 Nov 46

The involvement of the NMDA receptor in the neurotoxicity induced by soman, an organophosphorus compound which irreversibly inhibits cholinesterase, was studied in guinea pigs. The drug MK-801 (0.5, 1 or 5 mg/kg, i.p.) was given as a pretreatment before a convulsant dose of soman or as a posttreatment (30, 100 or 300 micrograms/kg, i.m.) 5 min after the development of soman-induced status epilepticus. Pyridostigmine, atropine and pralidoxime chloride were also given to each subject to counteract the lethality of soman. All subjects that were challenged with soman and given the vehicle for MK-801 (saline) exhibited severe convulsions and electrographic seizure activity. Neuronal necrosis was found in the hippocampus, amygdala, thalamus and the pyriform and cerebral cortices of those subjects surviving for 48 hr. Pretreatment with 0.5 or 1 mg/kg doses of MK-801 did not prevent nor delay the onset of seizure activity but did diminish its intensity and led to its early arrest. At the largest dose (5 mg/kg), MK-801 completely prevented the development of seizure activity and brain damage. Posttreatment with MK-801 prevented, arrested or reduced seizure activity, convulsions and neuronal necrosis in a dose-dependent manner. The NMDA receptor may play a more critical role in the spread and maintenance, rather than the initiation of cholinergically-induced seizure activity.
 ...
PMID:Dizocilpine (MK-801) arrests status epilepticus and prevents brain damage induced by soman. 152 53

A new model of status epilepticus (SE), which was induced by intermittent electrical stimulation (20 Hz for 20 sec every min for 180 min) of the deep prepyriform cortex, has been developed in the conscious rat. SE was induced in 9 of 16 rats in the drug-free group. The number of stimulation trains required to induce SE in this status subgroup was 125.6 +/- 12.7 (mean +/- SEM) and the mean duration of self-sustained seizure activity (SSSA) occurring after cessation of the stimulation session was 295.4 +/- 111.4 min. Some animals showed secondary generalized seizures. Significant cell loss was observed in the hippocampal CA3 pyramidal cell layer ipsilateral to the stimulation site and bilateral CA1 areas in the status subgroup compared with the group subjected to sham operation. In addition, there was a significant negative correlation between the duration of SSSA subsequent to the stimulation session and the total number of intact pyramidal neurons observed in the bilateral CA1 and ipsilateral CA3 subfields of the status subgroup. There were significant differences between the status and non-status subgroups with respect to the number of afterdischarges (ADs) and the total AD duration during the stimulation session. Pretreatment with phenobarbital (30 mg/kg) prevented the development of SE and hippocampal cell loss completely. Pretreatment with MK-801, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist (0.25 or 1 mg/kg), also prevented hippocampal cell loss, although it did not block SE generation completely, which suggests dissociation of the mechanisms underlying the development of SE and hippocampal damage. These results indicate that prolonged SSSA actually causes hippocampal damage and it is critically dependent upon NMDA receptor participation.
 ...
PMID:Mechanisms in the development of limbic status epilepticus and hippocampal neuron loss: an experimental study in a model of status epilepticus induced by kindling-like electrical stimulation of the deep prepyriform cortex in rats. 153 85

Distant damage, localized in the CA3 and CA1 areas, was observed in the hippocampus of rats as a consequence of status epilepticus (SE) induced by the injection of 2.5 nmol of kainic acid (KA) into the amygdala. In animals pretreated with an intraperitoneal injection of the non-competitive antagonist of the N-methyl-D-aspartate receptor, N-[1-(2-thienyl)cyclohexyl]-piperidine (TCP) (20 mg/kg), distant neuronal damage was reduced (CA1 neurons were always spared) whereas the rats still developed SE with an earlier onset. These results demonstrate the protective effect of TCP and confirm that epileptic activity and brain damage may be dissociated by NMDA receptor antagonists.
 ...
PMID:N-[1-(2-thienyl)cyclohexyl]-piperidine (TCP) does not block kainic acid-induced status epilepticus but reduces secondary hippocampal damage. 202 18

