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British Medical Bulletin 2005 71(1):77-92; doi:10.1093/bmb/ldh036
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Published online 31 January 2005

British Medical Bulletin, Vol. 71 © The British Council 2005; all rights reserved

{alpha}2-Adrenoceptor agonists: shedding light on neuroprotection?

Daqing Ma, Nishanthan Rajakumaraswamy and Mervyn Maze

Departments of Anaesthetics and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, SW10 9NH, UK

Correspondence to: Dr D. Ma, Department of Anaesthetics and Intensive Care, Imperial College London, Chelsea & Westminster Campus, London SW10 9NH, UK. E-mail: d.ma{at}imperial.ac.uk


   Abstract
Top
 Abstract
Introduction
 Molecular pharmacology
 Evidence for neuroprotection by...
 Putative mechanisms underlying...
 Which subtype of {alpha}2...
 Clinical relevance of...
 Conclusion
 References
 
Although {alpha}2-adrenoceptor agonists are widely used for analgesia, anxiolysis, sedation, sympatholysis and as anaesthetic-adjuncts for many years, their potential use as neuroprotectants has so far been confined to laboratory experiments. Despite the large body of evidence from both in vivo and in vitro studies, their exact neuroprotective mechanisms remain elusive. Herein, we review the available literature pertaining to the neuroprotective effect of {alpha}2-adrenoceptor agonists and the possible biochemical and physiological cascades involved in their mechanisms of action. The remarkable safety profile of {alpha}2-adrenoceptor agonists and their high potency of neuroprotection should prompt clinical trials to evaluate their neuroprotective efficacy in humans.


   Introduction
Top
 Abstract
 Introduction
Molecular pharmacology
 Evidence for neuroprotection by...
 Putative mechanisms underlying...
 Which subtype of {alpha}2...
 Clinical relevance of...
 Conclusion
 References
 
In late 1999, the United States approved dexmedetomidine for sedative use in intensive care. As the latest {alpha}2-adrenoceptor agonist to be developed, its emergence has fuelled a resurgence of work related to this class of drug. {alpha}2-Adrenoceptors mediate regulatory influence over various physiological, behavioural and endocrine functions, and are implicated in conditions such as hypertension, anxiety, endogenous depression and cognitive functions.1 However, in contrast with their extensive use in veterinary practice, clinical application of {alpha}2-adrenoceptor agonists has been more limited. {alpha}2-Adrenoceptor agonists produce diverse responses, including analgesia, anxiolysis, sedation and sympatholysis, as well as anaesthetic-sparing and haemodynamic-stabilizing effects, which have been reviewed elsewhere.2,3 Nevertheless, more than a decade since the first demonstration of the neuroprotective effect of clonidine, the prototype {alpha}2-adrenoceptor agonist, and numerous subsequent studies with dexmedetomidine, the potential use of {alpha}2-adrenoceptor agonists for neuroprotection has yet to receive adequate attention. Herein, we review the evidence and speculate on the possible underlying mechanisms for the use of {alpha}2-adrenoceptor agonists as neuroprotective agents.


   Molecular pharmacology
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 Abstract
 Introduction
 Molecular pharmacology
Evidence for neuroprotection by...
 Putative mechanisms underlying...
 Which subtype of {alpha}2...
 Clinical relevance of...
 Conclusion
 References
 
{alpha}2-Adrenoceptors are members of the G-protein-coupled family of transmembrane receptors, which are present in the central and peripheral nervous system at both pre- and post-synaptic autonomic ganglia. Binding of endogenous agonists (e.g. norepinephrine) or exogenous agonists (e.g. clonidine) results in G-protein coupling with the inhibition of both adenylyl cyclase and phospholipase C activity (Fig. 1). Subsequently, the inhibition of calcium ion (Ca+) entry and activation of outward-opening potassium ion (K+) channels result in membrane hyperpolarization.



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  		Fig. 1 Possible effector mechanisms coupled to the {alpha}2-adrenoceptors.

