Antiepileptic Drugs, 5th Edition

Lamotrigine

34

Mechanisms of Action

Michael J. Leach PhD*

Andrew D. Randall MA, PhD**

Alessandro Stefani MD***

Atticus H. Hainsworth MA, PhD****

* Reader in Pharmacology and Drug Development, Department of Chemical and Life Sciences. University of Greenwich, London. United Kingdom

** Head of Neurophysiology and Neuropharmacology, Department of Neurology, GlaxoSmithKline Pharmaceuticals, Harlow, Essex, United Kingdom

*** Diplomate Neuroscienze, University of Tor Vergata, Rome, Italy

**** Senior Lecturer in Pharmacology, School of Pharmacy, De Montfort University, Leicester. United Kingdom

Lamotrigine (LTG, Lamictal: 3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine) is emerging as a clinically useful antiepileptic drug in the treatment of refractory partial epilepsy, generalized seizures, typical absence seizures, and Lennox-Gastaut syndrome (5,51). Positive clinical trials with LTG have also been reported for the treatment of mania in bipolar disorder (2,24,35,52), neuropathic pain (20,72), migraine with aura attacks (18), and Huntington's disease (39). Experimental evidence supports the view that the principal mechanism of action of LTG is blockade of both voltage-gated sodium (Na) and calcium (Ca) channels (50,54,68,69,80,83), although other actions have been proposed (17,83).

PRECLINICAL ANTICONVULSANT STUDIES

Many of the clinical utilities for LTG were predicted from animal anticonvulsant studies, with the notable exception of absence seizures. Thus, LTG blocks hindlimb extension after maximal electroshock- and pentylenetetrazole-induced tonic seizures (rodent models of partial and generalized tonic-clonic seizures) (57,80).

Paradigms considered to be predictive for efficacy in absence epilepsy are increased clonus latency in the pentylenetetrazole model (38), the genetic absence epilepsy rat from Strasbourg (GAERS) (73), and genetic mouse variants that have been isolated (6,7). In particular, three voltage-dependent Ca channel subunit mutants—tottering (tg), lethargic (lh), and stargazer (stg)—display cortical spike-wave discharges with characteristics similar to those of human absence epilepsy (6,33). Lh/lh mice appear to have normal presynaptic N and P/Q-type channel densities (63), whereas tg/tg mice, despite lacking P/Q-type channels, have normal synaptic transmission because of a compensatory increase in N-type channel numbers (63). The action of LTG in tg and stg mice is unreported, but in lh mice, LTG is effective (32). LTG does not increase clonus latency in the pentylenetetrazole model (38), and LTG is ineffective in the GAERS rat, although unlike many other anticonvulsants (e.g., phenytoin, carbamazepine, vigabatrin, gabapentin, tiagabine), LTG does not aggravate the spike-wave discharges in the GAERS model (19). In the lethargic (lh/lh) mouse model, however, LTG (C50, 16 mg/kg) reduced seizure frequency (65% maximal effect), whereas vigabatrin and tiagabine (as in the GAERS model) increased seizure frequency (32).

The rat kindling model is a test for drugs effective against partial epilepsy and secondary generalized seizures. In early studies with cortically kindled rats, LTG reduced both the afterdischarge duration and the number of kindled responses but failed to block the development of kindling (59). LTG also blocked limbic-kindled seizures (60) and secondary generalized but not focal seizures after amygdala kindling (19), although this lack of effect against focal seizures has been attributed to method (19,21). LTG increased the afterdischarge threshold in phenytoin-resistant amygdala-kindled rats (21). This finding is consistent with LTG's clinical efficacy against partial seizures in patients refractory to other drugs (29) and indicates a mechanistic difference between phenytoin and LTG (21).

Despite LTG's broad-spectrum efficacy as an anticonvulsant, ion channel blockers, including LTG, were ineffective against cocaine-induced seizures in mice, in contrast to agents that enhance γ-aminobutyric acid (GABA)-ergic

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neurotransmission (28). Similarly, LTG did not alter behavioral responses to intranasal cocaine in humans (82).

EFFECT OF LAMOTRIGINE ON RECEPTOR AND BIOCHEMICAL SYSTEMS

LTG does not bind to dopamine (D1, D2), noradrenergic (α1, α2, β), adenosine (Al, A2), muscarinic, or σ sites (42,56). LTG appears to have little direct action on glutamatergic receptors of the α-amino-3-hydroxy-5-methyl-4-isoxaszole propionate and N-methyl-D-aspartate type (Table 34.1) (8,61), a finding suggesting that the anticonvulsant action of LTG is unlikely to involve blockade of ionotropic glutamate receptors (Table 34.1). LTG has also been shown to reduce markers of nitric oxide synthase activity in some preparations (27,49).

