Antiepileptic Drugs, 5th Edition



Mechanisms of Action

William J. Giardina PhD

Associate Research Fellow, Central Nervous System Diseases Research, Abbott Laboratories, Abbott Park, Illinois

Tiagabine HCl (R-N-(4,4-di-(3-methyl-2-thienyl)-3-butenyl)nipecotic acid, hydrochloride) (Figure 71.1) is a potent blocker of γ-aminobutyric acid (GABA) uptake by neurons and glia. Novo-Nordisk scientists discovered tiagabine HCl in 1987 in Denmark. GABA is the major inhibitory neurotransmitter in the central nervous system, and a reduction in GABA-mediated inhibition has been implicated in the origin of epilepsy and other neurologic disorders (1,2). Two important observations formed the basis of the Novo-Nordisk drug discovery program. First, nipecotic acid and several other cyclic amino acids, such as guvacine, hydroxynipecotic acid, and homo-β-proline, block GABA uptake into glia and neurons in vitro, and second, nipecotic acid protects mice against sound-induced seizures after intracerebroventricular injection (2,3). Nipecotic acid does not cross the blood-brain barrier after systemic administration. Novo-Nordisk scientists synthesized and evaluated a series of compounds in which nipecotic acid was linked by an aliphatic chain to different lipophilic groups. These compounds were designed to be orally active blockers of GABA uptake that would readily cross the blood-brain barrier. Tiagabine HCl emerged from this program as the best of these compounds to become a candidate for clinical study in epilepsy. Tiagabine HCl has received regulatory approval in the United States and in many countries around the world for use as adjunctive therapy in the treatment of partial seizures with and without generalization.

The anticonvulsant profile of tiagabine HCl in animal seizure models is summarized in Table 71.1. Tiagabine HCl blocks seizures induced by pentylenetetrazol (PTZ) and DMCM (6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate), but it only weakly inhibits maximal electroshock seizures (4,5). It blocks the kindling process and the expression of amygdala-kindled seizures in rats (6,7). Thus, the screening profile of tiagabine HCl is unique among the older, firstgeneration, and the newer, second-generation, anticonvulsants. Tiagabine HCl provides maximal protection of only 50% to 60% against PTZ and DMCM clonic seizures at doses in the range of 1 to 10 mg/kg intraperitoneally (i.p.), and a dose of 30 mg/kg i.p., it fails altogether to block clonic seizures. In contrast, tiagabine HCl blocks PTZ tonic seizures and death in a dose-related manner (4,5). Tiagabine HCl is effective in three animal models of reflex epilepsy: sound-induced seizures in the epilepsy-prone rat and the DBA/2 mouse and photic-induced seizures in the baboon (5,8,9). Tiagabine HCl is also effective in controlling status epilepticus in cobalt-lesioned rats (10). Anticonvulsant tolerance, an activity-dependent liability of benzodiazepine anticonvulsants and of other GABAergic compounds, does not develop after repeated doses of tiagabine HCl in the mouse (11). In rodents, tiagabine HCl produces sedation at doses 10 to 14 times higher than anticonvulsant doses and impairs motor coordination at doses four to six times higher than anticonvulsant doses (5). With long-term administration, a substantial tolerance develops to the sedative and motor-impairing effects of tiagabine HCl in rodents. In addition to its well-characterized anticonvulsant activity, tiagabine HCl has also been shown to have antiallodynic pharmacology in a rodent model of neuropathic pain and antinociceptive and anxiolytic pharmacology in rodent behavioral models (12, 13, 14).


FIGURE 71.1. Tiagabine HCl. R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride. Tiagabine HCl consists of nipecotic acid linked by an aliphatic chain to a lipophilic group (dimethylthienyl).



Seizure Model (Reference)

Effects of Tiagabine Hydrochloride

Pentylenetetrazol-induced tonic and clonic seizures in mice (5)

Blocks tonic seizures, ED50 = 0.8 mg/kg, i.p.


Blocks clonic seizures, ED50 = 2 mg/kg i.p., ineffective at 30 mg/kg, i.p.

