ANNUAL REVIEWS

Annu. Rev. Neurosci. 1990. 13:171-82 Copyright © 1990 by Annual Reviews Inc. All rights reserved

Further

Quick links to online content

THE ROLE OF GLUTAMATE NEUROTOXICITY IN HYPOXIC­ Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

ISCHEMIC NEURONAL DEATH Dennis W. Choi

Department of Neurology, Stanford University, Stanford, California 94305 Steven M. Rothman

Departments of Pediatrics, Neurology, and Anatomy and Neurobiology, Washington University, St. Louis, Missouri 63 1 10 The human brain depends on its blood supply for a continuous supply of oxygen and glucose. Irreversible brain damage occurs if blood flow is reduced below about 10 ml/ lOO g tissue/min and if blood flow is completely interrupted, damage will occur in only a few minutes. Unfortunately, such reductions (ischemia) are common in disease states: either localized to individual vascular territories, as in stroke; or globally, as in cardiac arrest. Cerebral hypoxia can also occur in isolation, for example in respiratory arrest, carbon monoxide poisoning, or near-drowning; pure glucose depri­ vation can occur in insulin overdose or a variety of metabolic disorders. As a group, these disorders are a leading cause of neurological disability and death; stroke alone is the third most common cause of death in North America. Despite its clinical importance, little is known about the cellular patho­ genesis of hypoxic-ischemic brain damage, and at present there is no effective therapy. A critical question has been why brain, more than most other tissues, is so vulnerable to hypoxic-ischemic insults. In particular, certain neuronal subpopulations, such as hippocampal field CA l and neocortical layers 3, 5, and 6, are characteristically destroyed after sub­ maximal hypoxic-ischemic exposure. A possible answer has emerged in the last few years: At least some of this special vulnerability may be accounted for by the central neurotoxicity of the endogenous excitatory 171 0147-o06Xj90j0301-o17 1$02.00

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

172

CHOI & ROTHMAN

amino acid neurotransmitter, glutamate, released into the extracellular space under hypoxic-ischemic conditions. A link between glutamate and cerebral hypoxia was anticipated 30 years ago by Van Harreveld ( 1959), who was studying cortical spreading depression (SD) in the rabbit. He had shown that the spreading depression could be produced by applying glutamate to the cortical surface and suspected that it was related to neuronal hypoxia. He then suggested that the two were connected: "If glutamic (aspartic) acid is involved in the mechanism of SD, it is likely that it also plays a major part in the asphyxial cortical changes which have a striking resemblance to this phenomenon." Evidence reviewed here and previously (Meldrum 1985, Rothman & Olney 1986, Choi 1988b) supports Van Harreveld's speculation. Glutamate Neurotoxicity

Befitting its dominant role in central excitatory neurotransmission (Curtis & Johnston 1974), glutamate is present in excitatory presynaptic terminals

throughout the brain, achieving millimolar whole tissue levels. It is some­ what counterintuitive-and unsettling-to consider that such a ubiqui­ tous agent can lethally injure neurons, but the neurotoxicity of intense exposure to extracellular glutamatc was established more than 30 years ago in the retina (Lucas & Newhouse 1957) and 20 years ago in the brain (Olney & Sharpe 1969). Olney went on to show that this neurotoxicity, which he later called "excitotoxicity," was a general property of excitatory amino acids on central neurons (Olney 1978). Under normal conditions, powerful neuronal and glial uptake systems rapidly remove synaptically released glutamate from the extracellular space before toxicity occurs (Schousboe 1981). Cellular uptake also serves to mask the neurotoxicity of exogenously administered glutamate in exper­ imental animals; as a result, many more studies have been done over the years with the plant excitotoxin, kainate, than with glutamate itself. More recently, it has been possible to examine directly glutamate neurotoxicity in neuronal cell cultures, where exposure can be controlled. These in vitro studies have suggested that glutamate neurotoxicity has several specific characteristics consistent with an important role in the pathogenesis of hypoxic-ischemic brain injury. First, glutamate appears to be a remarkably potent and rapidly acting neurotoxin. Exposure to only 100 pM glutamate for 5 min sufficed to destroy large numbers of cultured cortical neurons (Choi et aI1987). Thus it is possible that the transient release of only a small fraction of the ' intracellular stores of glutamate into the extracellular space can damage neurons, a finding that places glutamate neurotoxicity early in the chain of lethal events that might ensue in the wake of hypoxia-ischemia.

