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Epilepsy is a common neurological disorder characterised by frequent seizures which are signs and/or symptoms of abnormal neuronal activity in the brain. About 50 million people worldwide suffer from epilepsy, 90% of these people residing in developing countries (Hirtz et al. 2007). Medication is usually the first line of control but it is important to be aware that over 30% of patients do not have control of their seizures even with the best medication (J. Engel 1996). The purpose of this report is to attempt to describe what is known about the pathophysiology of epilepsy, and how this may be reflected in current and future drug therapies for this disease.
Investigations have revealed significant information about the mechanisms producing epilepsy which include insults to the brain such as infection, stroke or tumour or, it can result from genetic defects.
These genetic mutations include voltage-gated sodium channels NaV1.1, NaVβ1 and NaV1.2 (Davis et al. 2004 and Kalume et al. 2007). If these sodium channels become hyper-active it means that the cell will be closer to threshold for activation, thus making it easier to elicit an action potential.
In addition, voltage-gated calcium channels CaV3.2 (Aptel et al. 2007) and its associated voltage-dependent L-type calcium channel (subunit β4) have also been documented (Escayg et al. 1998) to be involved. These channels cause an increased permeability to calcium and cause more vesicle/s containing glutamate (or other excitatory transmitters e.g. aspartate) to bind to the pre-synaptic membrane and release their contents into the synaptic cleft for activation of the post-synaptic membrane.
Defects in potassium channels subunits KV7.2, KV7.3, KV1.1 and KV4.2 (Singh et al. 2008), GABAA receptor subunits α1, γ2 and δ (Vicini et al. 2001). These defects are assumed to make the channels hypo-active, causing the membrane potential of the cell to become less negative, thus making it easier to depolarise the cell.
Tissue organisation promptly follows epileptic seizures and can damage the high-affinity uptake systems normally in place to remove glutamate (Gjessing et al. 1972), which results in reduced re-uptake and accumulation of glutamate in the synaptic cleft. Therefore, there is a continuous diffusion of glutamate to activate neurones causing enhanced excitation.
The defects listed above are thought to involved in generating benign familial neonatal convulsions and generalised epilepsy with febrile seizures (GEFS) (Bialer and White 2010). Current and future therapies will be described for these two types of epilepsy below.
Pharmacological intervention of epilepsy works through a number of mechanisms which can be summarised in Figure 1. Ethosuximide, Gabapentin and Pregabalin all exert their effects by acting on the voltage-gated calcium channels on the pre-synaptic membranes, which prevents the neurotransmitter vesicle from binding to the membrane. Ethosuximide is a T-type Ca2+ channel blocker and reduces calcium entry when the cell is depolarised (Gomora et al. 2001). Pregabalin and Gabapentin bind to the α2δ subunit of calcium channels, reducing calcium entry into the terminals (Davies et al. 2008). However, Pregabalin also has the advantage that it increases the concentration of glutamic acid decarboxylase (GAD) which converts glutamate to GABA, thus increasing inhibitory neurotransmission.
Additional drugs include Clorazepate, Clonazepam, Tiagabine and Zonisamide which act on GABA receptors in similar ways. Clorazepate and Clonazepam are both pro-drugs for desmethyldiazepam and activate GABAA receptors, thus causing hyper-polarisation of the post-synaptic membrane by facilitating the entry of chloride ions into the cell (Skerritt and Johnston 1983). Zonisamide inhibits the reuptake of GABA and enhances the uptake of glutamate which reduces its concentration (Ueda et al. 2003). Finally, Tiagabine enhances the activity of GABA by binding to sites on the GABA uptake carrier and blocks GABA reuptake into pre-synaptic neurones (Pollack et al. 2005) resulting in greater inhibitory neurotransmissions due to a higher availability of GABA.
Topiramate, Phenobarbital, Valproic acid like the drugs above take effect by acting on GABA receptors and through other mechanisms. For example, Topiramate enhances the chloride channels that are activated by the GABAA receptor and inhibits excitatory neurotransmission by inhibiting Kainate and AMPA receptors (Rogawski and Löscher 2004). Phenobarbital activates GABAA receptors and inhibits the glutamate AMPA receptors thereby making the cell membrane more negative and decreasing excitatory transmission (Harrison et al. 2000). Valproic acid inhibits the breakdown of GABA effectively producing more GABA and it is also thought to block voltage-gated sodium channels required for depolarisation (G. Rosenberg 2007).
Carbamazepine, Lacosamide, Lamotrigine and Phenytoin act on voltage-gated sodium channels. Carbamazepine and Phenytoin prolong the inactivated state of sodium channels meaning that fewer channels are available to open making neurones less excitable, and it activates GABAA receptors which increase inhibition (Granger et al. 1995). Lamotrigine inhibits voltage-sensitive sodium channels (GlaxoSmithKline 2007) whereas Lacosamide prolongs the inactivation period of voltage-gated sodium channels and thus reducing the firing in those cells (Errington et al. 2008).
