Find information on thousands of medical conditions and prescription drugs.

Kainic acid

Kainic acid is an acid present in some algae. It is analogue to glutamate. more...

  • Chemical name : (2-Carboxy-4-isopropenyl-3-pyrrolidinyl)-acetic acid monohydrate

2-Carboxy-3-carboxymethyl-4-isopropenyl-pyrrolidine more...

Applications of Kainic Acid

  • antiworming agent
  • neuroscience research
    • neurodegenerative agent
    • modeling of epilepsy
    • modeling of Alzheimers disease


[List your site here Free!]

Adenosine, neurodegeneration and neuroprotection
From Neurological Research, 3/1/05 by Stone, Trevor W

Protection against neuronal damage is a major objective of current research in areas such as stroke medicine, Alzheimer's disease and other neurodegenerative conditions. Adenosine receptors are important modulators of cell survival, and thus agents targeting these receptors could be valuable therapeutic agents. Agonists at A^sub 1^ receptors and antagonists at A^sub 2A^ receptors are known to protect acutely against neuronal damage caused by toxins or ischemia-reperfusion, and these compounds can also protect against the cell damage inflicted by reactive oxygen species. Even endogenous adenosine may be neuroprotective, since its levels rise substantially in association with a period of ischemia-reperfusion. Unfortunately, there is growing evidence that the efficacy of adenosine receptor activation can be reduced by the concomitant activation of glutamate receptors responding to N-methyl-D-aspartate (NMDA), probably acting via the release of nitric oxide. Such problems will need to be resolved before adenosine receptor agonists can proceed far as neuroprotective agents. The use of receptor antagonists may prove a more valuable approach. [Neurol Res 2005; 27: 161-1681

Keywords: Glutamate; NMDA; ischemia; neurodegeneration; neuroprotection


Prevention of the brain damage caused by stroke, mechanical trauma or neurodegenerative diseases, such as Alzheimer's and Parkinson's disease has become a major focus of neurological research. While there is a range of hypotheses to explain the mechanisms linking a cerebrovascular accident or genetic mutations to the production of cellular injury in the brain, a central role is often postulated for the excitatory transmitter glutamate. For example, one of the initial consequences of a cerebral thrombosis or haemorrhage is the efflux of massive quantities of glutamate from neurons and glial cells. Glutamate then activates ionotropic receptors including those sensitive to N-methyl-D-aspartate (NMDA) leading to a rise of intracellular calcium levels and the activation of pro-oxidant and proteolytic enzymes causing cell damage1.

Adenosine has been considered for almost 20 years as a possible neuroprotectant against such cell damage, since it was first shown by Phillis and his colleagues to depress neuronal excitability2 partly by the direct hyperpolarisation of neurons and partly by the inhibition of glutamate release from excitatory neurons, and it suppresses the rise of intracellular calcium levels, which trigger neuronal damage. Indeed, adenosine may be an important endogenous neuroprotectant. During and following a hypoxic or ischemic episode, the extracellular concentration of adenosine may rise from the normal baseline levels of around 1 μM, up to 100 μM or more3-5. The importance of adenosine as a neuroprotectant is strongly suggested by reports that 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and other A1 receptor blockers increase the neuronal damage resulting from ischemia or excitotoxins5.

In terms of therapeutic relevance, interest in adenosine and the roles of its several receptors-A^sub 1^, A^sub 2A^, A^sub 2B^ and A^sub 3^-is heightened by the possibility that not only might those receptors be potential targets for the development of novel synthetic compounds acting on them, but also that adenosine itself might be an important endogenous neuroprotectant. The latter concept in turn raises the possibility of modifying adenosine's effectiveness as a protectant, the pathophysiological activity of other endogenous molecules able to modify its effectiveness, or increasing the effectiveness of adenosine directly by raising its endogenous concentration or by amplifying its activation of receptors.


