Effects of Anoxia on the Stimulated Release of Amino Acid Neurotransmitters in the Cerebellum <i>In Vitro</i>

Bosley, Thomas M.; Woodhams, P.L.; Gordon, Roger; Balázs, R.

doi:10.1111/j.1471-4159.1983.tb12670.x

Cited by 130 publications

(47 citation statements)

References 35 publications

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“…In contrast, mammals cannot survive on anaerobic metabolism alone. Oxygen deprivation induces elevations in excitatory amino acids, which leads to overexcitation of glutamate receptors, ATP loss, anoxic depolarization, excessive Ca 2ϩ influx, and rapid excitotoxic cell death (ECD) (6,11,24,36,41). Two glutamate receptors, the N-methyl-D-aspartate receptor (NMDAR) and the ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR), are the principle mediators of ECD.…”

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AMPA receptors undergo channel arrest in the anoxic turtle cortex

Pamenter¹,

Shin²,

Buck³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Without oxygen, all mammals suffer neuronal injury and excitotoxic cell death mediated by overactivation of the glutamatergic N-methyl-D-aspartate receptor (NMDAR). The western painted turtle can survive anoxia for months, and downregulation of NMDAR activity is thought to be neuroprotective during anoxia. NMDAR activity is related to the activity of another glutamate receptor, the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR). AMPAR blockade is neuroprotective against anoxic insult in mammals, but the role of AMPARs in the turtle's anoxia tolerance has not been investigated. To determine whether AMPAR activity changes during hypoxia or anoxia in the turtle cortex, whole cell AMPAR currents, AMPAR-mediated excitatory postsynaptic potentials (EPSPs), and excitatory postsynaptic currents (EPSCs) were measured. The effect of AMPAR blockade on normoxic and anoxic NMDAR currents was also examined. During 60 min of normoxia, evoked peak AMPAR currents and the frequencies and amplitudes of EPSPs and EPSCs did not change. During anoxic perfusion, evoked AMPAR peak currents decreased 59.2 Ϯ 5.5 and 60.2 Ϯ 3.5% at 20 and 40 min, respectively. EPSP frequency (EPSP ƒ) and amplitude decreased 28.7 Ϯ 6.4% and 13.2 Ϯ 1.7%, respectively, and EPSCƒ and amplitude decreased 50.7 Ϯ 5.1% and 51.3 Ϯ 4.7%, respectively. In contrast, hypoxic (PO2 ϭ 5%) AMPAR peak currents were potentiated 56.6 Ϯ 20.5 and 54.6 Ϯ 15.8% at 20 and 40 min, respectively. All changes were reversed by reoxygenation. AMPAR currents and EPSPs were abolished by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In neurons pretreated with CNQX, anoxic NMDAR currents were reversibly depressed by 49.8 Ϯ 7.9%. These data suggest that AMPARs may undergo channel arrest in the anoxic turtle cortex.N-methyl-D-aspartate receptor; excitotoxic cell death; spike arrest THE WESTERN PAINTED TURTLE (Chrysemys picta belli) can survive without oxygen for days to months (43). This tolerance is predicated on the turtle's ability to maintain neuronal function by using anaerobically produced ATP. In contrast, mammals cannot survive on anaerobic metabolism alone. Oxygen deprivation induces elevations in excitatory amino acids, which leads to overexcitation of glutamate receptors, ATP loss, anoxic depolarization, excessive Ca 2ϩ influx, and rapid excitotoxic cell death (ECD) (6,11,24,36,41). Two glutamate receptors, the N-methyl-D-aspartate receptor (NMDAR) and the ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR), are the principle mediators of ECD. In mammals, the activity of both receptors is increased during hypoxia (14, 29), and blockade of either receptor is neuroprotective against global or focal ischemia (15,42).A proposed mechanism used by facultative anaerobes to prolong anoxia tolerance and prevent ECD is a decrease in membrane permeability and downregulation of ion channel or receptor activity termed "channel arrest" (17). Indeed, in contrast to the commonly observed anoxic potentiation of mammalian NMDAR currents, turtle NMDARs underg...