DMCM (6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate)-induced tonic and clonic seizures in mice (4,5)

Blocks tonic seizures, ED50 = 0.8 mg/kg, i.p.

Blocks clonic seizures ED50 = 0.8 mg/kg, i.p., ineffective at 100 mg/kg, i.p.

Maximal electroshock seizures in mice (5)

Ineffective up to 30 mg/kg, i.p.

Bicuculline-induced seizures in mice (4)

40% antagonism at 8 mg/kg, i.p., ineffective at higher doses

Amygdala-kindled seizures in rats (6)

Suppresses the kindling process and expression of kindled seizures at 10 mg/kg, i.p.

Sound-induced tonic and clonic seizures in DBA/2 mice (5)

Blocks clonic seizures, ED50 = 0.4 mg/kg, i.p.


Blocks tonic seizures, ED50 = 0.4 mg/kg, i.p.

Sound-induced clonic seizures in genetically epilepsy-prone rats (8)

Blocks clonic seizures, ED50 = 10 mg/kg, i.p. at 30 min after dosing

Photically induced myoclonic seizures in Papio papio (9)

Reduces myoclonus at 0.2-1 mg/kg, i.v.


Approximate ED50 of 0.6 mg/kg, i.v.

Homocysteine thiolactone-induced status epilepticus in cobalt-lesioned rats (10)

Controls generalized tonic-clonic seizures at 8.3 mg/kg, i.p.

ED50, dose protecting 50% of animals; i.p., intraperitoneally; i.v., intravenously.


After release into the synapse from presynaptic nerve terminal vesicles, GABA binds to certain functional sites: GABAA and GABAB receptors and a family of GABA uptake transporters. The GABAA receptor, the more prevalent of the two GABA receptors in the central nervous system, is a postsynaptic, multisubunit, receptor-chloride ion channel complex that, when activated by GABA, increases chloride permeability (Figure 71.2). The increase in chloride permeability results in the hyperpolarization of the nerve membrane potential and thus a decrease in nerve excitability. Experimental evidence suggests that alterations in GABAA receptor activity are involved in the initiation and spread of seizure activity (1). The GABABreceptor is coupled to cellular membrane calcium and potassium ion channels


through intracellular second messenger systems. GABAB receptors are found on presynaptic terminals, where they function to decrease neurotransmitter release through depolarization, and on postsynaptic sites, where they serve to hyperpolarize cells. After release into the synapse, unbound GABA is removed from the synapse into presynaptic nerve endings and astroglia by high-affinity, sodium-dependent membrane transporter proteins. Molecular cloning has revealed four such GABA transporters in the central nervous system: GAT-1, GAT-2, GAT-3, and BGT-1 (15,16). Tiagabine HCl is a highly selective blocker of the GAT-1 transporter, which is the predominant transporter in rat forebrain (cortex, striatum, and hippocampus (15,16).


FIGURE 71.2. The GABAA synapse. Glutamate is metabolized by glutamic acid decarboxylase (GAD) to form GABA. After release from synaptic vesicles, GABA is inactivated by uptake in glia and presynaptic endings. GABA is metabolized by GABA transaminase (GABAT) in mitochondria to form succinic semialdehyde (SSA).

Braestrup and colleagues did the pioneering work that characterized the biochemistry and pharmacology of tiagabine HCl (17). Tiagabine HCl inhibits the uptake of [3H]-GABA into rat forebrain-derived synaptosomes with an IC50 value, which is the concentration that inhibits the uptake of [3H]-GABA by 50%, of 67 nmol/L, and in primary cultures of neurons and astrocytes with IC50 values of 466 and 182, respectively. Tiagabine HCl produces a mixed competitive-noncompetitive type of inhibition of [3H]-GABA uptake. In the same assays, tiagabine HC1 is more potent than nipecotic acid (IC50 values of 3,790, 16,800, and 33,000 in synaptosomes, neurons, and astrocytes, respectively), and it is more potent than a guvacine-derived uptake inhibitor SKF-100330A (IC50 values of 331, 1,772, and 559 in synaptosomes, neurons, and astrocytes, respectively). Tiagabine HCl (200 nmol/L) significantly reduces the uptake of GABA into human astrocytes cultured from human adult brain tissue (18). Tiagabine HCl, the (R)-(-)-enantiomer of the racemic compound, is more potent than the corresponding (S)-(+)-enantiomer in these assays, a finding indicating a stereospecific interaction at the GAT-1 transporter. Tiagabine HCl is a specific inhibitor of the GAT-1 transporter, as indicated by the finding that it has no significant binding affinity for catecholamine, serotonin, or glutamate transporters. It also does not bind to catecholamine, acetylcholine, adenosine, serotonin, histamine, opiate, glycine, or glutamate receptors, and it has no affinity for voltage-gated calcium or sodium ion channels.