A1 receptors and neuroprotection

Following an early report by von Lubitz et al.6 that the A1 receptor agonist N6-cyclohexyladenosine (CHA) protected neurones against damage following an ischemic episode in gerbils, several other A1 receptor agonists were shown to be effective7-11. We and others demonstrated that the A1 receptor agonist R-phenylisopropyladenosine (PIA) was also protective against the excitotoxic effects of glutamate receptor agonists such as quinolinic acid and kainic acid12-16. Protection could be prevented by the A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). R-PIA fully protected against kainate-induced damage in parts of the hippocampus, the basolateral amygdaloid nuclei, the pyriform cortex and rhinal fissure14.

The A1 receptor agonist N6-cyclohexyladenosine (CHA) also protects against damage induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)17. This may suggest that an A1 receptor agonist may be of value in the treatment of Parkinson's disease. The mechanism of protection against MPTP, however, remains unclear, although an interference with oxidative stress and mitochondrial oxidation systems may be involved. Alternatively, since antagonists at the NMDA receptors are also able to reduce toxicity caused by MPTP, it is possible that the same mechanisms are operating for A1 receptor protection against MPTP and against kainate or NMDA receptor activation, including the suppression of glutamate release, and the direct inhibition of NMDA receptor activation18,19.

Mechanisms of A1 receptor neuroprotection

As noted above, while the mechanisms of A1 receptor neuroprotection are not known with certainty, it is likely that they include suppression of the release of a variety of neurotransmitters, including glutamate20-21 acetylcholine22 and dopamine (Figure 1)23. On the other hand, the extracellular concentrations of glutamate do not always correlate with the degree of neuronal damage in the hippocampus24. The systemic administration of A1 receptor agonists was also reported not to suppress the elevation of glutamate levels caused by ischemia11,25,26, although cyclopentyladenosine (CPA) decreased glutamate release in a rat four-vessel occlusion model27.

A1 receptors can also reduce calcium influx in neuronal and cardiac tissues8,28,29, possibly secondary to the modulation of potassium conductances including the ATP-sensitive potassium channels in heart and hippocampal neurons30,31. Since it is believed that the rise of intracellular calcium levels represents the final common path of several injurious stimuli and that it is the attainment of a critical calcium concentration that is responsible for triggering the pro-oxidant and protease systems that ultimately cause neuronal death1, the lowering of intracellular calcium would be a key response to the presence of adenosine or its mimetic agonists.


The highest density of A^sub 2A^ receptors is in the striatum, mainly located on GABA-releasing striopallidal projection neurons and cholinergic neurons32-34. There is also a major presence of these receptors in the nucleus accumbens, and olfactory tubercle with lesser amounts in the hippocampus and cerebral cortex34. In human brain, A^sub 2A^ receptors were reported to be confined largely to striatal regions35, but later work has claimed their presence more widely36.

A2 receptor agonists and neuroprotection

Agonists acting at A^sub 2A^ receptors can protect against ischemia37,38 and excitotoxins such as kainate39,40. The protection was not prevented by the A^sub 1^ receptor antagonist DPCPX, but was largely prevented by 8-(p-sulphophenyl)-theophylline (8PST), a non-selective A1 and A2 adenosine receptor antagonist, which does not penetrate the blood-brain barrier. This demonstration suggests that protection by A2A agonists involves a peripheral site of action. Consistent with this hypothesis, the direct injection of CGS 21680 into the hippocampus failed to afford protection.

A2 receptor antagonists and neuroprotection

One of the most surprising discoveries relating to adenosine receptors and neuroprotection has been the observation of neuroprotection by an A^sub 2A^ receptor antagonist, as reported by Gao & Phillis41. This group found that the relatively non-selective A2 receptor antagonist 5-amino-9-chloro-2-(2-furyl)-1,2,4-triazolo[1,5-c]quinazoline (CGS 15943) could protect against cerebral ischemia in a gerbil model. This result was subsequently confirmed using other compounds and ischemic models42,43. We extended this work to show protection against excitotoxins using the kainate and quinolinic acid models of excitotoxicity39,40. The A^sub 2A^ receptor antagonist 4-{2-[7-amino-2-(2-furyl) (1,2,4)-triazolo(2,3-a)-(1,3,5)triazin-5-yl-amino]ethyl} phenol (ZM 241385), which is 80-fold selective for A^sub 2A^ versus A^sub 2B^ receptors, and 500-1000-fold selective for A^sub 2A^ versus A^sub 1^ receptors, can protect the hippocampus against damage produced by kainate. A combination of the agonist CGS21680 and ZM241385 produced an additive effect with complete preservation of all hippocampal neurones39,40, rather than the anticipated antagonistic interaction. The mutual potentiation of these ligands may indicate that they protection by different mechanisms.