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

GLUTAMATE NEUROTOXICITY

173

Second, glutamate neurotoxicity may be largely mediated by a toxic influx of extracellular calcium. Intense glutamate exposure produces immediate neuronal swelling, which can be prevented by the removal of extracellular sodium or chloride (Rothman 1985, Olney et aI1986), and is probably due to the entry of sodium, chloride, and water into the cells. However, even without this acute swelling, most neurons exposed briefly to glutamate will still go on to degenerate in a delayed fashion, dependent on the presence of extracellular calcium (Choi 1987). Removal of extra­ cellular calcium substantially attenuates excitatory amino acid-induced neuronal loss in cortical (Choi 1985) and hippocampal (Rothman et al 1987a) cultures, as well as in cerebellar slices (Garthwaite & Garthwaite 1986). Furthermore, glutamate-induced 45calcium accumulation by corti­ cal neurons is highly correlated with resultant neuronal degeneration (Mar­ coux et a1 1988; M. Kurth and D. Choi, unpublished observations). These findings provide an attractive link between glutamate neurotoxi­ city and earlier data suggesting that a large calcium influx accompanies hypoxic-ischemic neuronal injury in vivo (Siesjo 1988). Third, glutamate neurotoxicity may be blocked by antagonist compounds (Rothman 1984), in particular those effective against the N-methyl-D­ aspartate (NMDA) subtype of glutamate receptor-ionophore complexes (Choi et al 1988). Glutamate activates several SUbtypes of receptor-iono­ phore complexes, named for their preferred pharmacological agonists: NMDA, kainate, and quisqualate (Watkins & Olverman 1987). Both NMDA and non-NMDA (kainate and quisqualate) receptors mediate the ability of glutamate to excite neurons, or to produce acute excitotoxic neuronal swelling. Selective antagonism of NMDA receptors alone, how­ ever, while inadequate to prevent either neuroexcitation or acute neuronal swelling, suffices to block the late neuronal degeneration induced by brief glutamate exposure (Choi et al 1988). This prominent role of NMDA receptors in glutamate neurotoxicity is consistent with the latter's depen­ dence on extracellular calcium, since only the NMDA subtype of glutamate receptors opens a membrane channel that is highly permeable to calcium (MacDermott et aI1986). The NMDA receptor-activated channel may be the major route by which glutamate induces a toxic calcium influx, although one should keep in mind that additional calcium entry probably occurs through voltage-activated calcium channels, the sodium-calcium exchanger, and nonspecific membrane leakage (Choi 1988a), and also that calcium also may be released from intracellular stores by the action of glutamate on "metabotropic" quisqualate receptors (Sladeczek et al 1 985, Nicoletti et aI1986). In any casc, specific dependcnce on NMDA receptors provides a specific pharmacological link between glutamate neurotoxicity and hypoxic-ischemic injury (see below).

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

174

CHOI & ROTHMAN

Fourth, glutamate neurotoxicity can be attenuated by antagonists added after glutamate exposure (Rothman et al 1 987a, Choi et al 1 988). This finding suggests that toxic exposure to glutamate is self-propagating: i.e. that an initial toxic exposure to glutamate subsequently triggers further neuronal injury, mediated by the excessiv� release or leakage of endogen­ ous glutamate stores. The protective efficacy of late antagonist admin­ istration has been confirmed against excitatory amino acid neurotoxicity in vivo (Foster et al 1 988), and may represent the cellular substrate for auspicious reports that glutamate antagonists can be neuroprotective when administered after thc onset of hypoxic-ischemic injury both in vitro and in vivo (see below). Finally, neuronal vulnerability to excitatory amino acid-induced injury is not uniform. Cortical neurons containing NADPH-diaphorase (which co-localizes with somatostatin) (Koh & Choi 1 988a), or GABA (Tecoma & Choi 1 98 9), and striatal neurons containing acetylcholinesterase (Koh & Choi 1988c), all possess some intrinsic resistance to injury by NMDA in vitro; the former are also characterized by heightened vulnerability to injury by kainate or quisqualate. Such differences in intrinsic neuronal vulnerability may not directly predict survival after in vivo hypoxia­ ischemia, since several other factors [e.g. the density of glutamatergic inputs, or the co-release of zinc, which can alter the receptor distribution activated by glutamate (Koh & Choi 1 988b)] also can influence resultant injury. However, these differences could contribute to the phenomenon of selective neuronal loss, a basic feature of hypoxic-ischemic neuronal damage. Of special note, is the fact that cortical NADPH-diaphorase­ containing neurons appear to be selectively spared in a neonatal rat model of ischemic injury (Ferriero et al 1 988). In Vitro Hypoxia

Observations on dispersed rodent hippocampal neurons in tissue culture provided the first direct indication that excitatory synaptic transmission might influence the sensitivity of neurons to low levels of oxygen (Rothman 1 983). When these neurons are first dissociated and put into culture, they have no synaptic connections and survive a one-day exposure to 95% nitrogen/5% carbon dioxide ( 95% N2/5% CO2) or sodium cyanide ( l mM). However, after two weeks in culture, when excitatory glutamatergic synapses have developed (Rothman & Samaie 1 985), both of these treat­ ments leads to extensive neuronal degeneration. The addition of high concentrations of magnesium, which blocks trans­ mitter release, largely prevents this neuronal loss. The initial interpretation of these results was that blockade of transmitter release protected neurons from hypoxia, although a more modern interpretation recognizes that