 

Pre-synaptic activation of {alpha}2-adrenoceptors in sympathetic nerve endings and noradrenergic neurons leads to inhibition of norepinephrine release. Central nervous system activation of post-synaptic {alpha}2-adrenoceptors inhibits sympathetic activity, which results in hypotension and bradycardia as well as sedation. However, at higher doses {alpha}2-adrenoceptor agonists produce hypertension via activation of receptors on smooth muscle cells in the resistance vessels. The hypnotic action of these drugs seems to be mediated via {alpha}2-adrenoceptors in the locus coeruleus, whereas activation of spinal cord {alpha}2-adrenoceptors mediates analgesia. Clinically available {alpha}2-adrenoceptor agonists have an imidazole ring in their structure and interact with imidazoline receptors which may mediate some of their effects (see below).

Both dexmedetomidine (Dex) and clonidine are imidazoline compounds (Fig. 2). Dex displays an {alpha}2:{alpha}1 selectivity of 1600:1, which is eight times greater than that of clonidine. Clonidine is rapidly and almost completely absorbed after oral administration and reaches a peak plasma level within 60–90 min. Dex is much shorter acting than clonidine but eight times more potent. The elimination half-life of clonidine is between 9 and 12 h, whereas that of Dex is around 2 h. The distribution half-life of clonidine is more than 10 min, whereas that of Dex is approximately 5 min. Clonidine is only 20% bound to plasma protein and displays a volume of distribution of 1.7–2.5 l/kg. Dex is markedly protein bound (94%) to serum albumin and {alpha}1-glycoprotein, and has a volume distribution of approximately 200 litres. Both drugs are eliminated mainly via renal excretion.



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  		Fig. 2 The chemical structure of {alpha}2-adrenoceptor agonists.

 


   Evidence for neuroprotection by {alpha}2-adrenoceptor agonists
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 Abstract
 Introduction
 Molecular pharmacology
 Evidence for neuroprotection by...
Putative mechanisms underlying...
 Which subtype of {alpha}2...
 Clinical relevance of...
 Conclusion
 References
 
In vivo studies

An elegant study by Werner et al.4 first showed attenuation of neurological deficit after ganglionic blockade with the cholinergic antagonist hexamethonium in a rat model of incomplete cerebral ischaemia. This effect was partially reversed by intravenous administration of norepinephrine and epinephrine, which led to the speculation that sympathetic stimulation worsened outcome following cerebral ischaemia. This idea was strengthened by the detrimental effects of catecholamines on striatal neuronal tissue.5 Therefore it was postulated that agents that inhibit catecholamine release would reverse this effect. Subsequently, Hoffman et al.6 reported that, in rats given clonidine, the neurological outcome improved on each of the three days after incomplete cerebral ischaemia by attenuation of the ischaemia-induced increase in blood catecholamine levels. Subsequent studies evaluating the possible neuroprotective value of {alpha}2-adrenoceptor agonists have used Dex because of its potency and high selectivity for the {alpha}2-adrenoceptor.

The neuroprotective effects of Dex were first demonstrated by Hoffman et al.7 who found that pre-ischaemia administration of this agent significantly lowered plasma catecholamine levels and improved neurological outcome in a dose-dependent manner (10–100 µg); further evidence was obtained from histopathological examination of the caudate nucleus and hippocampus. The mechanism of action was confirmed using the selective {alpha}2-adrenoceptor antagonist atipamezole, which abolished both the decrease in catecholamines and subsequent improvement in neurological outcome. The neuroprotective effects of Dex have been further corroborated using incomplete brain ischaemia produced by unilateral common carotid artery occlusion in rats anaesthetized with fentanyl–nitrous oxide.8 A significant correlation was found between the plasma catecholamines during ischaemia and neurological outcome. Maier et al.9 independently evaluated the effect of Dex in a transient model of cerebral ischaemia in rabbits; they used a much lower dose of Dex administered post-ischaemically and maintained at a steady plasma concentration of 4 ng/ml throughout the study period. This significantly reduced neuronal damage induced by the occlusion of the internal carotid, anterior cerebral and middle cerebral arteries in the cortex, but not in the striatum where the blood supply was not compromised. Importantly, Dex did not significantly change any systemic physiological parameters such as mean arterial pressure, heart rate, end-tidal carbon dioxide or temperature. This indicates that the neuroprotective action of Dex was exerted directly on the neurons rather than resulting from any secondary changes in the systemic parameters.


