Intraventricular and intracerebral delivery of anti-epileptic drugs in the kindling model

Abstract

A means to avoid the pharmacokinetic problems affecting the anti-epileptic drugs may be their direct intracerebroventricular (ICV) or intracerebral delivery. This approach may achieve a greater drug concentration at the epileptogenic area while minimizing it in other brain or systemic areas, and thus it could be an interesting therapeutic alternative in drug-resistant epilepsies. The objective of this article is to review a series of experiments, ranging from actute ICV injection to continuous intracerebral infusion of anti-epileptic drugs or grafting of neurotransmitter producing cells, in experimental models, especially in the kindling model of epilepsy in the rat. Acute ICV injection of phenytoin, phenobarbital or carbamacepine is able to diminish the intensity of kindling seizures, but it is also associated with a high neurologic toxicity, especially phenobarbital. Continuous ICV infusion of anti-epileptic drugs can effectively control seizures, but neurologic toxicity is not improved compared with systemic delivery. However, systemic toxicity may be improved, as in the case of valproic acid, whose continuous ICV infusion results in very low plasmatic or hepatic drug concentrations. Continuous intracerebral infusion at the epileptogenic area was studied as an alternative to minimize neurologic toxicity. Thus, intra-amygdalar infusion of gamma-aminobutyric acid (GABA) controls seizures with minimal neurotoxicity in amygdala-kindled rats. Similarly, continuous infusion of GABA into the dorsomedian nucleus of the thalamus improves seizure spread, while not affecting the local epileptogenic activity at the amygdala. Grafting of GABA releasing cells may reduce kindling parameter severity without behavioral side effects. We may conclude that ICV or intracerebral delivery of anti-epileptic drugs or neurotransmitters may be a useful technique to modulate epilepsy.