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

GLUTAMATE NEUROTOXICITY

175

magnesium can gate the NMDA channel (Nowak et a11984, Mayer et al 1984) and thereby exert a post-synaptic effect as well. Subsequent in vitro experiments provided additional evidence linking glutamate to hypoxic­ ischemic neuronal damage. Pretreating cultures with the nonselective excit­ atory amino acid antagonist Y-D-glutamylglycine (Davies et al 1982) was as effective as magnesium in preventing neuronal loss (Rothman 1984). Selective antagonism of NMDA receptors with either competitive or non­ competitive antagonists also attenuated the neuronal injury caused by hypoxia (Goldberg et a11987, Rothman et a11987b, Weiss et al 1986) or glucose deprivation (Monyer & Choi 1988) in cortical or hippocampal cultures. A neuroprotective effect was also seen when the antagonist was added after completion of a combined oxygen and glucose deprivation insult (Goldberg et al 1988a). In contrast, excitatory amino acid antag­ onists were not effective against combined oxygen and glucose deprivation in cultures of rat basal ganglia (Goldberg et al 1986), perhaps reflecting the paucity of glutamatergic neurons in these cultures and the severity of the insult delivered. Parallel experiments examining the pathophysiology of hypoxia in rod­ ent brain slices have also indicated that excitatory transmission is related to neuronal injury. Kass & Lipton (1982) found that slices of rat dentate gyrus irreversibly lost evoked field potentials if they were exposed to 95% N2/5% CO2 for ten minutes. If the hypoxic exposure occurred after calcium was removed from the extracellular perfusate and the magnesium con­ centration elevated, this field potential reduction was markedly attenuated. As mentioned above, this manipulation should both diminish the release of the excitatory transmitter and block activity elicited by activation of NMDA receptors. The same laboratory has since shown that specific block of NMDA reccptors reduces hypoxic damage in their slices (Lobner & Lipton 1987). Similar observations have been made in hippocampal slices (Clark & Rothman 1987, Rothman et al I987b). Pretreatment with either nonselective excitatory amino acid antagonists, NMDA antagonists, or high extracellular magnesium almost completely prevents the irreversible loss of the evoked CAl synaptic potential which otherwise occurs after a 40-min exposure to 95% N 2/5% CO2• NMDA antagonists also repolarize neurons that have started to depolarize in hypoxic hippocampal slices (Rader et al 1988). Although there is some agreement among different investigators that excitatory transmitter release plays a role in hypoxic brain slice damage, experiments with excitatory amino acid antagonists have not been uni­ formly positive. Aitken and colleagues (1988) were not able to show a statistically significant recovery from hypoxia of NMDA antagonist­ treated slices. The severity of their model and the low dose of a com-

176

CHOI & ROTHMAN

petitive racemic antagonist that may have some agonist activity, are pos­ sible explanations for this negative result.

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

In Vivo Hypoxia-Ischemia

The first clear-cut demonstration that glutamate plays a role in hypoxic­ ischemic brain damage in vivo came from the experiments of Simon and his associates (1 984). They showed that direct intrahippocampal injection of the competitive NMDA antagonist 2-amino-7-phosphonoheptanoate (APH) reduced the loss of CAl pyramidal neurons produced by transient carotid ligation in the rat. APH was also found to protect the rat caudate from injury induced by hypoglycemia (Wieloch 1 985). A number of differ­ ent laboratories have now confirmed and extended these results with vari­ ous NMDA antagonists (Gill et al 1 988, Kochhar et al 1 988, Marcoux et al 1988, Church et al 1988, Natale et al 1988, Boast et al 1 988, Steinberg et al 1 988, Park et al 1 988). However, some negative results have been reported with global ischemia models (Block & Pulsinelli 1 987, Jensen & Auer 1 988, Wieloch 1988), and as W. A. Pulsinelli (personal communica­ tion) has pointed out, not all studies have excluded a neuroprotective effect of brain hypothermia. Other laboratories have found that glutamate antagonists can prevent much of the forebrain damage seen in neonatal rodents after combined hypoxic and ischemic insult (McDonald et a1 1 987, Prince & Feeser 1 988, Andine et al 1 988, Olney et al 1 98 9). Several of these laboratories have observed neuroprotcctivc benefits with systemic administration of the antagonist drug after the initiation of ischemia (McDonald et al 1 987, Boast et al 1988, Gill et al 1988, Steinberg et al 1988, Park et al 1988). In addition to the demonstration that antagonists of glutamate, especially those acting at the NMDA receptor-channel complex, limit damage from anoxia, other lines of evidence have implicated glutamate and excitatory synaptic transmission in the etiology of hypoxic-ischemic brain injury. Investigators in two different laboratories (Johansen et al 1986, Onadera et al 1 986) selectively lesioned some of the excitatory glutamatergic inputs to the hippocampus and allowed sufficient time for their terminals to degenerate. When these animals were subjected to carotid ligation, they showed dramatically preserved hippocampi. There is also an excellent correlation between the presence of glutamate receptors and vulnerability to brain ischemia. The CA l region of the hippocampus, which is particularly rich in NMDA receptors (Monaghan et al 1 983), is the most susceptible region to this type of injury. Some of the most convincing evidence linking extracellular glutamate and ischemic injury has been provided by direct measurement of extra­ cellular glutamate concentration with in vivo microdialysis. During a 10-

