Current Neuropharmacology - Volume 1, Issue 3, 2003

This, third, issue of Current Neuropharmacology marks a new departure from the format of previous issues. As part of this issue there is a special section of review papers centred around the theme of Gabapentin, a drug originally developed as an anti-epileptic but which has found uses in other spheres of clinical practice. The papers in this special section range from basic research to clinical findings with this drug, and these papers are introduced by the Guest Editor, Dr Rod Scott. It is a great pleasure to acknowledge the work which Rod has done in bringing this excellent range of papers together, and we hope that this will prove to be a valuable contribution to the understanding of the mechanisms of action of this drug. It is planned to compile special issues on other Hot Topics in the future, and I would welcome suggestions for suitable topics.

The role of serendipity in scientific research and in drug development is significant; if under appreciated. It is reported that we all make our own luck. The rational design of a drug that might mimic the actions of a major inhibitory neurotransmitter γ-aminobutyric acid) formed part of an antiepilepsy drug discovery program. The finding that this drug didn't mimic the transmitter but had antiepileptic properties anyway must have made some folk smile. Subsequently, the discoverers of gabapentin must have jumped with joy as this antiepileptic drug was found to have such diverse uses in pain clinics and in psychiatry. A major part of this impressive success story has been the ground-breaking off-label use of gabapentin for clinical cases that have escaped sensitivity to established therapies. This strategy, of investigating a spectrum of potential applications of drugs that dampen down neuronal excitability, has proved fruitful. The low incidence of reversible minor side effects produced by gabapentin makes gabapentin particularly exciting as a therapy for a wide variety of nervous system disorders. Therefore the clinical studies of gabapentin have been driving our understanding of the actions of gabapentin and related drugs. The basic understanding of the biological actions of the gabapentin particularly at the molecular level, really lags behind the clinical work. Substantial further investigations are required. However, a major success has been the discovery of high affinity binding sites for gabapentin and related compounds such as pregabalin. Tantalisingly, the binding sites are α2δ accessory sub-units of voltage-activated Ca2+ channels but there are some ugly anomalies in this near fairy story. Understanding the modulatory mechanism by which gabapentin and pregabalin attenuate Ca2+ flux, through differently assembled voltage-activated channels is starting to appear like quite a mountain to climb. Important areas of research are detailed studies of the molecular and cellular actions of gabapentin to improve our understanding of the drug's actions, to enable the design and evaluation of compounds with similar or better activities. However, it appears likely that gabapentin produces a number of complex molecular responses and one unifying theory of action may not be enough for this apparently simple molecule. This issue of Current Neuropharmacology includes six review articles in which the authors report and explore the recent findings in clinical and basic research on gabapentin. The paper by J.L. Megna, M.M. Iqbal & A. Aneja reviews aspects of the recent clinical use of gabapentin in psychiatry. A personal account is then presented by M.- M. Backonja of his experiences with gabapentin in a specialist pain clinic. These have been breakthrough clinical areas of research, and to quote Misha Backonja, “gabapentin has set a new standard in neuropathic pain research and therapy”. M.R. Cilio presents a review on the use of gabapentin as an antiepileptic drug and particularly considers its use in young people and assessments in animal models. In this review M.R. Cilio also discusses potential long-term adverse consequences of chronic gabapentin treatment on cognitive processes during development. The other end of the spectrum, on cellular and possible molecular actions of gabapentin and related compounds is the focus of the other reviews. C. Canti, A. Davies & A.C. Dolphin present a detailed and highly focused review on the α2δ accessory sub-units of voltage-activated Ca2+ channels; the highest affinity binding site for gabapentin, so far identified. Some of their data raises rather a spectre for gabapentin researchers! R.H. Scott, D.J. Martin & D. McClelland provide a review of cellular actions of gabapentin on cultured sensory neurones in the context of other studies carried out to investigate potential molecular mechanisms of action of this drug. A. Stefani & A. Hainsworth describe the cellular actions of gabapentin both in peripheral and central neurones and they evaluate our present understanding of the relationship between the effects of gabapentin on neuronal ion channels with the drug's clinical usage.