The use of knockout models present a valuable means of confirming that the effects of compounds, such as A^sub 2A^ receptor antagonists is indeed due to the blockade of receptors, rather than to an unrecognised or non-specific action of the compounds. Thus, Chen er al.44 have demonstrated that animals lacking A^sub 2A^ receptors are resistant to neuronal damage following ischemia. Blockade of A^sub 2A^ receptors can also protect against dopaminergic neurotoxins such as MPTP, and Ongini et al.45,46 have demonstrated a reduced neurotoxic effect of MPTP in mice lacking A^sub 2A^ receptors.

Mechanisms of A^sub 2A^ receptor antagonist protection

The A^sub 2A^ receptor agonist CGS 21680 has been reported to increase the efflux of glutamate in response to ischemia in the rat27,47, consistent with evidence for an excitatory action of A^sub 2A^ receptor activation on transmitter release. The A^sub 2A^ receptor antagonist CGS 15943 can depress glutamate release, possibly contributing to its neuroprotective effects by blocking the effects of endogenous adenosine at A^sub 2A^ receptors27.

Protection in neurodegenerative disorders

Although much of the interest in the therapeutic value of purine receptor ligands has centered on protection following strokes, there remains the possibility that over-activation of glutamate receptors may contribute to neurodegenerative disorders such as Alzheimer's disease and Huntington's disease. This possibility is the rationale for studying the protective effects of agents against excitotoxins. It has already been noted that A1 agonists and A^sub 2A^ receptor agonists and antagonists can protect against kainic acid induced damage12,39,40. One of the excitotoxins of greatest relevance, however, is quinolinic acid, a tryptophan metabolite for which the evidence for a role in some degenerative disorders is substantial48,49. Reggio et al.50 have reported that an A2 receptor antagonist, DMPX, can protect against neuronal loss induced by quinolinic acid injected into the striatum-a frequently used model of Huntington's disease.

Interference with reactive oxygen species

Quinolinic acid is an endogenous metabolite of tryptophan and is a selective agonist at N-methyl-D-aspartate (NMDA) receptors48,49. Its neurotoxic effects can be potentiated by the presence of free radicals generated by a mixture of xanthine and xanthine oxidase, a well-recognised superoxide and hydroxylradical generating system. Interestingly, toxicity produced by the quinolinate/free radical combination could be suppressed by three different A^sub 2A^ receptor antagonists-CSC, ZM 241385 and SCH 58261 (Figure 2)51. This result emphasises that A^sub 2A^ receptor antagonists may have a potentially wide use as neuroprotectants against cell injury in many situations where damage is produced by either glutamate receptor activation or oxygen radical generation, or their combination. It is presumably the latter that accounts for neuroprotection during ischemia, when glutamate and free radical levels are known to rise. The generation of endogenous quinolinic acid is increased in glia and macrophages in response to inflammation or immune activation48,49, and in parallel with increased levels of nitric oxide and superoxide. The mutual potentiation between these agents could therefore account for a significant fraction of the overall cell damage, which occurs with neurodegeneration and its associated inflammation (Figure 4). Since immune-activated macrophages can pass across the blood-brain barrier, part of the neuroprotective activity of A^sub 2A^ adenosine receptors may well involve the suppression of free radical generation by white cells and microglia activated by immune stimulation52,53.


Biochemical54 and electrophysiological work55 has supported the view that interactions occur between adenosine receptors. For example, A^sub 2A^ receptors can suppress the activity of A1 receptors. The A^sub 2A^ receptor agonist CGS 21680 reduces neuronal sensitivity to CPA55 and induces a low-affinity receptor site for 2-chloro-N6-cyclopentyladenosine (CCPA)54, possibly via protein kinase C. If this interaction operates in vivo, then the presence of an A^sub 2A^ receptor antagonist should release or 'unmask' A1 receptors, and allow the neuroprotective effect of these receptors to be seen. This was the conclusion drawn to explain the ability of an A1 receptor antagonist to reduce the neuroprotective effects of A^sub 2A^ antagonism39,40. Electrophysiological extracellular and intracellular studies have confirmed the inhibitory effect of A^sub 2A^ receptors on A1 receptor activation55.