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

GLUTAMATE NEUROTOXICITY

177

min period of experimental ischemia, glutamate levels rose from under 5 jiM to approximately 30 jiM (Benveniste et al 1 984, Hagberg et aI1 985). After 30 min of ischemia, the glutamate concentration exceeded 500 jiM, a concentration which is rapidly toxic to cultured cortical neurons (Choi et al 1987). The origin of the increased extracellular glutamate has not been unequivocally established. Glutamate reuptake is impaired in ischemic synaptosomes (Silverstein et al 1 986) and both anoxia and hypoglycemia reduce amino acid uptake into glia in vitro (Drejer et aI1 985). Release of glutamate may also increase under ischemic conditions, possibly because collapsed ion gradients lead to the leakage of glutamate from the intra­ cellular space (Kauppinen et al 1 988). These results suggest that both neuronal and glial dysfunction could contribute to the excessive "glu­ tamate burden." However, the protective effect of lesioning excitatory afferents implies that excitatory glutamatergic terminals must be present to initiate this process. Limitations of the Present Glutamate Hypothesis

The idea that hypoxic-ischemic brain damage can be explained by over­ stimulation of glutamate receptors is appealing. Unfortunately, glutamate is not the sole cause of ischemic neuronal damage and may have little importance under some conditions. Several variables outside the glutamate system, including ischemia type (focal vs. global), animal species, brain temperature, blood-brain barrier integrity, edema formation, and effects of other neurotransmitters, probably all influence the outcome following hypoxia-ischemia. Of note, ischemic damage is common in the myelinated tracts of the brain, which consist largely of axons and oligodendrocytes. Myelinated tracts do not show the sensitivity to excitotoxic damage that characterizes brain regions composed largely of neuronal cell bodies and dendrites (e.g. cortex and hippocampus); in fact, excitotoxic lesions were initially described as "axon sparing" (Olney 1 978). Therefore, ischemic injury to white matter cannot be attributed directly to glutamate. In addition, even neurons richly endowed with excitatory amino acid receptors are not indefinitely protected from anoxic damage by glutamate antagonists. Cul­ tured cortical neurons maintained in 95% N2/5% CO2 in the presence of high concentrations of NMDA antagonists still die after 16 hours (Gold­ berg et al 1 987). This result is not very surprising, as all mammalian cells will eventually die if deprived of oxygen and nutrients. An excessively severe ischemic insult may account for some of the negative outcomes reported with glutamate antagonists in stroke models. Along these lines, an important area for future investigation is the relationship between glutamate neurotoxicity and cerebral infarction-

178

CHOI & ROTHMAN

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

the consolidated zone of pancellular necrosis produced by profound focal ischemia. One might expect glutamate antagonists to lose effectiveness against ischemia sufficiently profound to destroy both neurons and glia, but recent evidence suggests that substantial reductions of infarct size may occur (Simon 1988 and personal communication, Park et aI1988). Why this might be so is unclear at present, but it is potentially of great therapeutic significance. Could glutamate-induced neuronal damage be responsible for other changes-a "bad neighborhood" effect involving a local buildup of lytic enzymes or other toxic factors, or changes in local blood flow­ that secondarily contribute to the destruction of non-neuronal elements? Therapeutic Issues

Although glutamate neurotoxicity is not the explanation for all ischemia­ related brain damage, the positive results discussed above suggest that it may be a highly appropriate target for rational stroke therapy at the present time. A variety of questions, however, will have to be answered before any extensive clinical trials can be considered (Albers et al 1989). First, we will have to determine the most effective pharmacological strategies for minimizing glutamate neurotoxicity. Since most glutamate damage is probably mediated via NMDA receptors, some type ofNMDA antagonist is a logical consideration. Different types ofNMDA antagonists will have to be studied to determine differences in efficacy. In addition, there are classes of neurons that are more susceptible to non-NMDA receptor-mediated damage, and it will be important to determine the incremental neuroprotective benefit to be gained by blocking non-NMDA receptors. Alternatively, it may be desirable to try to minimize the pre­ synaptic synthesis or release of glutamate. Hypoxic neuronal injury in cortical culture can be attenuated by removal of the glutamate precursor, glutamine, from the bathing medium (Goldberg et al 1988b). Adenosine agonists, which likely act presynaptically to reduce transmitter release, can improve neuronal survival in both in vitro (Goldberg et al 1988c) and in vivo models of hypoxia-ischemia (Evans et a1 1987, von Lubitz et al 1988); adenosine antagonists worsen injury (Wieloch et al 1986, Rudolphi et al 1987). Second, we will have to determine whether any such interference with glutamate leads to unacceptable side effects. If antagonism is restricted to the NMDA receptor system, non-NMDA receptor-mediated fast excit­ atory synaptic transmission should be preserved. However, many available non-competitiveNMDA antagonists interact with the phencyclidine bind­ ing site in the NMDA channel, and may share disturbing psychotomimetic effects with that compound. Of special concern is the fact that certain noncompetitive NMDA antagonists such as ketamine and MK-801