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  		Table 1 Postulated major neuroprotective mechanisms mediated by {alpha}2-adrenoceptor agonists

 
Ischaemic and epileptic cell damage share remarkable resemblance in the selective vulnerability of certain neurons and resistance of others in the temporal lobe structures. This suggests that a common mechanism, such as excitotoxicity, may account for the neuronal damage seen in both. Systemic injection of kainic acid, a glutamatergic kainate receptor agonist, induces seizures and produces neuronal damage in the hippocampus. Halonen et al.10 have reported that Dex protects neuronal cells in the CA3 and CA1 regions of the hippocampus, as well as suppressing the development, generalization and severity of convulsions induced in rats by kainic acid. In contrast, they found that rats treated with atipamezole experienced more severe convulsions and showed extensive neuronal degeneration in the hippocampus. This study also showed that Dex has a U-shaped dose–response curve against convulsions induced by kainic acid, thus demonstrating that lower doses are more effective. Kuhmonen et al.11 have evaluated the neuroprotective effects of Dex in gerbils using a transient global ischaemia model with neuropathological examination 7 days after the induction of ischaemia in order to evaluate delayed neuronal death. Similarly to Halonen et al.,10 they described a U-shaped dose–response curve for Dex, and importantly demonstrated that the lower doses were more effective in protecting against delayed neuronal death in both the hippocampal layer CA3 and the hilus of the dentate gyrus.

The large body of evidence from in vitro and in vivo animal models of ischaemic stroke and neurological diseases indicates that glutamate receptor antagonists have marked neuroprotective effects because of the central role of glutamate in the development of excitotoxic neuronal injury.12 Jolkkonen et al.13 found that, in a rat model of focal cerebral ischaemia, Dex had a greater neuroprotective efficacy than the glutamate receptor antagonists CGS-19755 and NBQX. In particular, Dex infusion at a dose of 9 µg/kg decreased total ischaemic volume by 40% and was less nephrotoxic than NQBX.

Asphyxia occurring at or shortly before birth precipitates hypoxic–ischaemic neuronal injury in neonates. Adrenelectomy or pharmacological blockade of the sympathoadrenal activity weakens the defence against asphyxia and increases mortality,14 which emphasizes the functional significance of {alpha}2-adrenoceptors in protecting against hypoxic–ischaemic brain damage. Yuan et al.15 showed that newborn rats treated with clonidine had a reduced size of hypoxic–ischaemic cortical infarct induced by unilateral carotid artery ligation and also a lower mortality rate than animals treated with the {alpha}2-adrenoceptor antagonist yohimbine. The neuroprotective effects of clonidine and Dex, as indicated by smaller cortical and white matter lesions, have further been demonstrated in mouse pups injected intracerebrally with the N-methyl-D-aspartate (NMDA) receptor agonist ibotenate.16

In vitro studies

In 1992, Shibata et al.17 first showed that clonidine attenuated the decline of 2-deoxyglucose uptake in hippocampal slices exposed to oxygen–glucose deprivation. Laudenbach et al.16 have since demonstrated the neuroprotective effects of clonidine and Dex in primary cortical neuronal cultures exposed to NMDA. Clonidine and Dex reduced the number of neuronal nuclei with features suggesting delayed cell death; furthermore, this effect was abolished in the presence of yohimbine. Recently, we have shown that Dex produced a concentration-dependent reduction in neuronal injury provoked by oxygen–glucose deprivation in glial–neuronal co-cultures derived from mice.18 Similarly, the neuroprotective effect of Dex was reversed by yohimbine and by atipamezole.


