Status epilepticus results in an N-methyl- d-aspartate receptor-dependent inhibition of Ca 2+/calmodulin-dependent kinase II activity in the rat

Abstract

Status epilepticus is a major medical emergency that results in significant alteration of neuronal function. Status epilepticus involves seizure activity recurring frequently enough to induce a sustained alteration in brain function. This study was initiated to investigate how status epilepticus affects the activity of calcium and calmodulin-dependent kinase II in the brain. Calcium and calmodulin-dependent kinase II is a neuronally enriched signal transducing system involved in the regulation of neurotransmitter synthesis and release, cytoskeletal function, gene transcription, neurotransmitter receptor function and neuronal excitability. Therefore, alteration of this signal transduction system would have significant physiological effects. Status epilepticus was induced in rats by pilocarpine injection, allowed to progress for 60 min and terminated by repeated diazepam injections. Animals were killed at specific time-points and examined for calcium and calmodulin-dependent kinase II activity. Calcium and calmodulin-dependent kinase II activity was significantly reduced in cerebral cortex and hippocampal homogenates obtained from status epilepticus rats when compared with control animals. Once established, the status epilepticus-induced inhibition of calcium and calmodulin-dependent kinase II activity was observed at all time-points tested following the termination of seizure activity. However, calcium and calmodulin-dependent kinase II activity was not significantly decreased in thalamus and cerebellar homogenates. In addition, status epilepticus-induced inhibition of calcium and calmodulin-dependent kinase II activity was dependent upon activation of N-methyl- d-aspartate subtype of glutamatergic receptors. Thus, status epilepticus induced a significant inhibition of calcium and calmodulin-dependent kinase II activity that involves N-methyl- d-aspartate receptor activation. The data support the hypothesis that inhibition of calcium and calmodulin-dependent kinase II activity may be involved in the alteration of neuronal function following status epilepticus.