In parallel with the direct studies of neuronal damage, we have developed an interest in endogenous molecules, which might modify the potential of endogenous adenosine to act as a neuroprotectant. As noted in the introduction, there is increasing evidence for interactions between adenosine and N-methyl-D-aspartate (NMDA) receptors. Our first observations in this area were that the inhibitory effect of adenosine on hippocampal population spikes and the decrease of paired-pulse inhibition were suppressed in magnesium-free medium, or by superfusing the slices with NMDA56. Agonists at the other glutamate-activated ionotropic receptors (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA] and kainite) did not reduce responses to adenosine and NMDA did not modify responses to the GABAB receptor agonist baclofen. Even the physiological activation of NMDA receptors associated with long-term potentiation reduced significantly the effects of adenosine. Consistent with these data was the weaker ability of adenosine receptor activation to suppress neuronal firing induced by microiontophoretically applied NMDA compared with firing induced by acetylcholine or quisqualate57. The interaction between NMDA and adenosine appeared to involve the enhancement of responses mediated by A^sub 2A^ receptors, since NMDA did not modify the inhibitory effect of the selective adenosine A^sub 1^ receptor agonist N6-cyclopentyladenosine, but did enhance the excitatory effect of the adenosine A2A receptor agonist 2-[p-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680). Furthermore, the response to a mixture of NMDA and CGS21680 was prevented by the adenosine A^sub 2A^ receptor selective antagonist 4-{2-[7-amino-2-(2-furyl)(1,2,4)triazolo-(2,3a)(1,3,5)triazin-5-ylamino]ethyl}phenol (ZM241385). This study indicated that the activation of NMDA receptor can suppress neuronal sensitivity to adenosine, probably via an increase in the action of adenosine A2A receptors58. However, as discussed above, the activation of A^sub 2A^ receptors can, in turn, suppress the activation of A1 receptors and this sequence may account for the apparent inhibitory effect of NMDA on A1 adenosine receptors.

We have recently returned to this problem in view of the increasing evidence that many effects of NMDA are mediated by the production of nitric oxide (NO). We have therefore examined the possibility that NO might mediate the suppressant effects of NMDA receptors on response to adenosine59. Field excitatory post-synaptic potentials (fEPSPs) were recorded extracellularly from the CA1 region of rat hippocampal slices and paired-pulse interactions were studied to localise the observed interactions to the pre-synaptic terminals. A NO donor, S-nitroso-N-acetylpenicillamine (SNAP) was applied to generate locally high concentrations of NO. SNAP reduced the pre-synaptic inhibitory effect of adenosine selectively, with no effect on responses to baclofen. The involvement of A1 receptors was indicated by the fact that responses to the selective agonist N^sup 6^-cyclopentyladenosine were also depressed by NO (Figure 1).

In order to determine whether this action of NO was mediated by the molecule itself or its free radical properties, we also tested the superoxide generating system of xanthine/xanthine oxidase (X/XO) (Figure 3). This combination also inhibited responses to adenosine and the inhibition was prevented by superoxide dismutase. The effects of superoxide were not affected by NO synthase inhibition. Interestingly, both SNAP and the X/XO produced a long-term potentiation of the fEPSP slope. When LTP was induced directly (by electrical high-frequency stimulation), it also reduced the responses to adenosine, but this effect was prevented by inhibiting NO synthesis using L-nitroarginine methyl ester, indicating the mediation of this effect by local NO generation. The testing of paired-pulse interactions indicated that the inhibition of the inhibitory effects of adenosine by NO and X/XO occurred pre-synaptically.

Since NO is believed to exert many of its actions through the activation of guanylate cyclase, we also examined the effects of the cyclase inhibitor (ODQ). This compound was able to prevent the inhibition of adenosine responses by both SNAP and X/XO but, surprisingly, it could not prevent the inhibition of adenosine by NMDA itself59.