Other drugs used in the treatment of epilepsy include Eslicarbazepine, Felbamate and Levetiracetam. Eslicarbazepine blocks voltage-gated sodium channels and increases permeability to potassium thus making it more difficult to depolarise the cell (Dulsat et al. 2009) but it is used as an adjunct with other drugs. Felbamate is an inhibitor of the CYP2C19 protein (part of the cytochrome P450 family which catalyse reactions involved in drug metabolism including Phenytoin and Desmethyldiazepam), (D. A. Flockhart 2007) a GABAA receptor agonist and an NMDA receptor antagonist. As a result is increases inhibitory transmission and decreases excitatory transmission. Finally, Levetiracetam binds to the synaptic vesicle protein SV2A and stops the uptake of NT into vesicles (Lynch et al. 2004). This hinders neurotransmission as it lowers the amount of transmitter available for release.
Fig 1 (Bialer and White 2010). Proposed mechanism of actions for current drug therapies in the treatment of epilepsy.
For those people unlucky enough to suffer from drug-resistance therapies the quest for more refined and targeted drug production is of upmost importance, as it would give them a possibility of managing their illness and one with potentially less dramatic side-effects. Emerging anti-epileptic drugs can be broken down into two categories: those which have a completely original chemical structure (e.g. Carisbamate, Ganaxolone and Retigabine) and those that have been modified from existing antiepileptic drugs (e.g. Brivaracetam, Valnoctamide, Propylisopropyl acetamide and Valrocemide).
Carisbamate has shown to be highly potent and wide-ranging, and is thought to work by blocking voltage-gated sodium channels to decrease excitatory transmission. However, the precise mechanism of action for its wide range anticonvulsant activity still needs to be identified (Bialer and White 2010).
Additionally, Ganaxolone, neuro-steroid, act as an allosteric modulator of the GABAA receptor and increases the chloride current into the cell, but works at a site other than that of the benzodiazapine or barbiturate-binding sites (Carter et al. 1997) in an attempt to increase inhibitory neurotransmission.
Retigabine enhances potassium conductance via the voltage-gated K+ channel KV7.2 and increases chloride entry by activating the GABAA receptor (Bialer and White 2010) to increase inhibitory transmission. However, it is used as an adjunct to other epileptic drugs to prevent wide-scale inhibition. Two more drugs have also been produced on the basis of Retigabine, currently under phase I clinical trials, named ICA-27243 and ICA-105655. These are KV7.2 and KV7.3-selective activators respectively (Roeloffs et al. 2008).
Talampanel and Perampanel are both AMPA-receptor antagonists but are a novel class of drug which specifically target (and block) glutamate receptors mediating fast, excitatory transmission as in complex partial and primary generalised tonic-clonic seizures (H. F. Bradford 1995).
Brivaracetam, a derivative of Levetiracetam, is currently in phase II and III clinical trials and has a 10-fold higher affinity for the synaptic vesicle protein SV2A. However, its main advantage over Levetiracetam is that is also binds to voltage-gated sodium channels to decrease their function thus promoting inhibition.
Valnoctamide and Propylisopropyl acetamide are derivatives of Valproic acid but have the advantage that they are not teratogenic or hepatotoxic. Their mechanism of action is the same as Valproic acid i.e. they inhibit the GABA-transaminase and inhibit voltage-gated sodium channels (46). However, the most potent derivative of Valproic acid is Valrocemide which is currently in phase II clinical trials. It has been specifically produced to penetrate the blood-brain barrier and thus possesses a greater efficacy.
We have seen that there are a number of factors that can cause epilepsy which, in one way or another, cause the release of excess glutamate from nerve terminals resulting in an increase in neuronal firing.
Current drug therapies in the treatment of epilepsy include agents which target excitatory and inhibitory ion channels, synaptic vesicles and enzymes that control the degradation of transmitters. Undoubtedly, current therapies have undesirable side-effects ranging from inconvenient rashes to life-threatening faults such as aplastic anaemia, hepatic failure and respiratory depression (Duncan et al. 2007). Thus, it is important to develop novel antiepileptic drugs for the large number of people who suffer from drug-resistant epilepsy and to minimise the adverse effects of current drugs.
Future therapies include novel anti-epileptic drugs which work by new mechansisms and second generation drugs based on existing therapies but with greater efficacy and fewer side effects. I believe in order to identify therapies that can effectively treat (not cure) epilepsy further research into its molecular basis of will be required.