Tiagabine HCl (100 to 300 nmol/L) and vigabatrin (100 µmol/L), an inhibitor of GABA transaminase, or the combination of both, reduce [14C]GABA uptake in primary cultures of rat cortical astrocyte (19). In these experiments, the inhibition of GABA uptake in cultures exposed to both compounds was greater than that observed for each drug alone, but the combined effect was infraadditive, a finding suggesting a common site of action for both compounds. Vigabatrin may affect GABA transport in these cultures by acting as a substrate for the GABA transporter (19). Tiagabine HCl is not a substrate for the GAT-1 transporter and is not transported into neurons (17). Because it is not transported into neurons, tiagabine HCl does not stimulate the release of GABA or act as a false neurotransmitter.

Several experiments show that the oral and parenteral administration of tiagabine HCl, at pharmacologically relevant doses, increases the extracellular levels of GABA. The ED50 (11.5 mg/kg i.p., the dose blocking seizures in 50% of animals) and ED85 (21 mg/kg i.p.) doses of tiagabine HCl for inhibiting PTZ-induced seizures in rats produce dose-related increases in the extracellular levels of GABA in rat brain (20). In these experiments, in which extracellular GABA was measured by in vivo microdialysis technique, GABA levels increased 250% and 350% over basal levels in the globus pallidus and ventral tegmentum. The time course of the increase in brain GABA levels coincides with peak anticonvulsant activity in the rat. In kindled rats in which the baseline extracellular GABA levels in rat frontal cortex are increased 100% over control animals, tiagabine HCl (10 mg/kg intravenously) causes a further increase in extracellular GABA levels (21). A delay between the rise in plasma concentrations of tiagabine HCl and the increase in GABA levels was observed in these kindled rats. Tiagabine HCl has also been reported to increase GABA levels in the hippocampus of human patients after oral administration (22). The antinociceptive and neuroprotective effects of tiagabine HCl in the rat and gerbil, respectively, are also correlated with increases in extracellular brain GABA levels (13,23).


GABA produces a fast inhibitory postsynaptic potential (IPSP) in neurons by increasing chloride conductance at the GABAA receptor-chloride ion channel complex. Tiagabine HCl enhances the GABA-induced increase in membrane conductance in CA1 pyramidal cells (24). In these experiments, GABA was applied iontophoretically to the dendritic or somatic regions of pyramidal neurons during the perfusion of the slice with tiagabine HCl. The decay time of the conductance increase was prolonged by tiagabine HCl, and tiagabine HCl did not affect resting membrane potential. Tiagabine HCl also increases endogenous GABA-mediated IPSPs that are evoked antidromically in the hippocampal slice by electrical stimulation of the axons of the pyramidal cells (24).

The effects of tiagabine HCl on IPSPs were also tested in rat hippocampal slice cultures, which contain large numbers of GABAergic interneurons that form correct axosomatic and axodendritic synapses with pyramidal cells (25). In this preparation, tiagabine HCl prolongs the duration of both GABAA and GABAB receptor-mediated monosynaptic IPSPs produced by excitatory amino acid antagonists. In the presence of tiagabine HCl, the mean decay time constant increased from 16 to 250 milliseconds. Tiagabine HCl also reduces the spontaneous and evoked epileptiform bursting induced by increasing extracellular potassium ion concentration. Tiagabine HCl (20 µmol/L) increases the


rise time and duration of IPSPs of CA1 pyramidal cells of genetically epileptic mice until they resemble those of control mice (26). A study comparing the effects of tiagabine, vigabatrin, gabapentin, and valproate on the function of the mouse brain GAT-1 transporter expressed in Xenopus oocytes found that all these anticonvulsant compounds inhibit the uptake of GABA at clinically relevant concentrations in this preparation, but only tiagabine HCl (20 µmol/L) blocks the GAT-1-mediated steady-state current and transient charge movement at clinically relevant concentrations (27).