TABLE 34.1. LAMOTRIGINE ACTIONS IN VITRO

Experimental Paradigm

Lamotrigine Action

Preparation

Neurotransmission

   
 

Veratrine-evoked transmitter efflux

Inhibition, IC50 25 µmol/L for glutamate, 44 µmol/L for GABA

Rat brain slices (42)

 

IC50200 µmol/L

Rat brain synaptosomes (48)

 

K+-evoked glutamate efflux

No effect, IC50 >300 µmol/L

Rat brain slices (42)
Synaptosomes (48)

 

Evoked extracellular field potentials

Inhibited amplitude, IC50 60 µmol/L

Rat cortical slices (10)

 

Glutamatergic synaptic responses

Inhibited EPSP amplitude, IC50 27 µmol/L,maximal: 60%

Medium spiny neurons, rat striatal slice (8)

 

Inhibited EPSP amplitude 50 µmol/L

Rat amygdala neurons (76,77)

   

Inhibited frequency of miniature post synaptic currents, IC50<100 µmol/L

Rat cortical neurons, primary culture (46)

   

Inhibited frequency of glutamatergic synaptic currents

Rat entorhinal cortical slice (17)

 

GABAergic synapses

Inhibited frequency, miniature postsynaptic currents, IC50 <100 µmol/L

Rat cortical neurons, primary culture (46)

   

Increased frequency and amplitude of GABAergic inhibitory currents (50 µmol/L)

Rat entorhinal cortical slice (17)

 

Paired pulse facilitation (index of presynaptic inhibition)

Enhanced ratio: 1.2, 1.7, 1.5, 1.25 (0, 30, 50, 100 µmol/L)

Glutamatergic EPSPs in rat brain slices (8,76)

 

Glutamate receptors

No effect on response to 1 mmol/L glutamate (30-100 µmol/L)

Rat striatal medium spiny neurons (8)

   

Weak inhibition of AMPA and NMDA responses, IC50 >100 µmol/L

Rat cortical wedges (61)

Action potential firing

   
 

Extracellular recording

Inhibited 0 mg induced firing, IC50 140 µmol/L

Rat hippocampal slice (83)

 

Intracellular recordings

Inhibited evoked spikes, IC50 20 µmol/L

Mouse cultured spinal neurons (11)

   

IC50 50 µmol/L maximal: 50% activity dependent (Figure 34.1)

Medium spiny neurons, rat striatal slice (8)

Ion channels

   
 

Sodium currents

IC50 90 µmol/L (Vhold -80 mV); activity-dependent inhibition

Mouse neuroblastoma (40)

   

IC50 60 µmol/L (Vhold -60 mV); ~1 mmol/L (Vhold -90 mV); activity-dependent inhibition

Recombinant type IIA Na channels (83,84)

   

Residues in helices IIIS6 and IVS6 required for lamotrigine action (Fig. 34.3)

Recombinant Na channel site mutants (85)

 

Potassium currents

Enhanced? (100 µmol/L)

Pyramidal neurons, rat hippocampal slices (30)

   

Weak inhibition (100 µmol/L)

Rat cortical or hippocampal neurons (46,83,84)

   

Weak inhibition <10% at 10 µmol/L)

Two-pore domain K channels, TREK 1 and TRAAK H (53)

 

Calcium currents

Spared I- and T-type (100 µmol/L)

GH3 rat pituitary cells (40)

   

Inhibited N-; P-type, spared L-type IC50 12 µmol/L (Vhold -70 to -40 mV)

Rat cortical pyramidal neurons (69)

   

Inhibited amplitude through N-type Ca channel action (50 µmol/L)

Rat amygdala neurons (76)

   

Weak inhibition IC50 ~1 mmol/L (Vhold -90, -60 mV)

Recombinant N-type, α1B (+α2-δ, β1) (83)

   

Weak inhibition IC50 >300 µmol/L (Vhold -90 mV)

Recombinant T-type, α1G, α1l [AHH and ADR, unpublished (see Fig. 34.2)]

   

Weak inhibition <10% at 100 µmol/L (Vhold -90 mV)

Recombinant R-type human α1E (+β3) (AHH, unpublished)

GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate.

