Elsevier

Neuropharmacology

Volume 39, Issue 9, August 2000, Pages 1483-1494
Neuropharmacology

Review
GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke

https://doi.org/10.1016/S0028-3908(99)00233-6Get rights and content

Abstract

It has been shown that enhancing the function of the major inhibitory neurotransmitter GABA decreases glutamatergic activity in the brain. Since increased glutamatergic activity is the major primary event that results in cell death following an acute hypoxic–ischaemic stroke, GABAmimetic drugs might therefore be expected to be neuroprotective. This review examines the evidence that GABAergic function is acutely depressed following an ischaemic insult, and also reviews the data that suggest that increasing cerebral GABA concentration has a neuroprotective effect, as does the administration of some (but not all) GABAmimetic agents. The GABA uptake inhibitor CI-966, the GABAA agonist muscimol and the GABAAmimetic clomethiazole have all been shown to be neuroprotective in animal models of stroke when given after the ischaemic insult. In contrast, benzodiazepines and particularly barbiturates, although potent GABAA potentiators, have shown little promise as neuroprotectants. The diversity of GABAA receptor subtypes and the in vivo efficacy of certain GABAA receptor ligands in animal models of stroke suggests that GABAmimetic drugs are an undervalued approach to stroke therapy.

Introduction

Stroke is the third leading cause of death in major industrialised countries and is also the major cause of long lasting disability (Bonita, 1992). It therefore produces enormous social, financial and personal problems in the community, consuming for example 5% of the UK National Health Service budget (Lees, 1998). Since the adult mammalian CNS has not been considered to regenerate after damage, stroke therapy has focused on (1) reducing risk factors (e.g. antihypertensive agents and stopping patients smoking) and (2) minimising secondary brain damage by restoring and maintaining perfusion. However, a third approach is now being investigated, that of ‘neuroprotection’. This approach relies on the fact that while the cerebral tissue in the area immediately adjacent to the infarct (the core) is probably irretrievably damaged, the tissue surrounding this area (the penumbra), although compromised, is probably capable of full recovery if the right conditions are provided rapidly. The concept of the ‘neuroprotective agent’, a drug which if given soon after the stroke will protect the brain from the damage (Green and Cross, 1997b) has thus developed. This concept has been given considerable impetus over the last 10–15 years with the explosion of information on the biochemical mechanisms occurring in the brains of experimental animals following an acute hypoxic–ischaemic episode. It is felt that interfering with some of these pathological changes should result in damage being attenuated (Green and Cross, 1997b).

A major focus of stroke research has been the role of the excitatory neurotransmitter l-glutamate. The initial observations that exogenously applied glutamate (Olney et al., 1989) or N-methyl-d-aspartate (NMDA) (Coyle, 1983) were neurotoxic, were followed by the demonstration that extracellular levels of glutamate rise during ischaemia (Benveniste et al., 1984) and the report that 2-amino-7-phosphonoheptanoic acid, a competitive NMDA antagonist, was neuroprotective when given to rats prior to an ischaemic insult (Simon et al., 1984). Subsequently, Gill et al. (1988) showed that the high affinity non-competitive NMDA antagonist dizocilpine (MK 801) was an effective neuroprotective agent against cerebral damage when given after a global ischaemic insult. This was followed by reports of its efficacy in focal models of ischaemia (Buchan et al., 1992) [see Green and Cross (1997a) and Hunter et al. (1995) for descriptions of the different types of animal models of ischaemia and their relevance to stroke research].

Numerous compounds have been discovered over the last 15 years that inhibit glutamate function and thereby minimise the neuropathological consequences of an acute ischaemic episode. Many have been effective in at least some of the experimental models of stroke (Small and Buchan, 1997), but none has been shown unequivocally to be of clinical value. A probable reason for this is that some clinical trials were launched with compounds that produced dose limiting, clinically significant adverse events which meant that the drugs could not be given at doses high enough to provide neuroprotection. Problems with the design of some of the clinical trials may also have been a factor (Muir and Grossett, 1999). Consequently we have good reason to believe that inhibition of glutamate function is still a valid approach to preventing ischaemia-induced cell death in the central nervous system.

