Mechanisms of action of AEDs

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1 Mechanisms of action of AEDs Wolfgang Löscher Department of Pharmacology, Toxicology and Pharmacy University of Veterinary Medicine Hannover, Germany and Center for Systems Neuroscience Hannover, Germany

2 Mechanisms of action (MOA) of AEDs Why are mechanisms important? To understand how AEDs work to symptomatically suppress seizures To understand why some AEDs are more effective than others To understand why not all AEDs act against all types of seizures To decide which drugs might work best in combination ( rational polypharmacy ) To understand CNS adverse effects of AEDs Are mechanisms important? Yes, but see next talk by Graeme Sills

3 Mechanisms of action (MOA) of AEDs Any MOA that is associated with anti-seizure activity in seizure models (e.g., MES, kindling) will be associated with anti-seizure activity in epilepsy patients MOA determines anti-seizure action However, apart from mechanism-based ( rational ) drug development, MOAs of most new AEDs have been discovered only after their approval MOA did not play a decisive role in development With respect to rational development, a new MOA does not imply that the drug is more effective clinically e.g., GABA potentiating drugs or glutamate/ampa antagonists Drugs combining several MOAs may be more effective than drugs acting by a single MOA

4 Mechanisms of action of AEDs Löscher and Schmidt, Nature Reviews Neurology 2012

5 Mechanisms of action of AEDs Although the actions of each AED have unique characteristics and some drugs may act by multiple mechanisms, the anti-seizure actions of these drugs can be grouped into four broad categories. (1) modulation of voltage-dependent sodium, calcium or potassium channels; (2) increase in GABAergic inhibition via actions on GABA A receptors or on GABA synthesis, reuptake, or degradation; (3) decreased synaptic excitation via actions on ionotropic glutamate receptors; (4) modulation of neurotransmitter release via presynaptic mechanisms. For some antiseizure drugs, the mechanism remains at least partially unknown. Porter et al., Handbook of Clinical Neurology, 2012

6 Drug Molecular targets of approved antiepileptic drugs Na + channels Ca 2+ channels K+ channels HCN channels Modulation of voltage-gated ion channels Phenytoin I NaT ( ) I NaP ( ) Carbamazepine I NaT ( ) Oxcarbazepine I NaT ( ) Eslicarbazepine I NaT ( ) Lacosamide Slow inactivation ( ) Lamotrigine I NaT ( ) HVA ( ) I H ( ) Zonisamide I NaT ( ) T-type ( ) Ethosuximide T-type ( ) Retigabine (ezogabine) KCNQ ( ) Increase in GABAergic inhibition Benzodiazepines Vigabatrin Tiagabine Decrease in glutamatergic excitation Perampanel Multiple mechanisms GABA GABA A R ( ) GABA-T ( ) GAT-1 ( ) Glutamate AMPA ( ) Valproate? I NaT ( ) I NaP ( )? T-type ( ) I K ( ) Turnover ( ) NMDA ( ) Felbamate I NaT ( ) HVA ( ) GABA A R ( ) NMDA ( ) Topiramate I NaT ( ) I NaP ( ) HVA ( ) I K ( ) GABA A R ( ) AMPA/KA ( ) Phenobarbital HVA ( ) GABA A R ( ) AMPA/KA ( ) Modulation of neurotransmitter release via presynaptic mechanisms Gabapentin/pregabalin α2δ protein (accessory subunit of Ca 2+ channels) Levetiracetam SV2A synaptic vesicle protein

7 Mechanisms of action (MOA) of AEDs But: Grouping of AEDs into mechanistic categories simplifies the reality AEDs within one category may differ in their anti-seizure efficacy e.g. lamotrigine, but not phenytoin, act against absence seizures e.g., phenytoin and carbamazepine may exert differential efficacy Most AEDs have additional MOA e.g., for phenytoin >150 MOA have been reported in the literature Highlighting a specific MOA for a new AED may be marketing-driven (ignoring other potential MOA) e.g., lamotrigine-induced decrease of glutamate release e.g., role of α2δ protein in MOA of gabapentin/pregabalin e.g., role of SV2A in MOA of levetiracetam e.g., role of KCNQ-type K + channels in MOA of retigabine

8 Lamotrigine Leach et al. (Wellcome), Epilepsia 1986 LTG acts at voltage-sensitive sodium channels to stabilise neuronal membranes and inhibit transmitter release, principally glutamate specific effect of lamotrigine on glutamate release? (was used as a marketing strategy) Lingamaneni and Hemmings, Neurosci. Lett Our results suggest that therapeutic concentrations of lamotrigine, phenytoin, and carbamazepine inhibit synaptic glutamate release by preferentially blocking presynaptic Na + channels. no difference between lamotrigine and other Na + channel modulators But: lamotrigine also modulates Ca 2+ (HVA) and HCN channels, which may explain ist broader efficacy

9 Gabapentin and pregabalin Gabapentin and pregabalin were developed as lipophilic, blood brain barrier permeable forms of GABA (3-alkylated GABA analogs) Unexpectedly, they did not directly interact with GABA receptors Current vision is that both drugs act via inhibitory effect on voltage gated calcium channels containing the α2δ subunit, thereby inhibiting glutamate release But: anti-seizure effects are only partially reduced in α2δ defective mice However, both drugs exert effects on the GABA system that may be involved in their therapeutic and adverse effects (e.g., weight gain)

