Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

Abstract

Epilepsy is one of the most common neurological disorders. Although epilepsy can be idiopathic, it is estimated that up to 50% of all epilepsy cases are initiated by neurological insults and are called acquired epilepsy (AE). AE develops in 3 phases: (1) the injury (central nervous system [CNS] insult), (2) epileptogenesis (latency), and (3) the chronic epileptic (spontaneous recurrent seizure) phases. Status epilepticus (SE), stroke, and traumatic brain injury (TBI) are 3 major examples of common brain injuries that can lead to the development of AE. It is especially important to understand the molecular mechanisms that cause AE because it may lead to innovative strategies to prevent or cure this common condition. Recent studies have offered new insights into the cause of AE and indicate that injury-induced alterations in intracellular calcium concentration levels [Ca 2+ ] i and calcium homeostatic mechanisms play a role in the development and maintenance of AE. The injuries that cause AE are different, but they share a common molecular mechanism for producing brain damage -an increase in extracellular glutamate concentration that causes increased intracellular neuronal calcium, leading to neuronal injury and/or death. Neurons that survive the injury induced by glutamate and are exposed to increased [Ca 2+ ] i are the cellular substrates to develop epilepsy because dead cells do not seize. The neurons that survive injury sustain permanent long-term plasticity changes in [Ca 2+ ] i and calcium homeostatic mechanisms that are permanent and are a prominent feature of the epileptic phenotype. In the last several years, evidence has accumulated indicating that the prolonged alteration in neuronal calcium dynamics plays an important role in the induction and maintenance of the prolonged neuroplasticity changes underlying the epileptic phenotype. Understanding the role of calcium as a second messenger in the induction and maintenance of epilepsy may provide novel insights into therapeutic advances that will prevent and even cure AE.

The adenosine kinase hypothesis of epileptogenesis

“…It is estimated that up to 50% of all cases are triggered by "initial precipitating injuries", such as status epilepticus (SE), stroke, and traumatic brain injury (TBI) (DeLorenzo et al, 2005;. The underlying pathophysiological process that is triggered by these and other initiating events and that transforms a healthy brain into an epileptic brain is termed epileptogenesis.…”

Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus

“…This process has been termed epileptogenesis and leads to the development of SRSs (Hauser and Hesdorffer, 1990). These long-term changes in plasticity that occur in surviving neurons induce essentially permanent alterations in these neurons that have been implicated in causing the long-term morbidity associated with AE (Delorenzo et al, 2005). The process of epileptogenesis may also be influenced by genetic predisposition (Scher, 2003;Chaix et al, 2007) and cause longterm genetic changes in the brain (Elliott et al, 2003;Lukasiuk et al, 2006).…”

“…Several studies have demonstrated that SE produces acute and chronic elevations in intracellular Ca 2+ ([Ca 2+ ] i ) and alterations in Ca 2+ homeostatic mechanisms in the hippocampus, suggesting that alterations in Ca 2+ dynamics play a major role in the development of many of the neuronal plasticity changes associated with the induction of AE and the maintenance of the epileptic phenotype Raza et al, 2001;Raza et al, 2004;Delorenzo et al, 2005). Thus, it is important to understand the effects of epileptogenesis on Ca 2+ homeostatic mechanisms.…”

“…Thus, it is important to understand the effects of epileptogenesis on Ca 2+ homeostatic mechanisms. Calcium plays a fundamental role in neurons as a second messenger governing cellular functions such as differentiation and growth, membrane excitability, exocytosis, and synaptic activity (Delorenzo et al, 2005). It has been shown that some of the long-term alterations in Ca 2+ homeostatic mechanisms observed after epileptogenesis are mediated by long-term alterations in the function of the endoplasmic reticulum Ca 2+ ATPase and IP 3 Ca 2+ induced Ca 2+ release system (Pal et al, 1999;Pal et al, 2000;Parsons et al, 2000;Pal et al, 2001;Parsons et al, 2001;Parsons et al, 2004).…”

Association of a synonymous GAT3 polymorphism with antiepileptic drug pharmacoresistance

“…Fortunately, the statistical power of the initial association remained significant after adjusting for the confounding factor, the etiology of epilepsy. In addition, given that the injuries that cause acquired epilepsy vary but share a common molecular mechanism for producing brain damage resulting in epileptogenesis, 36,37 the imbalance between excitatory and inhibitory neurotransmission due to an impaired GABA transporter reversal may not be lesion-specific, but rather a common mechanism underlying AED pharmacoresistance.…”