Because excessive glutamate function initiates a cascade of events (Fig. 1), a substantial number of experimental approaches have been proposed to modify these biochemical/pathological changes and a large number of compounds developed to act on them. Some of these are also illustrated in Fig. 1 and have been reviewed in detail elsewhere (Green and Cross, 1997a). However, none of these other approaches has been characterised or investigated to the depth of the glutamate excitotoxic hypothesis and inhibition of glutamate function remains the premier approach.

Meldrum (1990) suggested that the excitotoxic process probably depends on a balance between excitatory and inhibitory mechanisms. GABA (γ-aminobutyric acid) is the primary inhibitory neurotransmitter in mammalian brain and increasing GABA function via activation of the GABAA receptor complex results in increased chloride flux across the post-synaptic membrane (see 3 The GABA, 5 Compounds enhancing cerebral GABAergic function by acting at the GABA). There is good evidence that GABA exerts an inhibitory tone on glutamate mediated neuronal activity (Kanter et al., 1996) and several different approaches have revealed that increased GABA function can inhibit NMDA receptor-mediated responses. For example, application of GABA to cells can block NMDA stimulated calcium influx in the rat brain cortical slice (Riveros and Orrego, 1999) and cell death in the striato–nigral pathway induced by injection of the excitotoxin ibotenic acid (Saji and Reis, 1987). The GABAmimetic agents pentobarbitone and clomethiazole inhibit NMDLA-induced convulsions (Cross et al., 1993) and clomethiazole inhibits the NMDA-induced derangement of sensory evoked potentials (Thóren and Sjölander, 1993). More relevant to stroke research is the observation that the GABA agonist muscimol inhibited NMDA-induced neurotoxicity in primary cell cultures, an effect abolished by bicuculline (Ohkuma et al., 1994). Enhancing GABAergic inhibitory mechanisms in vivo therefore might also be expected to attenuate the excitotoxic process.

This review outlines the evidence that GABA function may be decreased following an ischaemic insult and then presents evidence that some, but by no means all, compounds that increase GABAergic function are neuroprotective. Because any clinical neuroprotective treatment regime will be initiated after the stroke, little weight has been placed on data on compounds that are only neuroprotective when administered to animals before the ischaemic insult. A compound must be protective when given some time after the start of the ischaemic episode for the finding to have clinical relevance (Green and Cross, 1997b, Hunter et al., 1995).

Section snippets

Changes in GABA biochemistry during an ischaemic episode

There is good evidence that an ischaemic episode results in a substantial acute increase in the extracellular concentration of GABA in the brain. Microdialysis probes implanted in selected brain regions have detected this increase in the permanent middle cerebral artery (MCA) occlusion model (Hagberg et al., 1985) the rat photochemical stroke model (Baldwin et al., 1993, Baldwin et al., 1994) and the gerbil global ischaemia model (Shuaib et al., 1994, Mainprize et al., 1995). Phillis and

The GABAA receptor complex

GABA actions are mediated by at least three different receptor classes. The GABAA receptor is linked to a chloride ion channel and is stimulated by GABA, muscimol and isoguvacine and inhibited by bicuculline (competitively) and picrotoxin (non-competitively). The GABAB receptor is linked via a second messenger system to Ca2+ channel inhibition or K+ channel activation and stimulated by baclofen and inhibited by phaclofen. The GABAC receptor is also linked to a chloride ion channel and may be

Drugs which increase synthesis or release

Various experimental attempts have been made to produce neuroprotection against ischaemic damage in the brain by increasing GABA function. However, any pharmacological approach to increase GABA synthesis and release requires the integrity of presynaptic GABA neurones. There are, in fact, not only in vitro observations that GABAergic neurones are relatively resistant to ischaemia-induced damage (Tecoma and Choi, 1989), but also crucially in vivo evidence using both focal (Johansen et al., 1991)