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

GLUTAMATE NEUROTOXICITY

179

increase the cerebral metabolic rate for glucose, an undesirable effect in ischemic brain (Hammer & Herkenham 1983, Nehls et alI988). Blocking NMDA currents with either potent competitive antagonists (Boast et al 1988) or antagonists of the glycine receptor (Fletcher & Lodge 1988, Kemp et al 1988) may avoid these problems (Mathisen et al 1 988, Nehls et al 1988). Third, we will have to have more precise information about the time course of the development of irreversible neuronal damage after the onset of hypoxia-ischemia in man. If most patients have already suffered irre­ versible damage by the time they seek attention, glutamate antagonists will offer them little. However, pathological evidence in both rodents and humans suggests that damage in the CA 1 region of the hippocampus develops hours to days after transient ischemia (Pulsinelli et a11982, Petito et aI1987). If much of this delay reflects ongoing glutamate neurotoxicity, there may be a substantial temporal "therapeutic window" -as seen in experimental stroke models-during which it may prove possible to halt progressive neuronal degeneration and improve neurological outcome. A CKNOWLEDGMENTS This work was supported by National Institutes of Health grants NS26907 (D. W. C.) and NS19988 (S. M. R.). We thank Deborah Howard for assistance with the manuscript.

Literature Cited

Aitken, P. G., Balestrino, M., Somjen, G. C. 1988. NMDA antagonists: Lack of pro­ tective effect against hypoxic damage in C A l region of hippocampal slices. Neuro­ sci. Lett. 89: 187-92 Albers, G. A., Goldberg, M. P., Choi, D. W. 1989. N-methyl-n-aspartate antagonists: Ready for clinical trial in brain ischemia? Ann. Neurol. 25: 398-403 Andine, P., Lehmann, A., Ellren, K., Wennberg, E., Kjellmer, L., et al. 1988. The excitatory amino acid antagonist ky­ nurenic acid administered after hypoxial ischemia in neonatal rats offers neuro­ protection. Neurosci. Lett. 90: 208-12 Benveniste, H., Drejer, J., Schousboe, A., Diemer, N. H. 1984. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J. Neurochem. 43: 1369-74 Block, G. A., Pulsinelli, W. A. 1987. Excit-

atory amino acid receptor antagonists: Failure to prevent ischemic neuronal dam­ age. J. Cereb. Blood Flow Metab, 7(1): SI49 (Abst.) Boast, C. A., Gearhardt, S. C., Pastor, E., Lehmann, J., Etienne, P. E., et al. 198!L The N-methyl-o-aspartate antagonists CGS 19755 and CPP reduce ischemic brain damage in gerbils. Brain Res. 442: 345-48 Choi, D. W. 1985. Glutamate neurotoxicity in cortical ccll culture is calcium depen­ dent. Neurosci. Lett. 58: 293-97 Choi, D. W. 1987. Ionic dependence of glu­ tamate neurotoxicity in cortical cell culture. J. Neurosci. 7: 369-79 Choi, D. W. 1988a. Calcium-mediated neuro­ toxicity: Relationship to specific channel types and role in ischemic damage. Trends Neurosci. 11: 465-69 Choi, D. W. 1988b. Glutamate neurotoxicity and diseases of the nervous system. Neuron I: 623-34

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

180

CHOI & ROTHMAN

Choi, D. W., Koh, J., Peters, S. 1988. Phar­ macology of glutamate neurotoxicity in cortical cell culture: Attenuation by NMDA antagonists . 1. Neurosci. 8: 18596 Choi, D. W., Maulucci-Gedde, M. A., Kriegstein, A. R. 1987. Glutamate neur­ otoxicity in cortical cell culture. J. Neuro­ sci. 7: 357-68 Church, J., Zeman, S., Lodge, D. 1988. Keta­ mine and MK-80I as neuroprotective agents in cerebral ischemia/hypoxia. See Domino & Kamenka 1988, pp. 747-56 Clark, G. D., Rothman, S. M. 1987. Block­ ade of excitatory amino acid receptors protects anoxic hippocampal slices. Neu­ roscience 21: 665-71 Curtis, D. R., Johnston, G. A. R. 1974. Amino acid transmitters in the mam­ malian central nervous system. Ergeb. Physiol. BioI. Chem. Exp. Pharmakol. 69: 98-188 Davies, J., Evans, R. H., Jones, A. W., Smith, D. A. S., Watkins, J. C. 1982. Differential activation and blockade of excitatory amino acid receptors in the mammalian and amphibian central ner­ vous systems. Compo Biochem. Physiol. C 72: 211-24 Domino, E. F., Kamenka, J. M., eds. 1988. Sigma and Phencyclidine-Like Compounds as Molecular Probes in Biology. Ann Arbor:NPP Books Drejer, J., Benven iste , R., Diemer, N. R., Schousboe, A. 1985. Cellular origin of ischemia-induced glutamate release from brain tissue in vivo and in vitro. J. Neurochem. 45: 145-51 Evans, M. c., Swan, .T. H., Me ldrum, B. S. 1987. An adenosine analogue, 2-chloro­ adenosine, protects against long term development of ischaemic eell loss in the rat hippocampus. Neurosci. Lett. 83: 28792 Ferriero, D. M., Arcavi, L. J., Sagar, S. M., Mcintosh, T. K., Simon, R. P. 1988. Selec­ tive sparing of NADPR-diaphorase neurons in neonatal hypoxia-ischemia. Ann. Neurol. 24: 670--76 Fletcher, E. J., Lodge, D. 1988. Glycine reverses antagonism of N-methyl­ D-aspartate (NMDA) by l-hydroxy-3aminopyrrolidone-2 (HA-966) but not by D-2-amino-5-phosphonovalerate (D­ AP5) on rat cortical slices. Eur. J. Pharma­ col. 151: 161-62 Foster, A., Gill, R., Woodruff, G. N. 1988. Neuroprotective effects of MK-801 in vivo: Selectivity and evidence for delayed degeneration mediated by NMDA recep­ tor activation. J. Neurosci. 8: 4745-54 Garthwaite, G., Garthwaite, J. 1986. Ncuro­ toxicity of excitatory amino acid receptor

