Biomedical Engineering Reference
In-Depth Information
3.1 As Antiepileptic Drugs
Epilepsy is a very common neurological disease that affect about 0.5-1.0% of
worldwide population [
91
]. It consists of a disorder of neuronal excitability,
characterized by episodes of excessive synchronized neuronal activity. Electroen-
cephalograms from patients suffering from epileptic disorders reveal two types of
anomalous activity: interictal events, which are short asymptomatic episodes recur-
ring periodically between seizures and consist of periods of relative inactivity, and
ictal discharges, which are protracted abnormalities in neuronal activity [
92
]. Both
ictal and interictal discharges are characterized by sustained firing of Na
+
-depen-
dent action potentials riding on a slow depolarized potential, mainly generated by
synaptic ligand-gated cation currents [
92
]. It is possible to distinguish epilepsies
based on the entity of seizures. In generalized seizures, the origin is in both
hemispheres, while focal seizures involve only a portion of the brain, in particular
structures in the temporal or frontal lobes. Current pharmacological approaches to
the treatment of epilepsy try to control seizures, the major symptom of this
pathological condition. Antiictogenic pharmacostrategies can free patients with
established epilepsy from seizures, but in approximately one-third of all cases
seizures cannot be controlled [
93
,
94
]. In particular, voltage-gated ion channels
are of great importance as targets for antiictogenic drugs. Sodium and calcium
channels, in fact, regulate firing of action potentials and contribute to the paroxys-
mal depolarization shift, and they also regulate neurotransmitter release that is
required for synaptic transmission [
95
].
3.1.1 VGSC Blockers for Epilepsy (AEDs)
The block of sodium channel currents is the most common and well-characterized
mechanism of action of currently available AEDs. These drugs prevent the return of
the channels to the active state by stabilizing the inactive form. The presynaptic and
postsynaptic blockade of axonal sodium channels stabilizes neuronal membranes,
blocks or prevents the potentiation of the electrical signal propagation, limits the
maximal seizure activity and reduces the spread of seizures. The most used AEDs
inhibit VGSCs at therapeutic concentrations; their capability to attenuate Na
+
currents is thought to be the main mechanism underlying their therapeutic efficacy
[
95
]. All the drugs proposed for the therapy are potentially effective in the maximal
electroshock seizure test, a model of tonic-clonic seizures that assesses the ability of
AEDs to suppress seizures induced in normal rodents by electrical stimuli, and/or
they are potentially effective in pentetrazol-treated rodents, a model used to identify
drugs that are efficacious for absence seizures.
Phenytoin (Fig.
3
): since its introduction in clinical practice, more than 70 years
ago, phenytoin has been the major VGSC-specific AED in the treatment of partial
and secondary generalized seizures. Its ability not to interfere with normal cogni-
tive function conferred great importance to this drug in the treatment of epilepsies