Tiagabine HCl produces hypersynchronous electroencephalograms (EEGs) at anticonvulsive doses in several different behavioral models in the rat and mouse. Repetitive 1-to 10-second episodes of hypersynchronous EEG waves in the frequency range of 4 to 7 Hz occur in the normal EEG of the rat after a dose of 10 mg/kg i.p. of tiagabine HC1 and, to a lesser extent, after a dose of 2 mg/kg i.p. (28). The hypersynchronous EEG episodes appear only during wakefulness and are accompanied by low muscle activity, generally within 15 minutes of a dose of tiagabine HCl. Apart from the hypersynchronous activity, tiagabine HCl has no other effect on EEG of the awake rat. In the sleeping rat, a dose of 10 mg/kg i.p. of tiagabine HCl significantly increases the latency to rapid eye movement sleep, but it does not affect the latency to non-rapid eye movement sleep or the number or average duration of the non-rapid eye movement sleep episodes (28). This dose of tiagabine HCl tends to elevate the EEG power density in the frequencies between 1 and 8 Hz during non-rapid eye movement sleep.

Tiagabine HCl produces a nonconvulsive type epilepsy in the WAG/Rij rats, an animal model of generalized nonconvulsive epilepsy (29). In these animals, tiagabine HCl increases the number and duration of spike-wave discharges in cortical EEG in a dose-related manner over the dose range of 1 to 10 mg/kg i.p., without causing behavioral effects and with little effect on the spectral EEG, except to increase the power in the β band of 25 to 39 Hz at doses of 3 and 10 mg/kg i.p. Tiagabine HCl produces a dose-dependent increase in the frequency and duration of absence seizures at doses greater than 1 mg/kg i.p., and absence status epilepticus at 11 mg/kg i.p., in the lethargic (lh/lh) mouse model of absence seizures (30). In nonepileptic rats, a very high dose of tiagabine HCl (100 mg/kg i.p.) produces an abnormal, hyporeactive behavioral state that is accompanied by an EEG pattern of high-amplitude, frontally dominant, rhythmic, 3-to 5-Hz spike-wave activity (10).

The effects of tiagabine HCl in normal and epileptic rodents suggest a potential association of tiagabine HCl with generalized spike-wave discharge of nonconvulsive status epilepticus. Such absencelike seizures may be mediated by GABAB receptor stimulation. Experimental absence seizures in rats are prolonged by baclofen, a GABAB agonist, and are attenuated by CGP35348, a GABAB antagonist (31). There have been case reports of possible nonconvulsive absence seizures associated with tiagabine HCl therapy (32, 33, 34, 35). However, the results of a clinical study of tiagabine HCl as initial treatment of adult-onset partial epilepsy did not find any confusional states or nonconvulsive status epilepticus associated with tiagabine HCl treatment, and tiagabine HCl was not associated with new interictal slow-wave discharges (36). An analysis of data on status epilepticus and tiagabine HCl that included an expert review of the EEGs of patients showing slow-wave discharge and a comparison of tiagabine HCl treated patients with placebo-treated patients showed that tiagabine HCl toxicity may be associated with spike-wave discharges, especially in patients with a history of spike-wave discharge, and the incidence of complex partial status epilepticus is not higher in patients taking tiagabine HCl (37).

