Novel Neuroprotective Strategies and Targets of Intervention in Epilepsy

Epilepsy is a debilitating disorder that affects over 50 million people worldwide, resulting in $15.5 billion in medical expenses and lost income/worker productivity in the United States every year (Patel, 2004). Epilepsy, also known as status epilepticus (SE), is described as the unregulated over stimulation of neurons throughout various regions of the brain. SE is characterized by seizures lasting for 30 or more minutes accompanied by a loss of consciousness. This disorder has been associated with significant rates of morbidity and mortality, possibly induced by neuronal damage and dysfunction (Sleven, et al., 2006). It is thought to be the result of an imbalance of excitatory and inhibitory input in a subset of neurons, which is then propagated to other regions of the brain, causing improper activation of multiple brain regions and uncontrolled cortical output (Rho, et al., 2004). Most patients are either under the age of 20 or over 65 years old, with a greater prevalence being in younger patients. While development of SE has a wide range of possible etiologies, whether spontaneously, as the direct result of trauma, brain tumors, metabolic abnormalities, or due to genetic predisposition, the exact mechanism(s) of the development of SE is poorly understood (Pellock, et al., 2001, Rho, et al., 2004). Oxidative stress has been associated with SE; however, it continues to be somewhat controversial whether it plays a causal role in the development of epilepsy or if it is simply the consequence of prolonged excitation (Patel, 2004). This increased excitation exerts high metabolic demands on cellular systems, such as Na+/K+ pumps and other ATP dependent mechanisms, required for maintaining normal cellular homeostasis. Mitochondria are the main source of ATP in neurons and mitochondrial dysfunction has been linked to many acute and chronic neurological disorders including Parkinson’s disease, traumatic brain injury, stroke/ischemia, and Alzheimer’s disease. Mitochondrial dysfunction is known to increase oxidative damage via increased mitochondrial reactive oxygen species (ROS) production, which has been shown to be a critical side effect of prolonged epileptic seizure and may cause increased susceptibility to subsequent seizures (Patel, 2002). It has also been shown that after prolonged seizure activity there is significant oxidative damage to mitochondrial DNA (mtDNA), which is responsible for encoding key proteins of the electron transport chain (ETC) required for oxidative phosphorylation and normal mitochondrial function (Patel and Li, 2003). Disruption of ATP production can cause impaired mitochondrial and plasma membrane transporter function, initiation of necrotic