   Putative mechanisms underlying neuroprotection {alpha}2-adrenoceptor agonists (Fig. 3)
Top
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 Molecular pharmacology
 Evidence for neuroprotection by...
 Putative mechanisms underlying...
Which subtype of {alpha}2...
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 Conclusion
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  		Fig. 3 Possible neuroprotective mechanisms mediated by {alpha}2-adrenoceptor agonists. Pre-synaptic: (1) activation of outward rectifying K+ channels causing hyperpolarization; (2) inhibition of inward translocation of Ca2+ ions; (3) hyperpolarization resulting from action (1) causes reduced Ca2+ entry; (4) reduced intracellular Ca2+ [as a result of actions (2) and (3)] causes diminished neurotransmitter release. Synaptic: (5) due to action (4) as well as reduced receptor sensitivity; (6) extra-synaptic scavenging of glutamate by astrocytes. Post-synaptic: (7) hyperpolarization reduces the activation of NMDA receptors by enhancing Mg2+ block, and also causes reduced firing and reduced intracellular Ca2+; (8) due to action (5); (9) reduced excitotoxic neuronal death due to combination of all actions but the main pathway is via reduced intracellular Ca2+.

 
Effects on catecholamine release

Cerebral hypoxic ischaemia appears to stimulate massive extracellular catecholamine release in the cortex, striatum and hippocampus. In vitro studies have also demonstrated elevated catecholamine concentrations and reduced uptake in gerbil synaptosomes during ischaemia.19 Catecholamines may worsen outcome from cerebral ischaemia, possibly by stimulating central {alpha}2-adrenoceptors (Fig. 4). Central norepinephrine release during brain ischaemia increases neuronal metabolism and exaggerates the discrepancy between impaired blood flow to ischaemic tissue and an increase in the metabolic demand. Further, metabolism of excessive norepinephrine can lead to the formation of neurotoxic free radicals, whereas prevention of oxidative deamination of catecholamines reduces hydrogen peroxide production during reperfusion.20 In addition to their direct detrimental effects, catecholamines also sensitize neurons to the excitatory amino acid glutamate, thus exacerbating the damage caused by glutamate during ischaemia.



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  		Fig. 4 Effects of catecholamines during cerebral hypoxic ischaemia.

 

Within the brain noradrenergic system there is a population of {alpha}2-adrenoceptors, located on pre-synaptic membranes, which modulate catecholamine release in most areas of the brain by functioning as autoreceptors in the synaptic cleft.1–3 This pre-synaptic auto-inhibtion is mediated through a decrease in Ca2+ conductance, regulated by a G (G0) protein (Fig. 1). The possibility of the existence of a central site of action inhibiting catecholamine release cannot be discounted, since such a site is present in rats.1 Pre-synaptic {alpha}2-adrenoceptors also modulate the release of serotonin, dopamine and acetylcholine as heteroreceptors at serotonergic, dopaminergic and cholinergic nerve terminals.1,2 Somato-dendritically located {alpha}2-adrenoceptors regulate the firing rates of central monoaminergic neurons. Therefore both clonidine and Dex decrease central sympathetic activity and consequently reduce plasma catecholamine levels, thereby attenuateing ischaemia-induced rise in catecholamine concentrations.21,22 However, a recent study has reported that Dex suppresses elevation of catecholamine concentrations in the plasma rather than the brain parenchyma during cerebral ischaemia,23 which suggests that excessive circulating catecholamines may alter outcome by crossing the blood–brain barrier during ischaemic insult. Conversely, the blood–brain barrier is seen to remain largely intact following ischaemia; thus brain norepinephrine levels remain low despite massive rises in plasma levels.24 Further, if the neuroprotective effect of Dex was transduced by lowering circulating catecholamine levels, a reduction in cerebral oxygen consumption would be expected. However, Dex would not alter cerebral oxygen consumption,25 possibly because catecholamine-induced changes in metabolism are mediated mainly through ß-adrenoreceptors.

