Mechanisms of Action of Antiepileptic Drugs

Abstract

Gamma-aminobutyric acid (GABA), one of the main inhibitory neurotransmitters in the brain, interacts with three types of receptors for GABA--GABA(A), GABA(B) and GABA(C). GABA(A) receptors, associated with binding sites for benzodiazepines and barbiturates in the form of a receptor complex, control opening of the chloride channel. When GABA binds to the receptor complex, the channel is opened and chloride anions enter the neuron, which is finally hyperpolarized. GABA(B) receptors are metabotropic, linked to a cascade of second messengers whilst the physiological meaning of ionotropic GABA(C) receptors, mainly located in the retina, is generally unknown. Novel antiepileptic drugs acting selectively through the GABA-ergic system are tiagabine and vigabatrin. The former inhibits neuronal and glial uptake of GABA whilst the latter increases the synaptic concentration of GABA by inhibition of GABA-aminotransferase. Gabapentin, designed as a precursor of GABA easily entering the brain, was shown to increase brain synaptic GABA. This antiepileptic drug also decreases influx of calcium ions into neurons via a specific subunit of voltage-dependent calcium channels. Conventional antiepileptics generally inhibit sodium currents (carbamazepine, phenobarbital, phenytoin, valproate) or enhance GABA-ergic inhibition (benzodiazepines, phenobarbital, valproate). Ethosuximide, mainly controlling absences, reduces calcium currents via T-type calcium channels. Novel antiepileptic drugs, mainly associated with an inhibition of voltage-dependent sodium channels are lamotrigine and oxcarbazepine. Since glutamate-mediated excitation is involved in the generation of seizure activity, some antiepileptics are targeting glutamatergic receptors--for instance, felbamate, phenobarbital, and topiramate. Besides, they also inhibit sodium currents. Zonisamide, apparently sharing this common mechanism, also reduces the concentration of free radicals. Novel antiepileptic drugs are better tolerated by epileptic patients and practically are devoid of important pharmacokinetic drug interactions.

Response to neonatal anesthesia: Effect of sex on anatomical and behavioral outcome

“…This cellular excitation is in stark contrast to chloride influx and membrane hyperpolarization (cellular inhibition) that occurs following GABA A receptor activation in the hippocampus in adulthood (Duggan, 1978). Phenobarbital, a potent anticonvulsant/barbiturate, binds directly to the GABA A receptor, resulting in enhanced receptor activation (Czapinski et al, 2005). The inhalant isoflurane has been documented to enhance GABA A receptor activity and increase the number of GABA A -mediated postsynaptic potentials (Hall et al, 2004;Haseneder et al, 2002).…”

Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus

“…Antiepileptic effect of ghrelin was also reported in an acute experimental epilepsy model in pentylenetetrazole-injected rats (Obay et al 2007). Neuropeptide Y (NPY) and g-aminobutyric acid (GABA) may be involved in the anticonvulsant effect of ghrelin because NPY and GABA exert antiepileptic effects in animal seizure models (Czapinski et al 2005, Stroud et al 2005 and ghrelin not only enhances NPY but also increases GABA-ergic activity in the brain (Cowley et al 2003). It is well known that a majority of epileptic seizures are due to an imbalance between the activities of inhibitory and excitatory neurotransmitters (Sharma et al 2007).…”

Zonisamide Prevents Olanzapine-Associated Hyperphagia, Weight Gain, and Elevated Blood Glucose in Rats

“…D 2 receptor agonists are known to inhibit feeding in rats (Kuo, 2002;Terry et al, 1995); therefore, it is also possible that the anorectic properties of ZNS may relate to the augmentation of dopamine synthesis and/or stimulation of D 2 receptors (Okada et al, 1995). The antiepileptic activity of ZNS may be mediated by a decreased production of GABA transporters, resulting in increased tissue and synaptic concentrations of GABA and enhanced GABA mediated neuronal inhibition (Czapinski et al, 2005). ZNS is also thought to potentially inhibit glutamate mediated neuronal excitation (Maldonado-Irizarry et al, 1995).…”