agonists in rat cerebellar slices: Depen­ dence on calcium concentration. Neurosci. Lett. 66: 193-98 Gill, R., Foster, A. C., Woodruff, G. M. 1988. MK-801 is neuroprotective in ger­ bils when administered during the post­ ischemic period. Neuroscience 25: 847-55 Goldberg, M. P., Monyer, R., Choi, D. W. 1988a. Cortical neuronal injury in vitro following combined glucose and oxygen deprivation: Ionic dependence and de­ layed protection by NMDA antagon­ ists. Soc. Neurosci. Abstr. 14: 745 Goldberg, M. P., Monyer, R., Choi, D. W. 1988b. Hypoxic neuronal injury in vitro depends on extracellular glutamine. Neurosci. Lett. 94: 52-57 Goldberg, M. P., Monyer, H., Weiss, J. H., Choi, D. W. 1988c. Adenosine reduces cortical neuronal injury induced by oxy­ gen or glucose deprivation in vitro Neuro­ sci. Lett. 89: 323-27 Goldberg, M. P., Weiss, J. R., Pham, P. c., Choi, D. W. 1987. N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture. J. Pharmacol. Exp. Ther. 243: 784-91 Goldberg, W. J., Kadingo, R. M., Barrett, J. N. 1986. Effects of ischemia-like con­ d itions on cultured neurons: Protection by low Na+, low Caz+ solutions. J. Neurosci. 6: 3144-51 Hagberg, R., Lehmann, A., Sandberg, M., Nystrom, B., Jacobson, I., et a l. 1985. Ischemia-induced shift of inhibitory and excitatory amino acids from intra- to extracellular compartments. J. Cereb. Blood Flow Metab. 5: 413-19 Hammer, R. P., Herkenham, M. 1983. Alt­ ered metabolic activity in the cerebral cortex of rats exposed to ketamine. J. Compo Neurol. 220: 396-404 Jensen, M. C., Auer, R. N. 1988. Ketamine fails to protect against ischemic neuronal necrosis in the rat. Br. J. Anaesth. 61: 20610 Johansen, F. F., Jorgensen, M. B., Diemer, N. R. 1986. Ischemic CAl pyramidal cell loss is prevented by preischemic colchcine destruction of dentate gyrus granule cells. Brain Res. 377: 344-47 Kass, I. S., Lipton, P. 1982. Mechanisms involved in irreversible anoxic damage to the in vitro rat hippocampal slice. J. Physiol. 332: 459-72 Kauppinen, R. A., McMahon, R. T., Nich­ olls, D. G. 1988. Ca2+-dependent and Ca2+-independent glutamate release, energy status and cytosolic free Ca 2+ c on­ centration in isolated nerve terminals fol­ lowing metabolic inhibition: Possible rel­ evance to hypoglycaemia and anoxia. Neuroscience 27: 175-82

