EMERGING INSIGHTS INTO MECHANISMS OF EPILEPSY - IMPLICATIONS FOR NEW ANTIEPILEPTIC DRUG DEVELOPMENT

Most currently available antiepileptic drugs (AEDs) were developed by testing new compounds in animal models of seizures. Increased knowledg e of the cellular and molecular mechanisms underlying normal CNS funct ion and seizure phenomena is now being used to design new AEDs specifi cally to interfere with epileptic mechanisms. Focal epilepsy develops in areas of cortex that are damaged and in which aberrant recurrent ex citatory circuits develop, producing spike discharges in the EEG. Occa sionally, normal membrane conductances and inhibitory synaptic current s break down and excess excitability spreads, either locally to produc e a focal seizure or more widely to produce a generalized seizure. Bot h 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 ef fects, focusing directly on multiple components of glutamate and GABA receptors. Intrinsic, voltage-dependent currents are also involved in the pathophysiology of epileptic processes. Calcium currents act to am plify excess neuronal depolarization during hypersynchronous activatio n, are involved in neurotransmitter release, and play a role in the de velopment of longer-term changes in synaptic efficacy, which may be in volved in some seizure phenomena. They also appear to be involved in s ome forms of primary generalized epilepsy, in which burst discharges d ue to calcium currents in deep diencephalic neurons with widely ramify ing axons may act as synchronizing influences. Neuromodulatory agents, including purines, peptides, cytokines, and steroid hormones, also pl ay important roles in regulating brain excitability. Adenosine in some experimental models acts as an endogenous antiepileptic substance, an d 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, s tress, and infections, possibly mediated via systemic factors acting o n brain excitability. Each of these areas may prove fruitful in develo ping new AEDs in the future. Epilepsy may develop after brain injury b ecause the axon sprouting, new synapse formation, and circuit reorgani zation, which occur as an attempt to repair damage and restore functio n, are also likely to produce epileptogenic local circuits. To address this class of epileptic syndromes, new agents must be developed to in terrupt these counterproductive processes without interfering with use ful restorative processes. These drugs will probably be ''antiepilepti c'' in the truest sense of the word.