Gabapentin is an antiepileptic drug, which decreases neuronal excitability and may act by increasing the availability of gamma-aminobutyric acid or by inhibiting Ca2+ channels. It has safe pharmacokinetic and side effect profiles. Not surprisingly, it has been tested as a treatment in a number of psychiatric conditions. The most robust evidence exists for it as an efficacious treatment in both social phobia and panic disorder. However, the extant literature indicates that it also holds promise in the treatment of other anxiety disorders, alcohol and cocaine dependence, nonrefractory bipolar disorder, as well as in behavioral agitation. Further, controlled, investigations of gabapentin's effectiveness in these disorders / conditions merit due consideration, especially given their associated morbidity and lost productivity.

Gabapentin is an important advancement for the treatment of neuropathic pain. This novel anticonvulsant has demonstrated efficacy and safety in multiple clinical trials. Its pharmacological properties especially lack of adverse effects on any major organ systems including cardiovascular and respiratory systems allows flexible titration in a wide range of patients. Certainly, there are many side effects but majority are manageable and all of them are reversible.

Gabapentin (GBP), one of the newer antiepileptic drugs (AEDs), is a structural analogue of gamma-aminobutyric acid (GABA), initially approved for add-on treatment of partial seizures in patients 12 years and older and now widely used also in younger patients. Recent studies demonstrated its efficacy not only as adjunctive therapy but also as monotherapy for patients with partial seizures. GBP has an extremely low propensity to cause drug interactions and is well tolerated. The main adverse effects reported are behavioral disorders, such as hostility and mood swings. Recent data, showing increased GBP clearance in children, indicate the potential need for higher doses in young patients. The goal of seizure control in pediatric patients with epilepsy must be balanced against the long-term effects of AEDs on brain function and development. The anticonvulsant action and the long-term effects of GBP on learning, memory and behavior were investigated in studies on immature animals using models of temporal lobe epilepsy and status epilepticus (SE). These data demonstrated that acute administration of a single dose increases the seizure threshold at all ages studied, while chronic treatment following SE reduces spontaneous seizure frequency and cell damage and has no long-term adverse consequences on cognitive processes during development.

In this review we describe the genes encoding α2δ subunits, their topology and predicted structure. We then review the electrophysiological effects of α2δ subunits. It is clear from most studies that α2δ subunits increase channel density at the plasma membrane, but there is less agreement between studies and between channel subtypes concerning the effects of α2δ subunits on voltage-dependence of activation and inactivation. Most studies agree that α2δ subunits increase the kinetics of inactivation, for a number of different calcium channel subtypes. We also discuss the link between α2δ subunits and disease, particularly in terms of Ducky, the spontaneously occurring mutant mouse strain that has mutations in α2δ-2, and exhibits cerebellar ataxia and absence epilepsy. Finally, we will examine the evidence that α2δ subunits are the site of action of the anti-epileptic, anti-nociceptive drug gabapentin.

In this review we outline the actions of gabapentin and pregabalin on the excitability of sensory dorsal root ganglion (DRG) neurones in culture and compare these effects with those seen in other neuronal and cultured cell preparations. We also consider the potential mechanisms of action of gabapentin and pregabalin that may contribute to their anti-nociceptive effects. Gabapentin and pregabalin have similar actions and at saturating concentrations do not have additive effects suggesting that they act at the same or closely associated sites. The only high affinity binding sites yet identified for these drugs are α2δ-subunits (types 1 and 2 but not 3 and 4) of voltage-activated Ca2+ channels. Consistent with this are the findings that gabapentin and pregabalin both attenuate Ca2+ influx through voltage-activated channels and these inhibitory actions may in part provide a mechanism by which multiple firing of action potentials in sensory neurones is reduced. However, it is clear that gabapentin and pregabalin have a number of novel characteristics. Although structural analogues of GABA they appear to act independently of GABA receptor activation in sensory neurones. The actions of gabapentin and pregabalin on sensory neurones are not consistent with selective effects on particular high voltage-activated Ca2+ channel subtypes (L, N, P, Q and R) yet a significant proportion (at least 50%) of the whole cell Ca2+ current is insensitive to these drugs. Cell culture conditions can alter Ca2+ channel subunit expression in such a way as to reduce sensitivity to gabapentin and this can be used to identify potential sites of action of this drug. Analysis of subunit mRNA in cell populations with different sensitivities to gabapentin surprisingly indicated that Ca2+ channel b2-subunits as well as α2δ-subunits may determine Ca2+ channel sensitivity to gabapentin in DRG neurones. In addition to Ca2+ channels, gabapentin and pregabalin modulate other whole cell currents, and in particular a delayed enhancement of voltage-dependent K+ conductances has been observed in cultured DRG neurones. The delayed and prolonged features of this enhancement of voltage-activated K+ currents may reflect gabapentin and pregabalin modulating channel activity via intracellular signalling pathways either via a surface receptor interaction leading to the production of a second messenger or by directly acting at intracellular sites. The wide variety of therapeutic effects achieved with gabapentin and pregabalin offer a considerable challenge when trying to determine cellular mechanisms of action of these apparently simple synthetic compounds.