Status epilepticus (SE) evolves through several stages when untreated. The later stages of SE are less responsive to standard anticonvulsants and may require general anesthesia to suppress seizures. Antagonists acting at the N-methyl-D-aspartate (NMDA) subclass of glutamate (excitatory) receptors have been demonstrated to exert antiepileptic activity in some seizure models. We report experiments performed to determine if NMDA receptor antagonists are effective in stopping seizures in the late stages of SE. A model of limbic SE induced by 90 min of 'continuous' electrical stimulation of the hippocampus in rats was employed. Three NMDA receptor antagonists, one 'competitive' (CPP) and two 'non-competitive' (ketamine and MK-801), were compared to 3 standard antiepileptic drugs (diazepam, phenobarbital, and phenytoin) for their ability to suppress seizures at a physiologically defined stage of SE. All NMDA receptor antagonists, diazepam and phenobarbital were effective in suppressing behavioral and electrographic seizures for varying periods of time. Phenytoin had no effect on SE. Ketamine and MK-801 induced a paradoxical enhancement of electrographic seizures that preceded SE suppression. We believe that NMDA-receptor antagonists offer a novel approach for treating the late stages of SE.
 ...
PMID:NMDA receptor antagonists and limbic status epilepticus: a comparison with standard anticonvulsants. 216 58

The time course and severity of the excitotoxic syndrome induced in rats by s.c. injection of 10 mg/kg kainic acid (KA) was modified by pretreatment with MK801, a non-competitive inhibitor of the NMDA receptor, at doses of 0.1, 1 and 10 mg/kg. A dose-dependent increase in the severity of the KA-induced electrographic (EEG) manifestations of epilepsy was seen after MK801. This consisted of an earlier appearance and higher number of EEG seizures, longer time spent in seizures, and an earlier onset of status epilepticus. In contrast, behavioral seizures were increased only in the 0.1 mg/kg MK801 group, but abolished by higher doses. On the contrary, wet dog shakes were progressively reduced with increasing doses of MK801. Four of the 9 animals receiving KA-only group and 3 of the 10 animals in the 1 and 10 mg MK801 groups were sacrificed 5 days after KA. The brain of the KA-only rats presented diffuse gross and microscopic evidence of hemorrhagic necrosis and neuronal damage; the MK801 rats showed only minimal neuronal loss in the CA3 hippocampal sector. This study demonstrates that neuronal damage and epileptiform activity can be dissociated. Furthermore, it confirms the protective effect of MK801 against neuronal damage caused by multiple factors. Lastly, it emphasizes the need for EEG monitoring in order to accurately assess any epileptic/antiepileptic effect.
 ...
PMID:Potentiation of kainic acid epileptogenicity and sparing from neuronal damage by an NMDA receptor antagonist. 254 57

MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, was tested for anticonvulsant effects in rats using two seizure models, coadministration of lithium and pilocarpine and administration of a high dose of pilocarpine alone. Three major results are reported. First, pretreatment with MK-801 produced an effective and dose-dependent anticonvulsant action with the lithium-pilocarpine model but not with rats treated with pilocarpine alone, suggesting that different biochemical mechanisms control seizures in these two models. Second, the anticonvulsant effect of MK-801 in the lithium-pilocarpine model only occurred after initial periods of seizure activity. This observation is suggested to be an in vivo demonstration of the conclusion derived from in vitro experiments that MK-801 binding requires agonist-induced opening of the channel sites of the NMDA receptor. Third, although it is relatively easy to block seizures induced by lithium and pilocarpine by administration of anticonvulsants prior to pilocarpine, it is more difficult to terminate ongoing status epilepticus and block the lethality of the seizures. Administration of MK-801 30 or 60 min after pilocarpine, i.e., during status epilepticus, gradually reduced electrical and behavioral seizure activity and greatly enhanced the survival rate. These results suggest that activation of NMDA receptors plays an important role in status epilepticus and brain damage in the lithium-pilocarpine model. This was further supported by results showing that nonconvulsive doses of NMDA and pilocarpine were synergistic, resulting in status epilepticus and subsequent mortality.
 ...
PMID:Anticonvulsant actions of MK-801 on the lithium-pilocarpine model of status epilepticus in rats. 255 70