Effects on systemic parameters

The vasoconstrictor action of {alpha}2-adrenoreceptor agonists causes a decrease in cerebral blood flow, mediated via {alpha}2-adrenoreceptors in the cerebral vasculature, which may be able to enhance perfusion of ischaemic tissue by increasing vascular resistance to non-ischaemic tissue.9 This hypothesis of a ‘reverse steal effect’ remains to be proved, as an effect of {alpha}2-adrenoreceptor agonists on regional blood flow during cerebral ischaemia has not yet been studied. An additional benefit conveyed by limiting cerebral reflow following ischaemia is the prevention of reperfusion injury caused by free-radical generation and lipid peroxidation. Activation of {alpha}2-adrenoreceptors located on the ß cells of the islets of Langerhans can temporarily increase plasma glucose levels. Hyperglycemia usually exacerbates ischaemic injury; however, both Dex and clonidine have been shown to be neuroprotective in ischaemic models irrespective of elevated plasma glucose levels. Also, through their action on peripheral adrenergic receptors, {alpha}2-adrenoreceptor agonists can decrease corticosterone synthesis by attenuating the ischaemia-provoked rise in plasma catecholamines, which would alleviate neuronal damage from hypoxic ischaemia.26 In humans, moderate hypothermia is an efficacious treatment for traumatic brain injury and enhances neurological outcome in survivors of out-of-hospital cardiac arrest.27 {alpha}2-Adrenoreceptor agonists, particularly Dex, potently suppress core temperature, principally through activation of post-synaptic {alpha}2-adrenoceptors in the preoptic hypothalamus which triggers a reduction in metabolic heat production. The mechanisms underlying hypothermia-induced neuroprotection are not fully defined, as many processes both outside and inside the brain are temperature sensitive. Although one cannot discount the possibility that hypothermia induced by {alpha}2-adrenoreceptor agonists may contribute to their neuroprotective action, both clonidine and Dex have previously exhibited neuroprotection while normothermia was maintained.11–13 In addition, the putative hypothermic action of {alpha}2-adrenoreceptor agonists cannot account for neuroprotection observed in vitro,16–18 where normothermia was maintained throughout the duration of experiments.

Effects on glutamate-mediated excitotoxicity and intracellular Ca2+ concentration

The excitatory amino acid neurotransmitter glutamate triggers neuronal death when released in excessive concentrations by overexcitation of its receptors. There is abundant evidence to suggest that cerebral ischaemia evokes a massive release of glutamate. Several lines of research indicate interactions between glutamate and norepinephrine, and also their corresponding receptors.28 Pre- and post-synaptic {alpha}2-adrenoceptor activation decreases either glutamate neurotransmission or the sensitivity of glutamate receptors within the CA1 and CA3 pyramidal neurons of the hippocampus.29 {alpha}2-Adrenoceptor agonists produce a dose-dependent inhibition of neuronal responses to applied glutamate receptor agonists.30 A recent study has also implicated inotropic glutamate receptors in the massive cytoplasmic release of norepinephrine seen within the CA1 region of hippocampus.31 Thus, by limiting the amount of synaptically or extrasynaptically released glutamate, {alpha}2-adrenoceptor agonists might reduce the pathological cascade of excitotoxicity.

Glutamate release in hippocampal brain slices, induced by either depolarization (stimulated by potassium chloride) or hypoxia, is inhibited by Dex.32 This may be due to the inhibitory relationship described between {alpha}2-adrenoceptors and N-type voltage-gated calcium channels, as antagonism of these calcium channels has a neuroprotective effect. Pre-synaptically, these calcium channels are recruited by NMDA-evoked depolarization and contribute to the cytosolic Ca2+ overload. Through antagonism of these ion channels there is a decrease in the cytosolic free Ca2+ concentration which blocks exocytosis of glutamate transmitter vesicles, thus preventing glutamate-mediated excitotoxicity. Furthermore, {alpha}2-adrenoceptors are also coupled with outward rectifying K+ channels (Figs 1 and 3) which cause hyperpolarization of neuronal membranes. This brings about a reduction in neuronal firing rate with a consequent decline in energy consumption, which is advantageous in ischaemia. Additionally, pre-synaptic hyperpolarization both slows of synaptic glutamate release and reduces the activity of voltage-dependent NMDA receptors. Neuronal membranes are further hyperpolarized through {alpha}2-adrenoceptor induced reduction in cellular cAMP and cGMP levels via the inhibition of adenylate cyclase and guanylate cyclase, respectively.