Tiagabine HCl has been reported to cause an activity-dependent enhancement of hyperpolarizing as well as depolarizing GABA-mediated responses in CA1 pyramidal cells of an in vitro rat hippocampal slice preparation (38). In contrast to the well-known inhibitory effects of GABA, the high-frequency stimulation (100 Hz) of inhibitory pathways in the hippocampal slice evokes GABA-mediated depolarization responses capable of triggering seizurelike bursts of action potentials in hippocampal pyramidal cells (39). The bath application of tiagabine HCl (20 µmol/L) prolongs the duration of hyperpolarizing IPSPs in CA1 pyramidal cells evoked by a single, high- or low-intensity electrical stimulation of inhibitory interneurons. In contrast, tiagabine HCl greatly increases the GABA-mediated depolarizing responses in the hippocampus evoked by lowor high-intensity, high-frequency stimulation of the same inhibitory interneurons (38). Tiagabine HCl (50 µmol/L) evokes large, slow depolarizations in cortical wedges prepared from audiogenic seizure-prone mice (40). The depolarizing and desensitizing effects of tiagabine HCl may be the mechanisms by which large doses of tiagabine HCl cause tremor and seizurelike movements of the forelimbs in animals (4). Such proconvulsant effects of tiagabine HCl are in line with the convulsant effects of direct-acting GABAA receptor agonists, which cause GABA receptor depolarization and desensitization (41).


A dose of 50 mg/kg/day of tiagabine HCl delivered by subcutaneous osmotic pump blocks generalized clonic seizures, prevents seizure-induced damage in the CA1 and CA3 areas of the hippocampus, and reduces impairment of spatial


learning and memory on the Morris water maze in the perforant pathway stimulation model of status epilepticus in the rat (42). In this study, the protective effects of tiagabine HCl were greater in the pyramidal cell layer than in the hilus of the dentate gyrus or in the extrahippocampal areas. A dose of 50 mg/kg i.p. of tiagabine HC1 administered immediately before and 1, 24, and 48 hours after transient global ischemia reduces ischemic cell loss of CA1 pyramidal cells in the rat four-vessel occlusion model (43). Tiagabine HC1 (45 mg/kg i.p.) also slows pyramidal cell loss in the gerbil hippocampus after global ischemia (23). The neuroprotective effect of this dose of tiagabine HC1 in gerbils is associated with an elevation of extracellular GABA levels and the induction of mild hypothermia. A dose of 20 mg/kg i.p. of tiagabine HC1 administered to rats 1 hour after occlusion of the middle cerebral artery significantly reduces infarction volume after focal ischemic injury (44). There is no neuroprotective effect when tiagabine HC1 is administered either 15 minutes before or 3 or 6 hours after focal ischemic injury. Taken together, the results of these studies indicate that tiagabine HC1 is neuroprotective in animals. It can be postulated that this protection is the result of a GABA-mediated decrease in nerve excitation that ultimately prevents calcium-induced neurotoxicity.


Tiagabine HC1 evolved from a discovery program that was designed to identify potent and specific GABA uptake inhibitors as anticonvulsants for the treatment of epilepsy. Impairment of GABA inhibitory function may play a role in the pathogenesis of epilepsy and other neurologic disorders. The results of in vitro neuropharmacology studies show the specificity and potency of tiagabine HCl as a GABA uptake inhibitor and demonstrate that tiagabine HCl can strengthen the inhibitory neuropharmacologic actions of GABA at both GABAA and GABAB receptors. In animal seizure models, the anticonvulsive pharmacology of tiagabine HCl is correlated with increases in extracellular GABA brain levels. Presumably, the increase in extracellular GABA levels results in a greater distribution and prolonged action of GABA. The ability of tiagabine HCl to block DMCM clonic seizures in mice suggests that it acts in vivo to block seizures at the GABAA receptor. DMCM, an inverse agonist at the benzodiazepine receptor on the GABAA receptor-ion channel complex, produces convulsions by impairing GABAergic neurotransmission (5). The anticonvulsant and antinociceptive effects of tiagabine HCl occur in the same dose range of 1 to 30 mg/kg i.p. Whereas the anticonvulsant effects of tiagabine HCl appear to be mediated by GABAA receptors, GABAB receptors appear to modulate the antinociceptive effects of tiagabine HCl in the mouse and rat because these effects are blocked by a GABAB receptor blocker (13). Taken together, the results of biochemical and pharmacologic mechanism of action studies support the hypothesis that the primary antiepilepsy effect of tiagabine HCl is achieved through inhibition of GABA uptake by nerves and glia that results in an increase in GABA-mediated inhibitory events.


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