Overall, this study showed that the pre-synaptic effects of adenosine can be inhibited by NO or superoxide, but that neither of these can fully account for the reduction of adenosine responses by NMDA. In contrast, electrically-induced LTP reduces sensitivity to adenosine via the generation of NO59. The pharmacological importance of these results for neurodegeneration, however, lies in the fact that NO or other reactive oxygen species generated during reperfusion injury in the heart of brain may compromise the potential protective actions of endogenous adenosine. Any approach to treatment of degeneration using adenosine receptor ligands should therefore be accompanied by measures to suppress free radical generation. These two approaches together would be expected to have a substantially synergistic neuroprotective activity.


These various findings have aroused great interest in the search for new drugs, which could be used to slow or prevent the neuronal damage, which characterises neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. That interest is attributable not only to the efficacy of the compounds available, but also to the fact that they should be relatively free of major side effects. Whereas the use of A1 receptor agonists would lead to a suppression of transmitter release at many sites within the central and peripheral nervous system, A^sub 2A^ receptor antagonists should not be limited in this way. The A^sub 2A^ receptors are relatively low affinity sites for adenosine, and the levels of adenosine present normally in most biological fluids are probably insufficient to activate them. Activation would only be expected under conditions in which there is a large increase in the generation and release of adenosine under pathological conditions.

In practice, this means that A^sub 2A^ antagonists have little effect on heart rate, blood pressure or other vital signs under normal conditions. During ischemia in the brain, however, the levels of adenosine may rise to levels at which A^sub 2A^ receptors are activated. Stimulation of A^sub 2A^ receptors is known to increase the release of the excitotoxic amino acid glutamate, which would tend to cause or facilitate the occurrence of damage. Under these circumstances, A^sub 2A^ receptor antagonists should reduce the enhanced release of glutamate and thus decrease the extent of neuronal damage. Their beneficial activity would therefore be restricted to those areas of brain experiencing ischemia, with little or no effect on other areas of the body.

A particularly exciting aspect of A^sub 2A^ receptor protection is that, following an early brief report of symptomatic relief by theophylline60, receptor blockade may contribute to the long-term benefits of treating patients with Parkinson's disease with A^sub 2A^ receptor antagonists. It is clear that A^sub 2A^ receptors potently modulate cell sensitivity to dopamine receptors, accounting for the beneficial effects of adenosine antagonists in this disease60-62. This phenomenon has led to clinical trials with A^sub 2A^ receptor antagonists in Parkinson's disease with promising, though as yet unpublished, results. Certainly, in animal models (including primates), A^sub 2A^ antagonists are effective against toxin-induced models of the disorder17,63,64. If A^sub 2A^ receptor antagonists can not only treat the symptoms of Parkinson's disease, but also slow the underlying neurodegeneration and thus disease progression, these compounds could become major additions to the anti-Parkinsonian pharmacopoeia.


1 Zipfel GJ, Babcock DJ, Lee JM, et al. Neuronal apoptosis after CNS injury: the roles of glutamate and calcium. J Neurotrauma 2000; 17: 857-869

2 Phillis JW, Kostopoulos GK, Limacher JJ. Depression of corticospinal cells by various purines and pyrimidines. Canad J Physiol Pharmacol 1974; 52: 1226-1230

3 Hagberg H, Andersson P, Lacarewicz J, et al. Extracellular adenosine, inosine, hypoxanthine, and xanthine in relation to tissue nucleotides and purines in rat striatum during transient ischemia. J Neurochem 1987; 49: 227-231

4 Globus MYT, Busto R, Dietrich WD, et al. Effect of ischemia on the in vivo release of striatal dopamine, glutamate, and gamma-aminobutyric acid studied by intracerebral microdialysis. J Neurochem 1988; 51: 1455-1464

5 Phillis JW. The effects of selective A1 and A^sub 2A^ adenosine receptor antagonists on cerebral ischemic injury in the gerbil. Brain Res 1995; 705: 79-84