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

GLUTAMATE NEUROTOXICITY Kemp, J. A., Foster, A. c., Leeson, P. D., Pries tl ey, T., Tridgett, R., et a!. 1988. 7Chlorokynurenic acid is a selective antago­ nist at the glycine modulatory site of the N-methyl-o-aspartate receptor complex. Proc. Nat!. Acad. Sci. USA 85: 6547-50 Kochhar, A., Zivin, J. A., Lyden, P. D., Mazzarella, V. 19l!l!. Glutamate antag­ onist therapy reduces neurologic deficits produced by focal central nervous system ischemia. Arch. Neuro/. 45: 148-53 Koh, 1., Choi, D. W. 1988a. Vulnerability of cultured cortical neurons to damage by excitotoxins: Differential susceptibility of neurons containing NADPH-di aphorase. J. Neurosci. 8: 2153--63 Koh, J., Choi, D. W. 1988b. Zinc alters excit­ atory amino acid neurotoxicity on cortical neurons. J. Neurosci. 8: 2164--71 Koh, J., Choi, D. W. 1988c. Cultured striatal neurons containing NADPH-diaphorase or acetylcholinesterase are selectively resistant to injury by NMDA receptor agonists. Brain Res. 446: 374--78 Lobner, D., Lipton, P. 1987. Glutamate receptors and irreversible anoxic damage in hippocampal slices: Mechanism of interaction. Soc. Neurosci. Abstr. 13: 647 Lucas, D. R., Newhouse, J. P. 1957. The toxic effect of sodium L-glutamate on the inner layers of the retina. Arch. Ophtha/­ mol. 58: 193-201 MacDermott, A. B., Mayer, M. L., Westbrook, G. L., Smith, S. J., Barker, J. L. 19l!6. NMDA-receptor activation in­ creases cytoplasmic calcium concentra­ tion in cultured spinal cord neurones. Nature 321: 519-22 Marcoux, F. W., Goodrich, J. E., Probert, A. W., Dominick, M. A. 1988. Ketamine prevents glutamate-induced calcium in­ flux and ischemic nerve cell injury. See Domino & Kamenka 1988, pp. 735-46 Mathisen, 1. E., Rothman, S. M., Contreras, P. c., Deuel, R. K. 1988. Comparison of regional 14C-2-deoxyglucose (2-DG) up­ take in rat brain following parenteral administration of either o-2-amino-5-pho­ sphonoheptanoate (APH) or ketamine. Soc. Neurosci. Abstr. 14: 480 Mayer, M. L., Westbrook, G. L., Guthrie, P. B. 1984. Voltage-dependent block by Mg2+ ofNMDA responses in spinal cord neurons. Nature 309: 261-63 McDonald, J. W., Silverstein, F. S., Johnston, M. V. 1987. MK-801 protects the neonatal brain from hypoxic-ischemic damage. Eur. J. Pharmacal. 140: 359--61 Meldrum, B. 1985. Possiblc thcrapcutic applications of antagonists of excitatory amino acid neurotransmitters. Clin. Sci. 68: 113-22 Monaghan, D. T., Holets, V. R., Toy, D.

181

W., Cotman, C. W. 1983. Anatomical dis­ tributions of four pharmacologically dis­ tinct 3H-L-glutamate binding sites. Nature 306: 176-79 Monyer, H., Choi, D. W. 1988. Morphinans attenuate cortical neuronal injury induced by glucose deprivation in vitro. Brain Res. 446: 144-48 Natale, J. E., Schott, R. J., D' Alecy, L. G. 1988. Ketamine reduces neurological deficit following 10 minutes of cardiac arrest and resuscitation in canines. See Domino & Kamenka 1988, pp. 717-26 Nehls, D. G., Kurumaji, A., Park, C. K., McCulloch, J. 1988. Differential effects of compe titiv e and non-competitive N­ methyl-o-aspartate antagonists on glucose use in the limbic system. Neurosci. Lett. 91: 204--1 0 Nicoletti, F., Wroblewski, J. T.,Novelli, A., Alho, H., Guidotti, A., Costa, E. 1986. The activation of inositol phospholipid metabolism as a signal-transducing systcm for excitatory amino acids in primary cul­ tures of cerebellar granule cells. J. Neuro­ sci. 6: 1905-11 No wak , L., Bregestovski, P., Ascher, P., Herbet, A., Prochiantz, A. 1984. Mag­ nesium gates glutamate activated channels in mouse central neurons. Nature 307: 462-65 Olney, J. W. 1978. Neurotoxicity of excit­ atory amino acids. In Kainic Acid as a Tool in Neurobiology, ed. E. G. McGeer, J. W. Olney, P. L. McGeer, pp. 95-171. New York: Raven Olney, J. W., Price, M. T., Samson, L., Labruyere, J. 1986. The role of specific ions in glutamate neurotoxicity. Neurosci. Lett. 65: 65-71 Olney, 1. W., Ikonomidou, c., Mosinger, 1. L., Frierdich, G. 1989. MK-801 prevents hypobaric-ischemic neuronal degenera­ tion in infant rat brain. J. Neurosci. 9: 1701-4 Olney, J. W., Sharpe, L. G. 1969. Brain lesions in an infant rhesus monkey treated with monosodium glutamate . Science 166: 386--88 Onodera, H., Sato, G., Kogure, K. 1986. Lesions to Schaffer collaterals prevent ischemic death of CA1 pyrami dal cells. Neurosci. Lett. 68: 169-74 Park, C. K., Nehls, D. G., Graham, D. I., Teasdale, G. M., McCulloch, J. 1988. Focal cerebral ischaemia in the cat: Treat­ ment with the glutamate antagonist MK80I after induction of ischaemia. J. Cereb. Blood. Flow Metab. 8: 757-62 Petito, C. K., Feldmann, E., Pulsinclli, W. A., Plum, F. 1987. Delayed hippocampal damage in humans following cardio­ respiratory arrest. Neurology 37: 1281-86

Annu. Rev. Neurosci. 1990.13:171-182. Downloaded from www.annualreviews.org by Pennsylvania State University on 07/29/12. For personal use only.