Effects on Monoamine Systems

In Balb/c mice, LTG (20 mg/kg) abolished audiogenic seizures and reduced dopamine synthesis, as evidenced by decreased striatal dihydrophenylacetic acid content (>50%) and tyrosine hydroxylase activity (74). By contrast, in C57 BL/6 mice treated with 1-methyl-4-phenyl-l,2,3,6-tetrahy-dropyridine, in which severe dopamine depletion occurs, LTG (3 mg/kg) coadministered with L-DOPA produced a synergistic improvement in motor behavior (25,67). This potentiation

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of the antiparkinsonian action of L-DOPA is unlikely to occur through LTG action at D1 or D2 receptors (see the preceding discussion on receptor binding data) (42,67).

LTG is a weak inhibitor of 5-hydroxytryptamine (5-HT) uptake into both human platelets and rat brain synaptosomes in vitro, and at 20 mg/kg, LTG only partially attenuates the p-chloroamphetamine-induced 5-HT syndrome (a measure of 5-HT uptake in vivo) in rats (IC50 >200 µmol/L) (66) (compare values for ion channel actions in Table 34.1). In children treated with LTG for intractable epilepsy, plasma 5-HT concentrations decreased in seven of 16 children who responded to LTG treatment (36). Urinary 5-HT and 5-hydroxyindoleacetic acid concentrations in these children were unchanged, a finding suggesting that 5-HT catabolism was increased after LTG treatment in some subjects (36). LTG had no effect on 5-HT1A receptor function in humans (64). The foregoing weak and inconsistent effects on 5-HT systems appear unlikely to contribute to the clinical efficacy of LTG in bipolar disorder and mood stabilization (83).

ACTION OF LAMOTRIGINE ON ION CHANNELS

Earlier work demonstrated that LTG inhibits voltage-activated Na channels (11,40,46,56) (Table 34.1). This action is characterized by use dependency (potency of inhibition increasing with action potential firing activity) (Figure 34.1) (8,84) and by increased potency at less-negative holding voltages (or resting voltages) (84). We present electrophysiologic information (Table 34.1) that has emerged since the previous review in this series (42).

 

FIGURE 34.1. Activity-dependent inhibition of voltage-activated Na+ channels by lamotrigine (LTG). Na+ channel-dependent action potential firing was induced by injection of a depolarizing current pulse (0.7 nA, 700 milliseconds) in control conditions (left) or in the presence of LTG (100 µmol/L) (right). Resting potential remained constant at -90 mV. Medium spiny neuron, rat striatal slice (From Calabresi P, Centonze D, Marfia GA, et al. An in vitro electrophysiological study on the effects of phenytoin, lamotrigine and gabapentin on striatal neurons. Br J Pharmacol 1999;126:689-696, with permission.)

Calcium Channels

LTG inhibited native high-voltage-activated Ca2+ channel populations (69,76), including the ω-conotoxin GVIA-sensitive N-type and ω-agatoxin (100 nmol/L)-sensitive P-type components, but spared the dihydropyridine-sensitive L-type component (69,76). Recombinant α1B subunit-mediated N-type currents, however, were weakly LTG sensitive (Xie and Hagan, unpublished data, 1998). Recombinant R-type currents, mediated by α1E subunit-containing channels, were also only weakly inhibited by LTG (A. H. Hainsworth, unpublished data) (Table 34.1). Presynaptic Ca channels on nerve terminals that mediate normal synaptic transmission are principally of the P/Q and N types. Inhibition of these channel types by LTG probably accounts for inhibition of neurotransmitter release (41) and inhibition of glutamate-mediated excitatory postsynaptic potentials (8,76,77). This mechanism may also underlie the enhancement produced by LTG (30 to 100 µmol/L) in the paired-pulse facilitation ratio (8,77), a marker for presynaptic inhibition.

Low-voltage-activated currents mediated by recombinant T-type Ca channels of the two isoforms that are highly expressed in brain tissue (α1G, α1I) showed little sensitivity to LTG (Figure 34.2). This finding agrees with earlier work showing that T-type currents in a pituitary cell line were LTG-resistant (40). T-type currents in thalamic neurons have been implicated in the slow-wave discharges characteristic of absence seizures (6,54), partly because of the inhibition of T-type Ca2+ currents in thalamic relay neurons by the classic antiabsence drug ethosuximide (14). However, T-type currents in many preparations, including some thalamic neurons, were ethosuximide resistant (14,47,70). Thus, the precise contribution of T-type inhibition to antiabsence therapy appears unclear, but it seems to contribute little to the antiabsence activity of LTG.

Potassium Channels

Negligible inhibition of potassium (K+) currents by LTG is seen in native neuronal populations (46,83). The drug also failed to inhibit recombinant two-pore domain K+ channels of the family thought to underlie background “leak” currents at negative voltages (53).