6 von Lubitz DKEJ, Dambrosia JM, Redmond DJ. Protective effect of cyclohexyladenosine in treatment of cerebral ischemia in gerbils. Neuroscience 1989; 30: 451-462

7 von Lubitz DJKE, Lin RCS, Bischofberger N, et al. Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist. Eur J Pharmacol 1999; 369: 313-317

8 Rudolphi KA, Schubert P, Parkinson FE, et al. Adenosine and brain ischemia. Cerebrovasc Brain Metab Revs 1992; 4: 346-369

9 Tominaga K, Shibata S, Watanabe S. A neuroprotective effect of adenosine A1-receptor agonists on ischemia-induced decrease in 2-deoxyglucose uptake in rat hippocampal slices. Neurosci Lett 1992; 145: 67-70

10 Daval J-L, Von Lubitz DJKE, Deckert J, et al. Protective effect of cyclohexyladenosine A^sub 1^-receptors, guanine nucleotide and forskolin binding sites following transient brain ischemia: a quantitative autoradiographic study. Brain Res 1989; 491: 212-226

11 Heron A, Lekiettre D, Le Peillet E, et al. Effects of an A^sub 1^ adenosine receptor agonist on the neurochemical, behavioural and histological consequences of ischemia. Brain Res 1994; 641: 217-224

12 MacGregor DG, Stone TW. Inhibition by the adenosine analogue, (R-) -N6-phenylisopropyladenosine, of kainic acid neurotoxicity in rat hippocampus after systemic administration. Br J Pharmacol 1993; 109: 316-321

13 MacGregor DG, Miller WJ, Stone TW. Mediation of the neuroprotective action of R-phenylisopropyladenosine through a centrally located adenosine A1 receptor. Br J Pharmacol 1993; 110: 470-476

14 MacGregor DG, Jones PA, Maxwell WL, et al. Prevention by a purine analogue of kainate-induced neuropathology in rat hippocampus. Brain Res 1996; 725: 115-120

15 Arvin B, Neville LF, Pan J, Roberts PJ. 2-Chloroadenosine attenuates kainic acid-induced toxicity within the rat striatum: relationship to release of glutamate and Ca2+ influx. Br J Pharmacol 1989; 98: 225-235

16 Connick JH, Stone TW. Quinolinic acid neurotoxicity: protection by intracerebral phenylisopropyl adenosine (PIA) and potentiation by hypotension. Neurosci Lett 1989; 101: 191-196

17 Lau Y-S, Mouradian MM. Protection against acute MPT-induced dopamine depletion in mice by adenosine. J Neurochem 1993; 60: 768-771

18 De Mendonca A, Sebastiao AM, Ribeiro JA. Inhibition of NMDA receptor-mediated currents in isolated rat hippocampal neurons by adenosine (A1) receptor activation. NeuroReport 1995; 6: 1097-1100

19 Wirkner K, Gerevich Z, Krause T, et al. Adenosine A(2A) receptor-induced inhibition of NMDA and GABA(A) receptor-mediated synaptic currents in a subpopulation of rat striatal neurons. Neuropharmacology 2004; 46: 994-1007

20 Andine P, Rudolphi KA, Fredholm BB, et al. Effect of propentofylline (HWA285) in extracellular purines and excitatory amino acids in CA1 of rat hippocampus during transient ischemia. Br J Pharmacol 1990; 100: 814-818

21 Butcher SP, Bullock R, Graham DI, et al. Correlation between amino acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion. Stroke 1990; 21: 1727-1733

22 Spignoli G, Pedata F, Pepeu G. A1 and A2 adenosine receptors modulate acetylcholine release from brain slices. Eur J Pharmacol 1984; 97: 341-342

23 Michaelis ML, Michaelis EK, Myers SL. Adenosine modulation of synaptosomal dopamine release. Life Sci 1979; 24: 2083-2092

24 Mitani A., Andou Y, Kataoka K. Selective vulnerability of hippocampal CA1 neurons cannot be explained in terms of an increase in glutamate concentration during ischemia in the gerbil: brain microdialysis study. Neuroscience 1992; 48: 307-313

