Nature And Mechanisms Of Seizures And Antiseizure Drugs Partial Epilepsies

Either reduction of inhibitory synaptic activity or enhancement of excitatory synaptic activity might trigger a seizure. The neurotransmitters mediating the bulk of synaptic transmission in the mammalian brain are amino acids, with g-aminobutyric acid (GABA) and glutamate being the principal inhibitory and excitatory neurotransmitters, respectively (see Chapter 12). Pharmacological studies showed that antagonists of the GABAa receptor or agonists of different glutamate-receptor subtypes (NMDA, AMPA, or kainic acid; see Table 12-1) trigger seizures in experimental animals. Conversely, drugs that enhance GABA-mediated synaptic inhibition or glutamate-receptor antagonists inhibit seizures. Such studies support the concept that pharmacological modulation of synaptic function can affect the propensity for seizures.

Electrophysiological analyses during a partial seizure demonstrate that the individual neurons undergo depolarization and fire action potentials at high frequencies. This pattern of rapid firing is characteristic of a seizure but is uncommon during normal neuronal activity. Thus, selective inhibition of this rapid firing would be expected to reduce seizures with minimal unwanted effects. Inhibition of the high-frequency firing may be mediated by reducing the ability of Na+ channels to recover from inactivation, thus prolonging the refractory period when another action potential cannot be evoked. Thus, reducing the rate of recovery of Na+ channels from inactivation would limit the ability of a neuron to fire at high frequencies, an effect that likely underlies the effects of carbamazepine, lamotrigine, phenytoin, topiramate, valproic acid, and zonisamide against partial seizures (Figure 19-1).

Enhancing GABA-mediated synaptic inhibition may reduce neuronal excitability and raise the seizure threshold. Several drugs may inhibit seizures by regulating GABA-mediated synaptic inhibition. The principal postsynaptic receptor of synaptically released GABA is the GABAA receptor (see Chapter 16). Activation of the GABAa receptor inhibits the postsynaptic cell by increasing Cl- inflow into the cell and hyperpolarizing the neuron. Clinically relevant concentrations of benzodiazepines and barbiturates enhance GABAa receptor-mediated hyperpolarization through distinct actions on the GABAA receptor; this enhanced inhibition probably underlies their effectiveness against partial and tonic-clonic seizures (Figure 19-2). At higher concentrations, such as might be used for status epilepticus, these drugs also inhibit high-frequency firing of action potentials. A second mechanism of enhancing GABA-mediated synaptic inhibition is thought to underlie the antiseizure mechanism of tiagabine which inhibits the GABA transporter GAT-1 and reduces neuronal and glial uptake of GABA and thereby enhancing GABA-mediated neurotransmission (Figure 19-2).

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