GABA agonists

Muscimol is a potent and selective GABAA agonist (Scotti DeCarolis et al., 1969) and there is substantial evidence that this compound has neuroprotective properties in a variety of experimental models of stroke. The earliest report was that of Sternau et al. (1989), who found muscimol to be efficacious in the gerbil global ischaemia model when given before the insult. A subsequent study also demonstrated neuroprotection when muscimol was infused intracerebroventricularly during three 2-min

Combination therapy

Lyden and Lonzo (1994) found that a combination of muscimol and dizocilpine provided enhanced neuroprotective efficacy in the microsphere embolism stroke model and it has been reported that administration of clomethiazole and dizocilpine provided at least additive protective effects against kainate-induced neurotoxic degeneration (MacGregor et al., 1997). The brain vacuolisation which can occur after administration of NMDA antagonists (Olney et al., 1989) is prevented by administering

Summary and conclusions

The evidence from experimental models of stroke that enhancing GABA function results in neuroprotection is considerable and there is a rational basis for this pharmacological approach to treatment. However, there are significant caveats. Most studies have been carried out using global models of ischaemia and many diverse compounds show efficacy in this model but are ineffective in focal models (particularly the MCA occlusion models) which are considered more relevant models of acute ischaemic

References (111)

  • A.J. Hunter et al.

    Animal models of acute ischaemic stroke: can they predict clinically successful neuroprotective drugs?

    Trends in Pharmacological Sciences

    (1995)
  • C. Jackson-Friedman et al.

    High dose baclofen is neuroprotective but also causes intracerebral hemorrhage: a quantal bioassay study using the intraluminal suture occlusion method

    Experimental Neurology

    (1997)
  • K.R. Lees

    Does neuroprotection improve stroke outcome?

    Lancet

    (1998)
  • S.P. Liang et al.

    Effects of clomethiazole on radial-arm maze performance following global forebrain ischemia in gerbils

    Brain Research

    (1997)
  • D.G. MacGregor et al.

    The attenuation of kainate-induced neurotoxicity by chlormethiazole and its enhancement by dizocilpine, muscimol, and adenosine receptor agonists

    Experimental Neurology

    (1997)
  • A. Marty et al.

    Modulation of inhibitory synapses in the mammalian brain

    Current Opinion in Neurobiology

    (1995)
  • A.K. Mehta et al.

    An update on GABAA receptors

    Brain Research Reviews

    (1999)
  • E.J. Moody et al.

    Chlormethiazole: neurochemical actions at the gamma-aminobutyric acid receptor complex

    European Journal of Pharmacology

    (1989)
  • C. Nitsch et al.

    Preservation of GABAergic perikarya and boutons after transient ischemia in the gerbil hippocampal CA1 field

    Brain Research

    (1989)
  • S. Ohkuma et al.

    Muscimol prevents neuronal injury induced by NMDA

    Japanese Journal of Pharmacology

    (1994)
  • J.W. Phillis

    CI-966, a GABA uptake inhibitor, antagonizes ischemia-induced neuronal degeneration in the gerbil

    General Pharmacology

    (1995)
  • J. Ravindran et al.

    High extracellular GABA levels in hippocampus — as a mechanism of neuronal protection in cerebral ischemia in adrenalectomized gerbils

    Neuroscience Letters

    (1994)
  • P. Rudomin

    Presynaptic inhibition of muscle spindle and tendon organ afferents in the mammalian spinal cord

    Trends in Neurosciences

    (1990)
  • R.D. Schwartz et al.

    Postischemic diazepam is neuroprotective in the gerbil hippocampus

    Brain Research

    (1994)
  • A. Shuaib et al.

    Gamma-vinyl GABA prevents hippocampal and substantia nigra reticulata damage in repetitive transient forebrain ischemia

    Brain Research

    (1992)
  • A. Shuaib et al.

    Clomethiazole protects the brain in transient forebrain ischemia when used up to 4 h after the insult

    Neuroscience Letters

    (1995)
  • A. Shuaib et al.

    Progressive decrease in extracellular GABA concentrations in the post-ischemic period in the striatum: a microdialysis study

    Brain Research

    (1994)
  • A. Shuaib et al.