25 Cantor SL, Zornow MH, Miller LP, et al. The effect of cyclohexyladenosine on the periischemic increases of hippocampal glutamate and glycine in the rabbit. J Neurochem 1992; 59: 1884-1892

26 Heron A, Lasbennes F, Seylez J. Adenosine modulation of amino acid release in rat hippocampus during ischemia and veratridine depolarisation. Brain Res 1993; 608: 27-32

27 Simpson RE, O'Regan MH, Perkins LM, et al. Excitatory transmitter amino acid release from the ischemic rat cerebral cortex: Effects of adenosine receptor agonists and antagonists. J Neurochem 1992; 58: 1683-1690

28 Fredholm BB, Dunwiddie TV. How does adenosine inhibit transmitter release? Trends Pharmacol Sci 1988; 9: 130-134

29 Scholz KP, Miller RJ. Inhibition of quantal transmitter release in the absence of calcium influx by a G protein-linked adenosine receptor at hippocampal synapses. Neuron 1991; 8: 1139-1150

30 Regenold JT, Illes P. Inhibitory adenosine A1-receptors on rat locus coeruleus neurones. An intracellular electrophysiological study. Naunyn-Schmied Arch Pharmacol 1990; 341: 225-231

31 Hosseinzadeh H, Stone TW. Tolbutamide blocks postsynaptic but not presynaptic effects of adenosine on hippocampal CA1 neurons. J Neural Transm 1998; 105: 161-172

32 Jarvis MF, Williams M. Direct autoradiographic localisation of adenosine A^sub 2^ receptors in the brain using the A^sub 2^-selective agonist, [3H]CGS21680. Eur J Pharmacol 1989; 168: 243-246

33 Schiffmann SN, Jacobs O, Vanderhaegen JJ. Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridisation histochemistry study. J Neurochem 1991; 57: 1062-1067

34 Dixon AK, Gubitz AK, Sirinathsinghji DJS, et al. Tissue distribution of adenosine receptor mRNAs in the rat. Br J Pharmacol 1996; 118: 1461-1468

35 Martinez-Mir MI, Probst A, Palacios JM. Adenosine A2 receptors: selective localisation in the human basal ganglia and alterations with disease. Neuroscience 1991; 42: 697-706

36 Svenningsson P, Hall H, Sedvall G, et al. Distribution of adenosine receptors in the postmortem human brain: an extended autoradiographic study. Synapse 1997; 27: 322-335

37 Phillis JW. The effects of selective A1 and A^sub 2A^ adenosine receptor antagonists on cerebral ischemic injury in the gerbil. Brain Res 1995; 705: 79-84

38 Sheardown MJ, Knutsen LJS. Unexpected neuroprotection observed with the adenosine A^sub 2A^ receptor agonist CGS21680. Drug Develop Res 1996; 39: 108-114

39 Jones P A, Smith R A, Stone T W. Protection against intrahippocampal kainate excitotoxicity by intracerebral administration of an adenosine A^sub 2A^ receptor antagonist. Brain Res 1998; 800: 328-335

40 Jones PA, Smith RA, Stone TW. Protection against kainate-induced excitotoxicity by adenosine A^sub 2A^ receptor agonists and antagonists. Neuroscience 1998; 85: 229-237

41 Gao Y, Phillis JW. CGS 15943, an adenosine A2 receptor antagonist, reduces cerebral ischemic injury in the Mongolian gerbil. Life Sci 1994; 55: PL61-PL65

42 von Lubitz DKJE, Lin RC-S, Jacobson KA. Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A^sub 2A^ receptor agonist and antagonist. Eur J Pharmacol 1995; 287: 295-302

43 Monopoli A, Lozza G, Forloni A, et al. Blockade of adenosine A^sub 2A^ receptors by SCH 58261 results in neuroprotective effects in cerebral ischemia in rats. NeuroReport 1998; 9: 3955-3959

44 Chen JF, Huang ZH, Ma JY, et al. A(2A) adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J Neurosci 1999; 19: 9192-9200

45 Ongini E, Adami M, Ferri C, et al. Adenosine A^sub 2A^ receptors and neuroprotection. Annl NY Acad Sci 1997; 825: 30-48

