Anticonvulsants: aspects of their mechanisms of action

Abstract

An ideal anticonvulsant drug would prevent or inhibit excessive pathological neuronal discharge without interfering with physiological neuronal activity and without producing untoward effects. Such an ideal compound is not yet available. However, during the last few years several new anticonvulsants have appeared (e.g. vigabatrine, gabapentin, topiramate, lamotrigine, tiagabine, felbamate and oxcarbazepine) which may challenge the older, more established substances (i.e. phenytoin, benzodiazepines, phenobarbital, valproate, carbamazepine and ethosuximide). Interestingly, several of the old and new anticonvulsants are beneficial in the treatment of various psychiatric conditions (most notably mood disorders) as well as neuropathic pain. The reason these various drugs are effective in the treatment of such disparate clinical conditions is unknown. The answer may be that the neuronal dysfunctions underlying these conditions are similar in a mechanistic sense, but are manifested in different neurons/locations of the nervous system, or that the drugs possess several mechanisms of action that contribute in different ways to the favourable effect depending on the condition studied. Even though all these drugs inhibit excessive neuronal activity, this acute effect appears to be produced by several mechanisms, which fall into three major categories: (1) blockade of voltage-gated sodium channels; (2) indirect or direct enhancement of inhibitory gamma-aminobutyric acid [GABAergic] neurotransmission; or (3) inhibition of excitatory glutamatergic neurotransmission. Moreover, several of these drugs fall into more than one category, and it is often unclear which category is responsible for a given effect of a drug. It is plausible that some of the beneficial effects observed in the clinic can be explained by the secondary neural depressant mechanisms of action of these substances, whereas other benefits may be due to long-term neuroplastic effects, which may either be common or different across the various conditions treated.

NMDA Receptor Antagonist Felbamate Reduces Behavioral Deficits and Blood–Brain Barrier Permeability Changes after Experimental Subarachnoid Hemorrhage in the Rat

“…FBM is a novel anti-epileptic drug with a broad anticonvulsivant profile (Arcadi et al, 1997;McCabe et al, 1993;Reckilin et al, 2003;Sbuaib et al, 1996;Soderpalm et al, 2002;Swiader et al, 2003;Wallis et al, 1992;Wasterlain et al, 1992;Taylor et al, 1995). The dosage of FBM as an anticonvulsant is 1200 mg/day for adults and 15 mg/kg/day for pediatric patients.…”

“…Several mechanisms of action for FBM have been identified, including inhibition of voltage-sensitive sodium and calcium channels, potentiation of ␥-amino-butyric acid (GABA)-mediated chloride currents, and interaction with the NMDA receptor complex through inhibition of the strychnine-insensitive glycine binding site (McCabe et al, 1993;Świader et al, 2003;Taylor et al, 1995). Specifically, FBM reduces excitatory glutamatergic neurotransmission and intracellular calcium concentrations (Soderpalm, 2002).…”

Effects of Topiramate on the Chronic Constriction Injury Model in the Rat

“…2,9,10,23,32,37 Topiramate is a relatively recent addition to the AEDs with various actions that are relevant to the treatment of traumatic neuropathies 10 and other pain syndromes. 11 Indeed topiramate is one of the few AEDs to possess five mechanisms that result in enhanced neuronal stability: blockage of voltage-gated sodium channels; reduction of L-type calcium channel activity; inhibition of glutamate activity; enhanced GABAergic neurotransmission; and mild inhibition of carbonic anhydrase isoenzymes.…”

Inhibitory effects of jujuboside A on EEG and hippocampal glutamate in hyperactive rat

“…Although all anticonvulsants inhibit excessive neuronal activity, this acute effect appears to be produced by several mechanisms, which fall into three major categories: (1) blockade of voltage-gated sodium channels; (2) indirect or direct enhancement of inhibitory gamma-aminobutyric acid (GABA) neurotransmission; or (3) inhibition of excitatory glutamatergic neurotransmission (Soderpalm, 2002).…”