Sodium Channels

A quantitative study of the holding-voltage dependence and activity dependence of Na channel blockade by LTG

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concluded that the drug stabilizes a long-lived inactivated state of the channel, only entered on prolonged depolarization (84). A mutagenesis study has identified residues in the Na channel α1 subunit that are required for inhibition by LTG (85) (Figure 34.3). The S6 helices of the four transmembrane domains in the α1 subunit are thought to line the pore region, at the intracellular end. Point mutation of successive amino acids in the IIIS6 and IVS6 α helices to alanine (a small, neutral amino acid) reveal six residues that significantly influence the potency of LTG blockade. These may form a binding site for LTG within the Na channel pore (85) (Figure 34.3), possibly also including amino acids from the IS6 and IIS6 helices. A combination of Na channel inhibition and N/P/Q-type Ca channel inhibition, all with some degree of voltage dependence and activity dependence, may explain most of the anticonvulsant actions of LTG.

 

FIGURE 34.2. Weak inhibition of T-type Ca2+ channels by lamotrigine (LTG). A: Time-course of peak current amplitude in HEK293 cell expressing α1G subunit, exposed to LTG (100, 300 µmol/L, as indicated). B: Example current traces at time points marked a, b, and c in A. Holding voltage -90 mV, test pulse -25 mV, 50 milliseconds, applied every 10 seconds. (From A. H. Hainsworth and A. D. Randall, unpublished data).

 

FIGURE 34.3. Regions of the Na+ channel proposed to form a lamotrigine (LTG) binding site. The pore-forming IIIS6 and IVS6 α helices of type IIA Na+ channel are shown (from side view and from above); residues affecting LTG sensitivity are shaded. (From Yarov-Yarovoy V, Brown J, Sharp E, et al. Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na+ channel a subunit. J Biol Chem 2000, with permission).

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OTHER ACTIONS OF LAMOTRIGINE

Neuroprotection

In animal models of cerebral ischemia, LTG and structural analogs (e.g., sipatrigine) are neuroprotective (31,43,55). LTG gives modest neuroprotection at doses usually five- to 10-fold higher than anticonvulsant doses (42,55). LTG (20 mg/kg intravenously) significantly reduced cortical infarct volume after focal ischemia induced by permanent middle cerebral artery occlusion in rats but provided no striatal protection, despite reducing striatal glutamate efflux (42,55). In models of global ischemia, LTG (10 to 50 mg/kg) is neuroprotective in gerbil (41,45,65,81), rat (16), and pig (13). In gerbil, coadministration with flunarizine, an inhibitor of L- and T-type Ca channel inhibitor, gave a further increase in neuroprotection (45). The drug also ameliorated neuronal damage in 3-nitropropionic acid-intoxicated rats (20 mg/kg) (44) and in a rat in vitro model of white matter ischemia (50% reduction in axonopathy at 300 µmol/L) (26). The role of ion channel blockade in neuroprotective processes has been extensively reviewed (9,31,71).

Pain Relief

Neuropathic pain disorders (e.g., postherpetic neuralgia, painful diabetic neuropathy, central poststroke pain syndrome) respond poorly to traditional analgesics, but ion channel-blocking agents have varying degrees of clinical efficacy (1). LTG was effective in treating painful diabetic neuropathy (23), as well as chronic refractory neuropathic pain, particularly in combination with morphine (20), but it had no effect in an acute pain model (37). LTG is analgesic in various rat models of neuropathic pain (4,34,58), and it inhibited mechanical allodynia after nerve injury (10 to 25 mg/kg orally) (4).

Ion channels are strongly implicated in pain relief (12,22,75,78,79), and changes in Na channel expression have been described after peripheral nerve or tissue injury (3,15). The TTX-resistant Na channel PN3/SNS (NaV1.8) found predominantly in small neurons of dorsal root ganglia may play a major role in the sustained repetitive firing of peripheral injured nerves. Antisense knockdown of PN3 mRNA in the dorsal root ganglion prevents hyperalgesia and allodynia after chronic nerve or tissue injury (15,62). Subtype-selective LTG action at peripheral Na channels as a basis for analgesic activity has yet to be reported.

CONCLUSION

LTG is an antiepileptic agent with a broad clinical spectrum of activity, including absence epilepsy and Lennox-Gastaut syndrome. In contrast to other Na channel blockers such as phenytoin, the clinical profile of LTG supports the notion of an additional novel mechanism of action. Data presented in this review now implicate inhibition of Ca conductances (including N and P type) in the anticonvulsant actions of LTG. Although the precise role of high-threshold Ca currents (N type in particular) in relation to epilepsy is not fully understood, we speculate that the antiabsence efficacy of LTG may reflect inhibition of N- and P/Q-type Ca channels in addition to Na channels.

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