46 Ongini E, Monopoli A, Impagnatiello F, et al. Dual actions of A^sub 2A^ adenosine receptor antagonists on motor dysfunction and neurodegenerative processes. Drug Develop Res 2001; 52: 379-386

47 O'Regan MH, Simpson RE, Perkins LM, et al. The selective A^sub 2^ adenosine receptor agonist CGS21680 enhances excitatory amino acid release from the ischemic rat cerebral cortex. Neurosci Lett 1992; 138: 169-172

48 Stone TW. The neuropharmacology of quinolinic acid and kynurenic acid. Pharmacol Rev 1993; 45: 309-379

49 Stone TW. Kynurenines in the CNS: from endogenous obscurity to clinical relevance. Progr Neurobiol 2001; 64: 185-218

50 Reggio R, Pezzola A, Popoli P. The intrastriatal injection of an adenosine A^sub 2A^ receptor antagonist prevents frontal cortex EEG abnormalities in a rat model of Huntington's disease. Brain Res 1999; 831: 315-318

51 Behan WMH, Stone TW. Enhanced neuronal damage by coadministration of quinolinic acid and free radicals and protection by adenosine A^sub 2A^ receptor antagonists. Br J Pharmacol 2002; 135: 1435-1442

52 Cronstein BN, Rosenstein ED, Kramer SB. Adenosine: a physiologic modulator of superoxide anion generation by human neutrophils. Adenosine acts via an A2 receptor on human neutrophils. J Immunol 1985; 135: 1366-1371

53 Burkey TH, Webster RD. Adenosine inhibits fMLP-stimulated adherence and superoxide anion generation by human neutrophils at an early step in signal transduction. Biochem Biophys Acta 1993; 1175: 312-318

54 Dixon AK, Widdowson L, Richardson PJ. Desensitisation of the adenosine A1 receptor by the A^sub 2A^ receptor in the rat striatum. J Neurochem 1997; 69: 315-321

55 O'Kane EM, Stone TW. Interactions between A1 and A2 adenosine receptor- mediated responses in the rat hippocampus in vitro. Eur J Pharmacol 1998; 362: 17-25

56 Bartrup JT, Stone TW. Activation of NMDA receptor-coupled channels suppresses the inhibitory action of adenosine on hippocampal slices. Brain Res 1990; 530: 330-334

57 Bartrup JT, Addae JI, Stone TW. Interaction between adenosine and excitatory agonists in rat hippocampal slices. Brain Res 1991; 564: 323-327

58 Nikbakht M-R, Stone TW. Suppression of presynaptic responses to adenosine by activation of NMDA receptors. Eur J Pharmacol 2001; 427: 13-25

59 Shahraki A, Stone TW. Blockade of presynaptic adenosine A1 responses by nitric oxide and superoxide in rat hippocampus. Eur J Neurosci 2004; 20, 719-728

60 Mally J, Stone TW. The effect of theophylline on Parkinsonian symptoms. J Pharm Pharmacol 1994; 46: 515-517

61 Mally J, Stone TW. Potential role of adenosine antagonist therapy in the treatment of pathological tremor disorders. Pharmacol Therap 1996; 72: 243-250

62 Mally J, Stone TW. Potential of adenosine A^sub 2A^ receptor antagonists in the treatment of movement disorders. CNS Drugs 1998; 10: 311-320

63 Grondin R, Bedard PJ, Tahar AH, et al. Antiparkinsonian effect of a new selective adenosine A^sub 2A^ receptor antagonist in MPTP-treated monkeys. Neurology 1999; 52: 1673-1677

64 Kanda T, Jackson MJ, Smith LA, et al. Adenosine A^sub 2A^ antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in Parkinsonian monkeys. Ann Neurol 1998; 43: 507-513

Trevor W. Stone

Institute of Biomedical & Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK

Correspondence and reprint requests to: T. W. Stone, West Medical Building, University of Glasgow, Glasgow G12 8QQ, UK. [t.w.] Accepted for publication December 2004.

Copyright Maney Publishing Mar 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

Return to Kainic acid
Home Contact Resources Exchange Links ebay