182

CHOI & ROTHMAN

Prince, D. A., Feeser, H. R. 1988. Dextro­ methorphan protects against cerebral infarction in a rat model of hypoxia­ ischemia. Neurosci. Lett. 85: 291-96 Pulsinelli, W. A., Brierley, J. B., Plum, F. 1982. Temporal profile of neuronal dam­ age in a model of transient forebrain ischemia. Ann. Neurol. 11: 491-98 Rader, R. K., Watson, G. B., Lanthorn, T. H. 1988. Pharmacological characteriza­ tion of the persistent depolarization in­ duced by experimental ischemia. Soc. Neu­ rosci. Abslr. 14: 189 Rothman, S. M. 1983. Synaptic activity mediates death of hypoxic neurons. Sci­ ence 220: 536-37 Rothman, S. M. 1984. Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J. Neuro­ sci. 4: 1884-91 Rothman, S. M. 1985. The neurotoxicity of excitatory amino acids is produced by pas­ sive chloride influx. J. Neurosci. 5: 148389 Rothman, S. M., Olney, J. W. 1986. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann. Neurol. 19: 105-11 Rothman, S. M., Samaie, M. 1985. The physiology of excitatory synaptic trans­ mission in cultures of dissociated rat hip­ pocampus.1. Neurophysiol. 54: 701-13 Rothman, S. M., Thurston, J. H . , Hauhart, R. E. 1987a. Delayed neurotoxicity of excitatory amino acids in vitro. Neuro­ science 22: 471-80 Rothman, S. M., Thurston, J. H., Hauhart, R. E., Clark, G. D., Solomon, J. S. 1987b. Ketamine protects hippocampal neurons from anoxia in vitro. Neuroscience 21: 673-78 Rudolphi, K. A., Keil, M., Hinze, H. J. 1987. Effect of theophylline on ischemically induced hippocampal damage in mon­ golian gerbils: A behavioral and histo­ pathological study. J. Cereb. Blood Flow Metab. 7: 74-81 Schousboe, A. 1981. Transport and metab­ olism of glutamate and GABA in neurons and glial cells. Int. Rev. Neurobiol. 22: 145 Siesjo, B. K. 1988. Historical overview. Cal­ cium, ischemia, and death of brain cells. Ann. NY Acad. Sci. 522: 638-61 Silverstein, F. S., Buchanan, K., Johnston, M. V. 1986. Perinatal hypoxia-ischemia

disrupts high-affinity [3H]-glutamate up­ take into synaptosomes. J. Neurochem. 47: 1614-19 Simon, R. P. 1988. Focal ischemia, exci­ tatory amino acid antagonists and pen­ umbra. Neurochem. Int. 12(Supp\. I): 23 Simon, R. P., Swan, J. H., Griffiths, T., Mel­ drum, B. S. 1984. Blockade of N-methyl­ o-aspartate receptors may protect against ischemic damage in the brain. Science 226: 850-52 Siadeczek, F., Pin, J. P., Recasens, M., Bockaert, J., Weiss, S. 1985. Glutamate stimulates inositol phosphate formation in striatal neurones. Nature 317: 717-19 Steinberg, G. K., Saleh, J., Kunis, D. 1988. Delayed treatment with dextromethor­ phanand dextrorphan reduces cerebral dam­ age after transient focal ischemia. Neuro­ sci. Lett. 89: 193-97 Tecoma, E. S., Choi, D. W. 1989. GABA­ nergic neocortical neurons are resistant to NMDA receptor-mediated inj ury . Neurol­ ogy 39: 676-82 Van Harreveld, A. 1959. Compounds in brain extracts causing spreading depres­ sion of cerebral cortical activity and contrac­ tion of crustacean muscle. J. Neurochem. 3: 300-15 von Lubitz, D. K. J. E., Dambrosia, J. M., Kempski, 0., Redmond, D. J. 1988. Cyclohexyl adenosine protects against neuronal death following ischemia in the CA I region of the hippocampus. Stroke 19: 1133-39 Watkins, J. C., Olverman, H. J. 1987. Agon­ ists and antagonists for excitatory amino acid receptors. Trends Neurosci. 10: 26572 Weiss, J. H., Goldberg, M. P., Choi, D. W. 1986. Ketamine protects cultured neo­ cortical neurons from hypoxic injury. Brain Res. 380: 186-90 Wieloch, T. 1985. Hypoglycemia-induced neuronal damage prevented by an N­ methyl-o-aspartate antagonist. Science 230:681-83 Wieloch, T. 1988. MK-801 does not protect against brain damage in a rat model of cerebral ischemia. Neurochem. Int. 12 (Supp\. I): 24 Wieloch, T., Koide, T., Westerberg, E. 1986. Inhibitory neurotransmitters and neuro­ modulators as protective agents against ischemic brain damage. In Pharmacology of Cerebral Ischemia, ed. 1. K rieglestein , pp. 191-97. New York: Elsevier

The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death.

ANNUAL REVIEWS Annu. Rev. Neurosci. 1990. 13:171-82 Copyright © 1990 by Annual Reviews Inc. All rights reserved Further Quick links to online conte...
429KB Sizes 0 Downloads 0 Views