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Acute cellular alterations in the hippocampus after status epilepticus.
Epilepsia. 1999; 40 Suppl 1:S9-20; discussion S21-2.E

Abstract

The critical, fundamental mechanisms that determine the emergence of status epilepticus from a single seizure and the prolonged duration of status epilepticus are uncertain. However, several general concepts of the pathophysiology of status epilepticus have emerged: (a) the hippocampus is consistently activated during status epilepticus; (b) loss of GABA-mediated inhibitory synaptic transmission in the hippocampus is critical for emergence of status epilepticus; and, finally (c) glutamatergic excitatory synaptic transmission is important in sustaining status epilepticus. This review focuses on the alteration of GABAergic inhibition in the hippocampus that occurs during the prolonged seizures of status epilepticus. If reduction in GABAergic inhibition leads to development of status epilepticus, enhancement of GABAergic inhibition would be expected to interrupt status epilepticus. Benzodiazepines and barbiturates are both used in the treatment of status epilepticus and both drugs enhance GABA(A) receptor-mediated inhibition. However, patients often become refractory to benzodiazepines when seizures are prolonged, and barbiturates are often then used for these refractory cases of status epilepticus. Recent evidence suggests the presence of multiple GABA(A) receptor isoforms in the hippocampus with different sensitivity to benzodiazepines but similar sensitivity to barbiturates, thus explaining why the two drug classes might have different clinical effects. In addition, rapid functional plasticity of GABA(A) receptors has been demonstrated to occur during status epilepticus in rats. During status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. The loss of sensitivity of the animals to diazepam during status epilepticus was accompanied by an alteration in the functional properties of hippocampal dentate granule cell GABA(A) receptors. Dentate granule cell GABA(A) receptor currents from rats undergoing status epilepticus had reduced sensitivity to diazepam and zinc but normal sensitivity to GABA and pentobarbital. Therefore, the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABA(A) receptors, possibly explaining why benzodiazepines and barbiturates may not be equally effective during treatment of the prolonged seizures of status epilepticus. A comprehensive understanding of the cellular and molecular events leading to the development, maintenance, and cytotoxicity of status epilepticus should permit development of more effective treatment strategies and reduction in the mortality and morbidity of status epilepticus.

Authors+Show Affiliations

Department of Neurology, University of Michigan Medical Center, Ann Arbor 48104-1687, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.
Review

Language

eng

PubMed ID

10421557

Citation

Macdonald, R L., and J Kapur. "Acute Cellular Alterations in the Hippocampus After Status Epilepticus." Epilepsia, vol. 40 Suppl 1, 1999, pp. S9-20; discussion S21-2.
Macdonald RL, Kapur J. Acute cellular alterations in the hippocampus after status epilepticus. Epilepsia. 1999;40 Suppl 1:S9-20; discussion S21-2.
Macdonald, R. L., & Kapur, J. (1999). Acute cellular alterations in the hippocampus after status epilepticus. Epilepsia, 40 Suppl 1, S9-20; discussion S21-2.
Macdonald RL, Kapur J. Acute Cellular Alterations in the Hippocampus After Status Epilepticus. Epilepsia. 1999;40 Suppl 1:S9-20; discussion S21-2. PubMed PMID: 10421557.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acute cellular alterations in the hippocampus after status epilepticus. AU - Macdonald,R L, AU - Kapur,J, PY - 1999/7/27/pubmed PY - 1999/7/27/medline PY - 1999/7/27/entrez SP - S9-20; discussion S21-2 JF - Epilepsia JO - Epilepsia VL - 40 Suppl 1 N2 - The critical, fundamental mechanisms that determine the emergence of status epilepticus from a single seizure and the prolonged duration of status epilepticus are uncertain. However, several general concepts of the pathophysiology of status epilepticus have emerged: (a) the hippocampus is consistently activated during status epilepticus; (b) loss of GABA-mediated inhibitory synaptic transmission in the hippocampus is critical for emergence of status epilepticus; and, finally (c) glutamatergic excitatory synaptic transmission is important in sustaining status epilepticus. This review focuses on the alteration of GABAergic inhibition in the hippocampus that occurs during the prolonged seizures of status epilepticus. If reduction in GABAergic inhibition leads to development of status epilepticus, enhancement of GABAergic inhibition would be expected to interrupt status epilepticus. Benzodiazepines and barbiturates are both used in the treatment of status epilepticus and both drugs enhance GABA(A) receptor-mediated inhibition. However, patients often become refractory to benzodiazepines when seizures are prolonged, and barbiturates are often then used for these refractory cases of status epilepticus. Recent evidence suggests the presence of multiple GABA(A) receptor isoforms in the hippocampus with different sensitivity to benzodiazepines but similar sensitivity to barbiturates, thus explaining why the two drug classes might have different clinical effects. In addition, rapid functional plasticity of GABA(A) receptors has been demonstrated to occur during status epilepticus in rats. During status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. The loss of sensitivity of the animals to diazepam during status epilepticus was accompanied by an alteration in the functional properties of hippocampal dentate granule cell GABA(A) receptors. Dentate granule cell GABA(A) receptor currents from rats undergoing status epilepticus had reduced sensitivity to diazepam and zinc but normal sensitivity to GABA and pentobarbital. Therefore, the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABA(A) receptors, possibly explaining why benzodiazepines and barbiturates may not be equally effective during treatment of the prolonged seizures of status epilepticus. A comprehensive understanding of the cellular and molecular events leading to the development, maintenance, and cytotoxicity of status epilepticus should permit development of more effective treatment strategies and reduction in the mortality and morbidity of status epilepticus. SN - 0013-9580 UR - https://www.unboundmedicine.com/medline/citation/10421557/Acute_cellular_alterations_in_the_hippocampus_after_status_epilepticus_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0013-9580&date=1999&volume=40&issue=&spage=S9 DB - PRIME DP - Unbound Medicine ER -