Emerging Insights Into Mechanisms of Epilepsy: Implications for New Antiepileptic Drug Development

Summary: Most currently available antiepileptic drugs (AEDs) were developed by testing new compounds in animal models of seizures. Increased knowledge of the cellular and molecular mechanisms underlying normal CNS function and seizure phenomena is now being used to design new AEDs specifically to interfere with epileptic mechanisms. Focal epilepsy develops in areas of cortex that are damaged and in which aberrant recurrent excitatory circuits develop, producing spike discharges in the EEC Occasionally, normal membrane conductances and inhibitory synaptic currents break down and excess excitability spreads, either locally to produce a focal seizure or more widely to produce a generalized seizure. Both original synchronous activation and seizure spread appear to utilize normal synaptic pathways and mechanisms. Much new development of AEDs is targeted at modulating these excitatory and inhibitory synaptic effects, focusing directly on multiple components of gluta‐mate and GABA receptors. Intrinsic, voltage‐dependent currents are also involved in the pathophysiology of epileptic processes. Calcium currents act to amplify excess neuronal depolarization during hypersynchronous activation, are involved in neurotransmitter release, and play a role in the development of longer‐term changes in synaptic efficacy, which may be involved in some seizure phenomena. They also appear to be involved in some forms of primary generalized epilepsy, in which burst discharges due to calcium currents in deep diencephalic neurons with widely ramifying axons may act as synchronizing influences. Neuromodulatory agents, including purines, peptides, cytokines, and steroid hormones, also play important roles in regulating brain excitability. Adenosine in some experimental models acts as an endogenous antiepileptic substance, and agents that enhance the actions of adenosine are often antiepileptic in animal models. Somatostatin may modulate synaptic inhibition, and this modulation may be lost when somatostatin levels are decreased in epileptic lesions. Seizures are also influenced by hormonal changes, stress, and infections, possibly mediated via systemic factors acting on brain excitability. Each of these areas may prove fruitful in developing new AEDs in the future. Epilepsy may develop after brain injury because the axon sprouting, new synapse formation, and circuit reorganization, which occur as an attempt to repair damage and restore function, are also likely to produce epileptogenic local circuits. To address this class of epileptic syndromes, new agents must be developed to interrupt these counterproductive processes without interfering with useful restorative processes. These drugs will probably be “antiepileptic” in the truest sense of the word.