The mechanisms of action of gabapentin and pregabalin

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Gabapentin and pregabalin are structurally related compounds with recognized efficacy in the treatment of both epilepsy and neuropathic pain. The pharmacological mechanisms by which these agents exert their clinical effects have, until recently, remained unclear. The interaction of gabapentin and pregabalin with conventional antiepileptic and analgesic drug targets is likely to be modest, at best, and has been largely dismissed in favour of a selective inhibitory effect on voltage-gated calcium channels containing the α2δ-1 subunit. This mechanism is consistently observed in both rodent- and human-based experimental paradigms and may be sufficiently robust to account for much of the clinical activity of these compounds.

Introduction

The past 15 years has witnessed the unprecedented development of novel antiepileptic agents [1]. One of the first compounds to emerge from this era was gabapentin (GBP), which was licensed for the treatment of refractory localisation-related epilepsies in the UK and Europe in 1993. GBP has since gained world-wide recognition, not just for its antiepileptic properties, but also its efficacy in the management of chronic pain syndromes, especially neuropathic pain [2]. Pregabalin (PGB) is structurally related to GBP and has been marketed for the treatment of seizures and neuropathic pain in the UK since mid-2004. Both drugs are derivatives of the inhibitory neurotransmitter γ-aminobutyric acid (GABA; Figure 1), with GBP originally designed as a GABA-mimetic agent that could freely cross the blood–brain barrier.

GBP was initially evaluated as an anti-spastic compound because of its structural similarity to baclofen and its ability to attenuate the polysynaptic spinal reflex in animal models of spasticity [3]. Although the anti-spastic effects of GBP proved to be modest, the drug demonstrated considerable efficacy in a range of experimental seizure models [4]. These observations led to its initial development as an antiepileptic agent, with its antinociceptive effects emerging, somewhat serendipitously, at a later stage [5]. PGB can be considered as a successor to GBP, at least in terms of its basic chemical structure and therapeutic profile. Clinical experience with GBP encouraged the search for additional GABA derivatives with efficacy in both epilepsy and pain syndromes, and PGB emerged as one of the most promising candidate compounds [6].

As with many other agents, GBP was licensed for the treatment of epilepsy with little or no understanding of its mechanism of action. Continued research and the parallel development of PGB have contributed to a contemporary pharmacological view of GBP (and PGB) as drugs with multiple modest cellular effects at therapeutic concentrations, but with a single predominant mechanism of action that is sufficient to explain much of their efficacy in the treatment of both seizure disorders and pain syndromes. This review considers the pre-clinical pharmacology of GBP and PGB, with specific focus on individual pharmacological targets that have been investigated as potential contributors to their clinical activity.

Section snippets

L-amino acid transporter

Early efforts to identify the mechanism of action of GBP proposed an interaction with the L-amino acid transport system, which is responsible for the absorption of the drug from the small intestine and which is also expressed at the blood–brain barrier and in the nervous system [7]. Acute exposure to GBP produced alterations in the cytosolic and extracellular concentrations of several amino acids, including L-leucine, L-valine and L-phenylalanine, in rat cortical astrocytes and synaptosomes,

GABA receptors

Neither GBP nor PGB has any appreciable effect on the GABAA receptor complex [11, 12••]. A series of recent research reports has, however, addressed the possibility that GBP may exert its effects, at least in part, by activation of presynaptic GABAB receptors. In addition to a structural similarity to baclofen, GBP was initially reported to produce ‘baclofen-like’ effects on paired-pulse inhibition in the dentate gyrus of the rat hippocampus [13]. Although the involvement of GABAB receptors in

GABA turnover

Despite its structural similarity to GABA, GBP does not bind to GABA receptors, is not converted metabolically into GABA, and is neither a substrate for, nor a direct inhibitor of, GABA transport [20]. Nevertheless, inhibitory neurotransmission remained a principal focus in early attempts to unravel the pharmacology of GBP. Anecdotal evidence emerged to suggest that GBP increased the synthesis [21] and non-vesicular release of GABA [22, 23] and prevented its metabolism [24]. Interestingly,

Glutamate-mediated excitatory neurotransmission

With a predominant focus on GABA, the effects of GBP and PGB on the glutamatergic neurotransmitter system have received little attention. There is evidence to suggest that both drugs produce a modest reduction in rat forebrain glutamate concentrations [25], although whether this effect is of sufficient magnitude to be clinically significant is debatable. Previous studies showed no effect of GBP on mouse brain glutamate or glutamine concentrations following acute drug administration [24]. GBP

Voltage-gated sodium channels

Neuronal voltage-gated sodium channels are one of the foremost targets amongst contemporary antiepileptic drugs and the ability to prevent the sustained repetitive firing of sodium-dependent action potentials is a common marker for potential anticonvulsant activity. Investigations of sodium channel function suggest that GBP does not affect sustained repetitive firing in spinal cord or cortical neurones following acute exposure [20, 37, 38] and, although modest inhibitory effects can be elicited

Voltage-gated potassium channels

GBP has been reported to augment ATP-sensitive potassium channel conductance in rat hippocampal and human neocortical slices [43], an effect which was not, however, reproduced in rat dorsal root ganglion neurones [44] and which did not appear to extend to delayed rectifier potassium channels expressed in HEK293 cells [45]. Recent studies have suggested that prolonged exposure to both GBP and PGB produces a delayed allosteric enhancement of an unspecified voltage-activated potassium current in

Voltage-gated calcium channels

The discovery of a specific binding site for GBP in mammalian brain, and its subsequent identification as the α2δ subunit of the voltage-gated calcium channel [48, 49], has stimulated a considerable volume of research aimed at characterising the potential role of calcium channels in the clinical activity of GBP, and latterly PGB. Current evidence favours the existence of four isoforms of the α2δ subunit, only two of which (α2δ-1 and α2δ-2) bind GBP [50••]. The α2δ-1 subunit is widely expressed

Conclusions

GBP and PGB are structurally related agents with similar spectra of antiepileptic and antinociceptive activity [12••]. On current evidence, it would appear that these drugs are largely indistinguishable in terms of their pharmacological profile. Although multiple cellular effects have been proposed for GBP and PGB, including modest actions on the GABAergic neurotransmitter system [26, 27, 29] and on voltage-gated potassium channels [43, 46••], a single common mechanism is believed to

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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