10 Gabapentin and pregabalin Both drugs increase the activity of the GABA synthesizing enzyme glutamate decarboxylase (GAD) Percent control Effects on GAD activity Gabapentin Pregabalin Valproate mm 1 mm 2.5 mm Drug concentration Silverman et al., J. Med. Chem. 1991

11 Gabapentin and pregabalin Similar to valproate, gabapentin increases GABA turnover (synthesis) in several brain regions at anticonvulsant doses in rats in vivo Percent control Effect on GABA turnover Gabapentin Valproate * * * * * * * * 0 Bulbus olfact. Frontal cortex Striatum Hippocampus Amygdala Thalamus Hypothalamus Tectum S. nigra Pons Cerebellum Löscher, Brain Res. 1989; Löscher, Hönack, Taylor, Neuroscience Lett. 1991

12 Gabapentin and pregabalin Similar to valproate, gabapentin increases GABA turnover (synthesis) in several brain regions at anticonvulsant doses in rats in vivo Löscher, Hönack, Taylor, Neurosci. Lett Gabapentin increases GABA release in vitro Götz et al., Drug Res. 1993; Honmou et al., Epil.Res Gabapentin increases brain GABA in epilepsy patients in vivo (shown with MRI-spectroscopy) Petroff et al., Ann. Neurol. 1996; Petroff et al., Epilepsia 2000

13 Gabapentin increases GABA in epilepsy patients 3 Edited GABA (mm/kg) Time After 1200 mg Gabapentin (hr) Petroff et al., Epilepsia 41:675-80; 2000

14 Gabapentin and pregabalin Similar to valproate, gabapentin increases GABA turnover (synthesis) in several brain regions at anticonvulsant doses in rats in vivo Löscher, Hönack, Taylor, Neurosci. Lett Gabapentin increases GABA release in vitro Götz et al., Arzneimittelforschung 1993; Honmou et al., Epil.Res Gabapentin increases brain GABA in epilepsy patients in vivo (shown with MRI-spectroscopy) Petroff et al., Ann. Neurol. 1996; Petroff et al., Epilepsia 2000 Pregabalin has not been studied in this respect Pfizer claims that GABA effects do not contribute to the pharmacological action of gabapentin or pregabalin e.g., Taylor et al., Epilepsy Res Additional effects on H-currents and K + channels

15 Levetiracetam (LEV) Current vision is that LEV acts via modulation of the synaptic vesicle glycoprotein SV2A, thereby regulating transmitter release However, because SV2A plays a modulatory, but not essential, role in neurotransmission, it is unclear how a ligand binding to SV2A might alter neurotransmitter release Anti-seizure effects are only partially reduced in SV2A deficient mice How LEV interacts with this protein and how it exerts its antiseizure action is, at present, obscure LEV exerts various other effects that could contribute to its antiseizure action e.g., inhibition of high voltage activated (HVA) calcium currents Inhibition of calcium release from intraneuronal stores Effects on metabolism and turnover of GABA in discrete brain regions and the activity of GABAergic neurons in substantia nigra pars reticulata in vivo reversal of zinc-induced inhibition of GABA A receptors in epileptic tissue Inhibition of AMPA receptors

16 Levetiracetam (LEV) Our results clearly show that LEV removes the Zn 2+ - induced suppression of GABA A mediated presynaptic inhibition, resulting in a presynaptic decrease in glutamate-mediated excitatory transmission. Our results provide a novel mechanism by which LEV may inhibit neuronal activity.

17 Retigabine (ezogabine) Current vision is that retigabine acts as a positive modulator of KCNQ2 - KCNQ5 (Kv7.2 Kv7.5) potassium channels KCNQ2 5 channels are important determinants of neuronal excitability; mutations in KCNQ2/3 cause the syndrome of benign familial neonatal seizures The KCNQ inhibitor XE-991 partially blocks the anticonvulsant effect of retigabine in the MES test Mice with a genetic defect in KCNQ2 show reduced sensitivity to the anticonvulsant activity of retigabine However, retigabine also exerts other effects that could contribute to its antiseizure action It potentiates GABA-mediated inhibitory transmission by acting as a positive allosteric modulator of the GABA A receptor It increases GABA synthesis Weak inhibitory effects on voltage gated Na + and Ca 2+ channels

18 Retigabine (ezogabine) Comparison of free plasma concentrations of retigabine associated with anticonvulsant efficacy in epilepsy patients and the pharmacological effects measured at KCNQ2/3 in vitro Gunthorpe et al., Epilepsia 2012

19 Mechanisms of action of AEDs In recent years, there have been considerable advances in our understanding of how AEDs exert their effects at the cellular level The mechanism of action of each AED has unique characteristics Most AEDs seem to act by more than one mechanism grouping of AEDs into broad mechanistic categories has didactic advantages and is often used for guiding the choice of AED combinations but simplifies the reality Knowing how AEDs work has important implications for clinical practice However, how AEDs precisely interact with disease mechanisms is still only incompletely understood

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