TheN-methyl-D-aspartate antagonists aminophosphonovalerate and car☐ypiperazinephosphonate retard the development and expression of kindled seizures

Holmes, Keith H.; Bilkey, David K.; Laverty, R.; Goddard, Graham V.

doi:10.1016/0006-8993(90)91255-f

Cited by 192 publications

(21 citation statements)

References 34 publications

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“…For example, Holmes et al [25] have demonstrated that the selective NMDA receptor blockers 2-amino-phosphonovalerate (APV) and carboxypiperazine-phosphate (CPP) blocked the development of the kindled state. These agents had only small depressant effects on seizure expression in fully kindled rats.…”

Section: Discussionmentioning

confidence: 99%

The in vivo proconvulsant effects of corticotropin releasing hormone in the developing rat are independent of ionotropic glutamate receptor activation

Brunson¹,

Schultz²,

Baram³

1998

Developmental Brain Research

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Corticotropin releasing hormone (CRH) produces age-dependent limbic seizures in the infant rat. Both the phenotype and the neuroanatomic matrix of CRH-induced seizures resemble the seizures induced by the rigid glutamate analogue, kainic acid (KA), and by rapid amygdala kindling. The experiments described in this study tested the hypothesis that the in vivo proconvulsant effects of CRH require activation of ionotropic glutamate receptors. Non-competitive (+MK-801) or competitive (CGP-39551) antagonists of N-methyl-D-aspartate (NMDA) receptors decreased or eliminated the motor effects of CRH, but electrographic CRH-induced seizures were unaffected. Administration of CRH antagonists did not affect the acquisition or the maintenance of rapid kindling, which are mediated by NMDA and α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor activation, respectively. CRH receptor blockers failed to alter the latency or duration of seizures induced by activation of KA receptors, and threshold doses of CRH and KA had additive effects. CRH given repeatedly decreased the convulsant threshold dose of KA, probably via injury to hippocampal neurons. These results suggest that CRH and glutamate increase neuronal excitability via independent mechanisms. Because the proconvulsant effects of CRH are highly specific to the developmental period, glutamate-receptor-independent, CRHreceptor mediated excitation may account for some of the enhanced susceptibility to seizures during this period.

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Section: Discussionmentioning

confidence: 99%

The in vivo proconvulsant effects of corticotropin releasing hormone in the developing rat are independent of ionotropic glutamate receptor activation

Brunson¹,

Schultz²,

Baram³

1998

Developmental Brain Research

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“…Second, glutamatergic transmission plays a critical role in kindling. Many studies, including some early reports (e.g., (Holmes et al 1990), have shown that nonspecific NMDA antagonists delay kindling and suppress kindled seizures. Furthermore, pharmacological data with subunit-specific antagonists have implicated the NR2A subunit (Chen et al 2007) in establishment of kindling and the triggering of generalized kindled seizures and the NR2B subunit (Barton and White 2004) in the triggering of generalized kindled seizures.…”

Section: 19mentioning

confidence: 98%

Regional Changes in Gene Expression after Limbic Kindling

Corcoran

Kroes²,

Burgdorf

et al. 2011

Cell Mol Neurobiol

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Repeated electrical stimulation results in development of seizures and a permanent increase in seizure susceptibility (kindling). The permanence of kindling suggests that chronic changes in gene expression are involved. Kindling at different sites produces specific effects on interictal behaviors such as spatial cognition and anxiety, suggesting that causal changes in gene expression might be restricted to the stimulated site. We employed focused microarray analysis to characterize changes in gene expression associated with amygdaloid and hippocampal kindling. Male Long-Evans rats received 1 s trains of electrical stimulation to either the amygdala or hippocampus once daily until five generalized seizures had been kindled. Yoked control rats carried electrodes but were not stimulated. Rats were euthanized 14 days after the last seizures, both amygdala and hippocampus dissected, and transcriptome profiles compared. Of the 1,200 rat brain-associated genes evaluated, 39 genes exhibited statistically significant expression differences between the kindled and non-kindled amygdala and 106 genes exhibited statistically significant differences between the kindled and non-kindled hippocampus. In the amygdala, subsequent ontological analyses using the GOMiner algorithm demonstrated significant enrichment in categories related to cytoskeletal reorganization and cation transport, as well as in gene families related to synaptic transmission and neurogenesis. In the hippocampus, significant enrichment in gene expression within categories related to cytoskeletal reorganization and cation transport was similarly observed. Furthermore, unique to the hippocampus, enrichment in transcription factor activity and GTPase-mediated signal transduction was identified. Overall, these data identify specific and unique neurochemical pathways chronically altered following kindling in the two sites, and provide a platform for defining the molecular basis for the differential behaviors observed in the interictal period.

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“…Phenytoin (PHT), a potent anticonvulsant not associated with NMDA receptors, potentiates ['HIDM binding (Craviso and Musacchio, 1983). Addition of a small amount of DM (15 m&g) potentiates the anticonvulsant activity of PHT on maximal electroshock convulsions (Tortella and Musa%chiO, 1986 Holmes et al, 1990). These data suggest that DM may have multiple recognition sites in the brain, and the mechanism of the anticonvulsant effects of DM cannot be explained simply by NMDA antagonism.…”

Section: Discussionmentioning

confidence: 90%

Effects of Dextromethorphan, a Nonopioid Antitussive, on Development and Expression of Amygdaloid Kindled Seizures

1990

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The effects of dextromethorphan (DM), a nonopioid antitussive and a functional N-methyl-D-aspartate (NMDA) antagonist, on expression and development of amygdaloid kindled seizures were examined. The maximum anticonvulsant effect of DM (30 mg/kg) on fully kindled seizures appeared within 30 min of administration and lasted for at least 2 h. DM decreased, in a dose-dependent manner [10-70 mg/kg, intraperitoneally (i.p.)], the severity of kindled seizures 30 min after injection, but the estimated ED50 was 3 times higher than the previously reported value for maximal electroshock convulsions. Furthermore, the high dose (70 mg/kg), while suppressing kindled seizures, produced myoclonus which coincided with EEG spike activity in the amygdala and the cortex. When tested on the development of kindling, 30 mg/kg DM retarded the growth of afterdischarge in the amygdala and the cortex, but had no effect on the development of behavioral seizures. DM 60 mg/kg accelerated development of kindling and produced spontaneous seizures. These results indicate that DM, unlike other NMDA antagonists, has a narrow therapeutic window as an anticonvulsant on kindled seizures and that higher doses may potentiate the kindling process.

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TheN-methyl-D-aspartate antagonists aminophosphonovalerate and car☐ypiperazinephosphonate retard the development and expression of kindled seizures

Cited by 192 publications

References 34 publications

The in vivo proconvulsant effects of corticotropin releasing hormone in the developing rat are independent of ionotropic glutamate receptor activation

The in vivo proconvulsant effects of corticotropin releasing hormone in the developing rat are independent of ionotropic glutamate receptor activation

Regional Changes in Gene Expression after Limbic Kindling

Effects of Dextromethorphan, a Nonopioid Antitussive, on Development and Expression of Amygdaloid Kindled Seizures

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