    GABA agonist ‘muscimol’ is neuroprotective in repetitive transient forebrain ischemia in gerbils

    Experimental Neurology

    (1993)
  • A. Shuaib et al.

    The neuroprotective effects of gamma-vinyl GABA in transient global ischemia: a morphological study with early and delayed evaluations

    Neuroscience Letters

    (1996)
  • A. Shuaib et al.

    Neuroprotection with felbamate: a 7- and 28-day study in transient forebrain ischemia in gerbils

    Brain Research

    (1996)
  • M.F. Snape et al.

    The effects of chlormethiazole and nimodipine on cortical infarct area after focal cerebral ischaemia in the rat

    Neuroscience

    (1993)
  • J. Srinivasan et al.

    Effects of felbamate on veratridine-and K+ stimulated release of glutamate from mouse cortex

    European Journal of Pharmacology

    (1996)
  • S.G. Sydserff et al.

    The neuroprotective effect of chlormethiazole on ischaemic neuronal damage following permanent middle cerebral artery ischaemia in the rat

    Neurodegeneration

    (1995)
  • M.S. Abel et al.

    Elevated gamma-aminobutyric acid levels attenuate the metabolic response to bilateral ischemia

    Journal of Neurochemistry

    (1992)
  • H.A. Baldwin et al.

    Histological biochemical and behavioural evidence for the neuroprotective actions of chlormethiazole following prolonged carotid artery occlusion

    Neurodegeneration

    (1993)
  • H.A. Baldwin et al.

    Attenuation by chlormethiazole administration of the rise in extracellular amino acids following focal ischaemia in the cerebral cortex of the rat

    British Journal of Pharmacology

    (1994)
  • E.A. Barnard et al.

    International Union of Pharmacology AV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function

    Pharmacological Reviews

    (1998)
  • H. Benveniste et al.

    Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis

    Journal of Neurochemistry

    (1984)
  • J.M. Bowdler et al.

    Regional rat brain benzodiazepine receptor number and y-aminobutyric acid concentrations following a convulsion

    British Journal of Pharmacology

    (1982)
  • A.W. Brown et al.

    Selective chromatolysis of neurons in the gerbil brain: a possible consequence of ‘epileptic’ activity produced by common carotid artery occlusion

    Annals of Neurology

    (1979)
  • A.M. Buchan et al.

    The effect of the NMDA receptor antagonist MK801 on cerebral blood flow and infarct volume inexperimental focal stroke

    Journal of Phsysiology

    (1992)
  • M.I. Colado et al.

    Role of hyperthermia in the protective action of clomethiazole against MDMA (‘ecstasy’)-induced neurodegeneration, comparison with the novel NMDA channel blocker AR-R15896AR

    British Journal of Pharmacology

    (1998)
  • M.I. Colado et al.

    5-HT loss in rat brain following 3,4-methylenedioxymethamphetamine (MDMA), p-chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine

    British Journal of Pharmacology

    (1993)
  • E. Costa

    From GABAA receptor diversity emerges a unified vision of GABAertic inhibition

    Annual Review of Pharmacology and Toxicology

    (1998)
  • J.T. Coyle

    Neurotoxic action of kainic acid

    Journal of Neurochemistry

    (1983)
  • A.J. Cross et al.

    Clomethiazole attenuates hypoxia-induced damage to rat cerebellar granule cells in vitro

    British Journal of Pharmacology

    (1999)
  • A.J. Cross et al.

    Neuroprotective activity of chlormethiazole following transient forebrain ischaemia in the gerbil

    British Journal of Pharmacology

    (1991)
  • A.J. Cross et al.

    The protective action of chlormethiazole against ischaemia-induced neurodegeneration in gerbils when infused at doses having little sedative or anticonvulsant activity

    British Journal of Pharmacology

    (1995)
  • A.J. Cross et al.

    Chlormethiazole antagonises seizures induced by N-methyl-dl-aspartate without interacting with the NMDA receptor complex

    Psychopharmacology

    (1993)
  • A.J. Cross et al.

    The modulation by chlormethiazole of the GABAA-receptor complex in rat brain

    British Journal of Pharmacology

    (1989)
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