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).

Was this article helpful?

0 0
Free Yourself from Panic Attacks

Free Yourself from Panic Attacks

With all the stresses and strains of modern living, panic attacks are become a common problem for many people. Panic attacks occur when the pressure we are living under starts to creep up and overwhelm us. Often it's a result of running on the treadmill of life and forgetting to watch the signs and symptoms of the effects of excessive stress on our bodies. Thankfully panic attacks are very treatable. Often it is just a matter of learning to recognize the symptoms and learn simple but effective techniques that help you release yourself from the crippling effects a panic attack can bring.

Get My Free Ebook

Post a comment