During hypoxic ischaemia, Ca2+ ions accumulate in the cytosol through voltage-sensitive and ligand-gated (mainly glutamate) calcium channels. Elevated cytosolic Ca2+ compromises the viability of neurons by activating apoptotic enzymes, causing the formation of oxygen free radicals and membrane disintegration.33 Thus activation of post-synaptic {alpha}2-adrenoceptor by agonists (Fig. 1) will limit hypoxic–ischaemic brain damage by inhibiting intracellular influx of Ca2+. The {alpha}2-adrenoceptor agonists clonidine and mivazerol produce this effect, but Dex has not been shown to decrease glutamate receptor activity or Ca2+ changes in hippocampal slices during hypoxia.30–32

Effects on apoptotic neuronal death

The severity of cerebral ischaemia determines whether neurons die of necrosis or apoptosis. Activation of {alpha}2-adrenoceptors by catecholamines or activation of NMDA receptors by glutamate induces not only necrotic but also apoptotic death. Cerebral ischaemia is associated with elevated expression of death-effector apoptotic protein Bax as well as reduction of the death depressor Bcl-2. Recent evidence suggests that Dex upregulates anti-apoptotic proteins such as Bcl-2, while suppressing the expression of Bax after incomplete ischaemia and reperfusion.34 During global ischaemia Dex inhibits the expression of c-fos and heat shock protein hsp70,35 both of which are upregulated during ischaemia. Also, following the administration of Dex, there is a reduction in the number of brain {alpha}1-, {alpha}2- and ß-adrenoceptors within 24 h of unilateral carotid artery occlusion in gerbils.36 It remains to be seen whether downregulation of the receptors is due to modulation of gene expression by Dex. These anti-apoptotic effects have not been assessed for other {alpha}2-adrenoceptor agonists.

Effects mediated via actions on astrocytes

Post-synaptic targets of norepinephrine also include astrocytes and glial cells, which both express {alpha}2-adrenoceptors. Excess glutamate and its precursor glutamine, which is also toxic to neurons, are disposed of within astrocytes via oxidative degradation.37 In astrocytes, Dex increases both glutamate uptake and its subsequent oxidative degradation, thus reducing glutamate availability and its harmful effects. This process could be linked to a Dex-induced increase in intracellular Ca2+ concentration. A reduction in extrasynaptic glutamate concentrations has been observed in hippocampal slices exposed to hypoxia in the presence of {alpha}2-adrenoceptor agonists. This could be explained by {alpha}2-adrenoceptor-mediated glutamate scavenging action of astrocytes.30–32 However, a recent study has reported that Dex does not affect ischaemia-induced glutamate release in the intact adult animal.23

Effects on imidazoline receptors

Most clinically used {alpha}2-adrenoceptor agonists, including clonidine and Dex, contain an imidazole ring which can bind to noradrenergic imidazoline receptors.1–3 There is evidence suggesting that some of the actions of {alpha}2-adrenoceptor agonists are mediated via activation of imidazoline receptors. Many regions of the brain, including the cerebral cortex, express the imidazoline subtype I2 receptor. Cortical I2 receptors are predominantly astrocytic and their primary subcellular location is on the mitochondrial membrane.3 A role for imidazoline receptors in neuroprotection has been suggested by the findings that both idazoxan, an imidazole antagonist, and rilmenidine, an imidazole agonist, protect neurons against ischaemic damage and reduce the volume of infarction.38 The reputed neuroprotective effect associated with I2 receptor binding comes from the observation that drugs occupying these receptor binding sites, including clonidine and rilmenidine, increase the influx of Ca2+ into chromaffin cells and thus create a Ca2+ sink, an action that could be neuroprotective.


   Which subtype of {alpha}2-adrenoceptor mediates the neuroprotective action of {alpha}2-adrenoceptor agonists?
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 Abstract
 Introduction
 Molecular pharmacology
 Evidence for neuroprotection by...
 Putative mechanisms underlying...
 Which subtype of {alpha}2...
Clinical relevance of...
 Conclusion
 References
 