Light and electron microscopy were used to study the effect of hypoglycaemia on selectively vulnerable neurons of rat hippocampus with and without pharmacologic blockade of the N-methyl-D-aspartate (NMDA)-preferring receptor with 2-amino-7-phosphonoheptanoic acid (AP-7). In control hypoglycaemic hippocampi, dark cell change occurs predominantly in dentate granule cells. The topography and ultrastructural appearance of these changes is distinct from that produced by ischaemia or status epilepticus. In hypoglycaemia, mitochondrial calcium accumulation characteristic of ischaemia or status epilepticus is not seen. NMDA receptor blockade markedly attenuates the hypoglycaemic cell injury. Similar attenuation of ischaemic and epileptic brain damage by NMDA receptor blockade suggest that excessive neuronal excitation is a common mechanism of injury in each of the three conditions.
 ...
PMID:Excitotoxic mechanisms in hypoglycaemic hippocampal injury. 303 25

We studied the efficacy of the competitive NMDA receptor antagonist CGP 40116 in protecting against seizure-induced neuronal necrosis from lithium-pilocarpine-induced status epilepticus (SE). Rats were given CGP 40116 either before SE (12 mg/kg i.p.) or 15 min after the onset of SE (4, 12 and 24 mg/kg); controls received normal saline 15 min after SE began. Diazepam and phenobarbital were given i.p. after 3 h of SE to stop the seizures. Rats were killed 24 h later, and their brains were processed for light microscopic examination. Neuronal damage occurred in 24 of 25 brain regions examined in saline-injected animals. Protection was maximal in rats given 12 and 24 mg/kg CGP 40116 after SE onset: 19 and 21 of the 24 damaged regions were protected respectively, but the 24 mg/kg group had a mortality rate comparable to saline-injected controls. No necrotic neurons were found in posterior cingulate and retrosplenial neurons at the two highest CGP 40116 doses, suggesting that the transient cytoplasmic vacuolization induced by NMDA receptor antagonists does not progress to frank necrosis. In rats given CGP 40116 seizure discharges were not eliminated, but their amplitudes were significantly reduced 2 h after SE began. The periodic epileptiform discharge (PED) EEG pattern, probably a sign of widespread neuronal damage, developed in saline-injected controls after 2-2.5 h of SE but not in rats given 12 and 24 mg/kg of CGP 40116. CGP 40116 provided widespread protection against seizure-induced neuronal necrosis, suggesting that an essential step in its production is NMDA receptor activation by endogenous glutamate. The neuroprotection provided was not simply an antiepileptic effect, since electrographic seizures persisted despite NMDA receptor blockade. CGP 40116 and NMDA receptor antagonists in general could be useful as adjunctive neuroprotectants in patients with refractory SE.
 ...
PMID:The competitive NMDA receptor antagonist CGP 40116 protects against status epilepticus-induced neuronal damage. 791 91

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate (Glu) receptor have become the focus of considerable attention as potential neurotherapeutic agents in view of mounting evidence implicating NMDA receptors in acute central nervous system (CNS) injury syndromes such as stroke, trauma, and status epilepticus. In addition, NMDA receptor antagonists are of potential interest for the clinical management of neuropathic pain and preventing the development of tolerance to opiate analgesics. A potentially serious obstacle to the development of NMDA antagonists as neurotherapeutic drugs is the paradoxical fact that whereas these agents do have significant neurotherapeutic potential, they also have psychotogenic and neurotoxic properties. We have been intensively investigating the mechanisms underlying these adverse properties and have discovered several methods of suppressing or preventing their expression. In addition, we have been exploring the possibility that a common mechanism may underlie the psychotogenic and neurotoxic actions of these agents and that this mechanism may have relevance to the pathogenesis of idiopathic psychotic processes such as schizophrenia. In this chapter, we will review our findings pertaining to NMDA antagonists in the dual context of their value as tools for exploring mechanisms underlying neuropsychiatric disturbances, particularly schizophrenia, and their potential promise as therapeutic agents. For additional references and a more complete elaboration of our hypothesis pertaining to NMDA receptor dysfunction and schizophrenia, please see a recent review (Olney and Farber 1995).
 ...
PMID:NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia. 874 58


1 2 3 4 5 6 7 8 9 10 Next >>