Inhibition of the Calcium Plateau Following In Vitro Status Epilepticus Prevents the Development of Spontaneous Recurrent Epileptiform Discharges

Status epilepticus (SE) is a major clinical emergency resulting in continuous seizure activity that can cause brain injury and many molecular and pathophysiologic changes leading to neuronal plasticity. The neuronal plasticity following SE-induced brain injury can initiate epileptogenesis and lead to the ultimate expression of acquired epilepsy (AE), characterized clinically by spontaneous, recurrent seizures. Epileptogenesis is the process wherein healthy brain tissue is transformed into hyperexcitable neuronal networks that produce AE. Understanding these alterations induced by brain injury is an important clinical challenge and can lend insight into possible new therapeutic targets to halt the development of AE. Currently there are no means to prevent epileptogenesis following brain injury; thus, the elucidation of mechanisms of epileptogenesis will be useful in preventing the long-term clinical sequela. It has been demonstrated in vivo that calcium (Ca2+) dynamics are severely altered during SE and that elevations in intracellular Ca2+ ([Ca2+]i) in hippocampal neurons are maintained well past the duration of the injury itself (Ca2+ plateau). Here we report that similar changes in [Ca2+]i are observed in the hippocampal neuronal culture model of SE-induced AE. As an important second messenger, the maintenance of a Ca2+ plateau following injury can lead to several changes in gene expression, neurotransmitter release, and overall, neuronal plasticity. Thus, changes in post-SE [Ca2+]i and Ca2+ homeostasis may be important in understanding epileptogenesis and eventually preventing the progression to chronic epilepsy. This dissertation examines the development and maintenance of the Ca2+ plateau after SE and demonstrates the novel finding that pharmacological modulation of [Ca2+]i following SE may inhibit epileptogenesis in vitro.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmacology & Toxicology

Year dc:date.available

2009

Author dc:creator

• Nagarkatti, Nisha

Contributors dc:contributor

• Robert DeLorenzo

• Epilepsy
• Status Epilepticus
• Calcium
• Ryanodine Receptor
• Hippocampal Neuronal Culture
• Sprague-Dawley Rat
• Medical Pharmacology
• Medical Sciences
• Medicine and Health Sciences

Statement dc:rights

• © The Author

Identifier

https://scholarscompass.vcu.edu/etd/38

OAI identifier oai:identifier

oai:scholarscompass.vcu.edu:etd-1037