Molecular cloning has led to the identification of three structurally and pharmacologically distinct {alpha}2-adrenoceptor subtypes, termed {alpha}2A, {alpha}2B and {alpha}2C. All three {alpha}2-adrenoceptor subtypes are widely distributed in the nervous system, although the {alpha}2A and {alpha}2C subtypes appear to predominate in the central nervous system. Several experimental limitations have precluded investigation of biological functions specific to each {alpha}2-adrenoceptor subtype. Available pharmacological ligands lack sufficient subtype selectivity, and even when subtype selectivity has been noted in vitro, varying and unknown in vivo bioavailability prohibits positive correlation of the administered dose with the amount of drug at the receptor site. Thus, as an alternative to using pharmacological ligands, transgenic mice that are deficient in individual {alpha}2-adrenoceptor subtypes have been successfully used to assign the effects of non-selective {alpha}2-adrenoceptor agonists, such as clonidine and Dex, to individual {alpha}2-adrenoceptor subtypes. Transgenic mice have been used to investigate the cardiovascular properties demonstrated by Dex and clonidine. It has been found that {alpha}2A-adrenoceptors predominantly exert the central hypotensive action of these agents, whereas {alpha}2B-adrenoceptors mediate a transient pressor effect.39 Similar studies have shown that the well-documented effects of hypnotic sedation, hypothermia, analgesia, anxiolysis and spatial working memory modulation by {alpha}2-adrenoceptor agonists are relayed via the {alpha}2A subtype.40 A few studies have reported a significant role for the {alpha}2C-adrenoceptor subtype in both brain monoamine release and hypothermia.41 However, our investigations show that the neuroprotective action of Dex is mediated exclusively via the {alpha}2A subtype both in vivo and in vitro.18


   Clinical relevance of neuroprotection mediated by {alpha}2-adrenoceptor agonists
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 Abstract
 Introduction
 Molecular pharmacology
 Evidence for neuroprotection by...
 Putative mechanisms underlying...
 Which subtype of {alpha}2...
 Clinical relevance of...
Conclusion
 References
 
Clonidine was developed as a nasal decongestant in the early 1970s and was subsequently found to be an effective antihypertensive. Currently, its application for this purpose has been largely superseded by the advent of other treatment regimes. However, {alpha}2-adrenoceptor agonists have been successfully used to treat patients withdrawing from long-term drug, alcohol and nicotine abuse as well as patients with severe, acute and chronic pain conditions following either epidural or spinal administration in clinical practice. The invaluable role of epidural clonidine has been proved consistently in the management of pain in a variety of clinical settings.42 Since the late 1980s Dex has been evaluated as an anaesthetic or an anaesthetic-sparing agent, but more recently it has been evaluated as a peri- or postoperative sedative/analgesic agent in healthy volunteers. These studies have reported that while providing sedation and analgesia, Dex decreases catecholamine output, heart rate, blood pressure and cardiac output despite there being no significant neuromuscular blockade or change in baroreflex sensitivity.42 No idiosyncratic adverse events have been discovered since the beginning of clinical use of {alpha}2-adrenoceptor agonists in the 1970s.1,2

To our knowledge, only two studies have reported that neuroprotection induced by the {alpha}2-adrenoceptor agonist Dex is ineffective against ischaemia. In a rat model of severe forebrain ischaemia, induced by bilateral carotid artery occlusion combined with bleeding to a mean arterial pressure of 50 mmHg, Dex did not affect the outcome of neuronal injury.43 In a separate study using middle cerebral artery occlusion (MCAO) in rats, Dex demonstrated a trend towards neuroprotection following transient MCAO but not after permanent MCAO.44 These observations suggest that Dex could serve as a neuroprotective agent against mild to moderate hypoxic neuronal damage. In the clinical setting, Dex would be an ideal adjunct to an anaesthetic regimen for patients undergoing major surgical procedures such as cardiopulmonary bypass or intracranial operations for neoplasms, where there is a high risk of mild to moderate cerebral ischaemia.

Major invasive surgical procedures are coupled with an identifiable risk for cerebrovascular events and central nervous system impairment. Administration of Dex prior to or during such procedures may alleviate the detrimental outcome of potential ischaemic injury. Perioperative administration of Dex to patients having non-cardiac surgery induces sympatholysis, with ensuing haemodynamic and neuroendocrine stability, as well as a reduction in perioperative ischaemia.45 A significant reduction in perioperative ischaemia has been detected by monitoring critical ST depression in patients undergoing cardiac revascularization surgery who received intravenous clonidine compared with controls.46 Intraoperative infusion of Dex has been found to cause a decrease in sympathetic tone and attenuate hyperdynamic responses to anaesthesia and surgery in patients undergoing coronary artery revascularization, which predisposes toward hypotension.47 Hypotension is usually avoided with appropriate fluid management or by reducing the loading dose. Bradycardia has been reported following the administration of {alpha}2-adrenoceptor agonists, in particular after rapid infusion and in patients with pre-existing cardiac problems.45 However, Dex has not been shown to effect baroreflex sensitivity,42 which suggests that patients will be able to produce an appropriate heart rate response to changes in blood pressure. Dex also attenuates sympathetic activity during the immediate postoperative period, which may help to sustain the myocardial oxygen supply–demand ratio.