Gabapentin ( Neurontin) is currently utilised in the treatment of a range of neurological and psychiatric conditions, including partial epilepsy, neuropathic pain and bipolar disorders. Gabapentin (GBP) mechanisms of action, although extensively investigated, are only partially known. This review examines GBP-mediated effects on voltage- and ligand-gated neuronal ionic currents. GBP binds in vivo to the alpha-2-delta sub-unit of the calcium channel and, in dorsal root ganglia, GBP-induced modulation of calcium conductance plays a central role in the drug's inhibitory effect on pain transmission. Less clear is the relevance of GBP as a calcium current modulator in central neo-cortical neurons and the potential use of GBP as add-on therapy for resistant seizures. GBP is also reported to interact with NMDA receptor currents, inwardly rectifying potassium channels and a subtype of baclofen-sensitive-receptors. The potential utility of GBP in modifying the balance among released endogenous amino-acids, and also in neuroprotection, has been suggested. It is, however, unclear whether - and through which cellular pathways - GBP might give therapeutic benefit in the course of neurodegenerative disorders.

Microglia are bone marrow-derived, monocyte-lineaged cells in the central nervous system (CNS). They are considered to serve as sensor cells, receiving a variety of alterations in the circumstances and responding with morphological and functional transformations. These responses of microglia in the injured or the pathologically damaged brain have been generally described as “microglial activation”. The main function of the activated microglia is to serve at the defense line of the CNS as brain macrophages / scavengers, and as immune or immunomodulator cells. Furthermore, microglia are supposed to regulate the survival, growth, and functions of neurons and other glial cells by producing a wide variety of physiologically active substances. They can actually produce both deleterious factors to induce neuronal cell death / degeneration and the trophic / protective molecules for neurons. The molecular mechanism by which the activated microglia are oriented in a harmful or a protective state was investigated by comparing both signal transduction molecules and the secretion of harmful and trophic molecules. As a result, p38MAPK activation was proved to be crucial for the induction of harmful factors, and PKC activity to be additionally required for the harmful state. In conclusion, the signal transduction pathway including p38MAPK activation linked to PKC activity is required for the induction of deleterious factors in microglia.

Several converging lines of evidence from molecular, animal, and clinical studies have demonstrated that the gamma-aminobutyric type A (GABAA) receptor complex plays a central role in the modulation of anxiety. While currently available therapeutic agents that act on this receptor (e.g., benzodiazepines) are effective anxiolytics, they are limited by side effects, tolerance, and abuse potential. Promising strategies to address these limitations include the development of subunit-selective agonists and partial agonists, which specifically ameliorate anxiety without causing sedation or motor impairment. In vivo neuroimaging studies have identified several limbic and paralimbic brain regions involved in the generation or modulation of anxiety and fear responses, suggesting that the neuroinhibitory processes of GABAA receptors may be localized in certain brain areas which may serve as specific sites for drug action. Indeed, neurochemical brain imaging studies have reported decreased ligand binding to GABAA benzodiazepine receptors in prefrontal and medial temporal cortex in a variety of anxiety disorders. This paper reviews recent findings from molecular neuropsychopharmacology and in vivo neuroimaging of GABAA benzodiazepine receptors which offer novel perspectives on the genesis of normal anxiety and on pathophysiology of anxiety disorders. Collectively, these findings suggest several potentially successful avenues for future development of GABAA receptor-mediated anxiolytic treatments, and prompt further exploration of this neurochemical system in pathogenesis of anxiety disorders.