The use of {alpha}2-adrenoceptor agonists as an anaesthetic adjunct has been assessed in vascular, cardiac, abdominal, gynaecological and intracranial surgical procedures, and reports from these studies are promising.1–3,43 Moreover, clinical responses to {alpha}2-adrenoceptor agonists, such as anxiolysis, analgesia, sedation and anaesthetic sparing, would allow a more optimal care of the surgical patient. The use of Dex as a general anaesthetic was limited in the past mainly by the speed of onset of its clinical effects and dose-related haemodynamic sequelae following rapid infusion. Recent studies have provided more promising results through the use of a lower dose and slower bolus loading.43 Atipamezole has emerged as an effective antagonist that is able to reverse the unfavourable actions of Dex, and its use in clinical practice is imminent.48


   Conclusion
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 Molecular pharmacology
 Evidence for neuroprotection by...
 Putative mechanisms underlying...
 Which subtype of {alpha}2...
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The clinical promise of the {alpha}2-adrenoceptor agonists has been under investigation since the 1970s, and their potential use as neuroprotective agents adds another dimension. Since the market authorization of Dex as a sedative, it has become a valuable part of the anaesthesiologists’ therapeutic armamentarium. The precise mechanisms and the physiological cascades involved in the neuroprotective action of {alpha}2-adrenoceptor agonists still remain elusive. However, a large body of experimental evidence indicates that their role in anaesthetic practice as a neuroprotectant should be exploited. The remarkable safety profile of {alpha}2-adrenoceptor agonists and the preliminary clinical experience with Dex further supports this proposal. The next step should be to embark on large-scale clinical trials to evaluate the neuroprotective efficacy of Dex in humans.


   References
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 Molecular pharmacology
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 Conclusion
 References
 

  1. Maze M, Tranquilli DVM (1991) {alpha}2-adrenoceptor agonists: defining the role in clinical anesthesia. Anesthesiology, 74, 581–605.[ISI][Medline]
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  4. Werner C, Hoffman WE, Thomas C, Miletich DJ, Albrecht RF (1990) Ganglionic blockade improves neurologic outcome from incomplete ischemia in rats: partial reversal by exogenous catecholamines. Anesthesiology, 73, 923–929.[ISI][Medline]
  5. Globus MY, Busto R, Dietrich WD, Martinez E, Valdes I, Ginsberg MD (1988) Intra-ischemic extracellular release of dopamine and glutamate is associated with striatal vulnerability to ischemia. Neurosci Lett, 91, 36–40.[CrossRef][ISI][Medline]
  6. Hoffman WE, Cheng MA, Thomas C, Baughman VL, Albrecht RF (1991) Clonidine decreases plasma catecholamines and improves outcome from incomplete ischemia in the rat. Anesth Analg, 73, 460–464.[Abstract/Free Full Text]
  7. Hoffman WE, Kochs E, Werner C, Thomas C, Albrecht RF (1991) Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat: reversal by the {alpha}2-adrenergic antagonist atipamezole. Anesthesiology, 75, 328–332.[ISI][Medline]
  8. Hoffman WE, Baughman VL, Albrecht RF (1993) Interaction of catecholamines and nitrous oxide ventilation during incomplete brain ischemia in rats. Anesth Analg, 77, 908–912.[Abstract/Free Full Text]
  9. Maier C, Steinberg GK, Sun GH, Zhi GT, Maze M (1993) Neuroprotection by the {alpha}2-adrenoceptor agonist dexmedetomidine in a focal model of cerebral ischemia. Anesthesiology, 79, 306–312.[CrossRef][ISI][Medline]
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