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AMPA receptors undergo channel arrest in the anoxic turtle cortex

Pamenter¹,

Shin²,

Buck³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Increased release of excitatory amino acids has been reported during cerebral ischemia in vivo 12 " 15 and during simulated ischemic conditions in vitro. 16 " 18 A number of in vitro and in vivo experimental studies have shown that excitatory amino acid receptor antagonists have a protective effect on brain following cerebral ischemia. 19 -28 One putative source of oxygen free radicals during cerebral ischemia is the arachidonic acid cascade.…”

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Interaction between free radicals and excitatory amino acids in the formation of ischemic brain edema in rats.

Betz

1991

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Both oxygen free radicals and excitatory amino acids have been implicated as important cellular toxins in ischemic brain. Recent in vitro studies suggest that there may be a mutual interaction between these two mediators. We explored the relation between oxygen free radicals and excitatory amino acids in the development of ischemic brain edema in vivo. Male Sprague-Dawley rats were treated with the free radical scavenger dimethylthiourea 1 hour before ischemia or with the excitotoxin antagonist MK-801 30 minutes before ischemia produced by occlusion of the middle cerebral artery. Groups of seven or eight animals were treated with vehicle, low-dose (375 mg/kg) dimethylthiourea, high-dose (750 nig/kg) dimethylthiourea, low-dose (0.5 mg/kg) MK-801, high-dose (2.0 mg/kg) MK-801, or both high-dose dimethylthiourea and low-dose MK-801. After 4 hours of ischemia, brain water content was determined. In eight vehicle-treated controls, mean±SEM water content of tissue in the center of the ischemic zone was 83.29±0.18%. A significant reduction of brain edema was observed in all drug-treated groups: for example, 50.2% (p<0.001) in the high-dose dimethylthiourea group, 53.7% (p<0.001) in the low-dose MK-801 group, and 66.4% (/?<0.001) in the combined dimethylthiourea and MK-801 group. Combined treatment with dimethylthiourea and MK-801 provided no significant additive effect over that resulting from treatment with MK-801 alone. These results indicate that pretreatment with either dimethylthiourea or MK-801 can reduce brain edema during the early stages of cerebral ischemia and further suggest that excitatory amino acids and oxygen free radicals may damage the brain by a common pathway. Supported by a grant-in-aid from the American Heart Association of Michigan.Address for correspondence: A. Lorris Betz, MD, PhD, D3227 Medical Professional Building, University of Michigan, Ann Arbor, MI 48109-0718.Received December 28, 1990; accepted March 18, 1991. have shown that excitatory amino acid receptor antagonists have a protective effect on brain following cerebral ischemia. -28One putative source of oxygen free radicals during cerebral ischemia is the arachidonic acid cascade. 29 " 31 Since the activation of excitatory neurotransmitter receptors leads to the release of arachidonic acid, 32 excitatory amino acids could theoretically cause the generation of oxygen free radicals by this mechanism during cerebral ischemia. In support of this hypothesis, oxygen free radical quenchers or lipid peroxidation inhibitors were recently shown to reduce excitatory amino acid-induced neuronal injury in vitro. 33- 34 Other recent reports suggest that oxygen free radicals can themselves cause excitatory amino acid release. PellegriniGiampietro et al 35 reported that oxygen free radicals generated from xanthine-xanthine oxidase stimulated the release of excitatory amino acids from rat hippocampal slices. Furthermore, in an in vitro ischemic model, oxygen free radical quenchers prevented the release of excitatory amino acids. jury mechanisms dur...

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“…In the present study, we compared changes in the concentrations of other EAA neurotransmitters and nontransmitter amino acids with CBF decreases and electrophysiologic impairment. [1], costocervical trunk [2], superficial cervical artery [3], and internal thoracic artery [4]) through transverse skin incision along upper margins of pectoral muscles in cat.…”

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Differences in ischemia-induced accumulation of amino acids in the cat cortex.

Shimada¹,

Graf²,

Rösner³

et al. 1990

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It is well established that excitatory amino acid neurotransmitters are extensively liberated during ischemia and that they have neurotoxic properties contributing to neuronal injury. To study changes in the liberation of excitatory and other amino acids during cerebral ischemia, we measured their extracellular concentrations and related them to blood flow levels and electrophysiologic activity (electrocorticogram and auditory evoked potentials) before and for up to 2 hours after multiple cerebral vessel occlusion in 14 anesthetized cats. Blood flow levels between 0 and 43 ml/100 g/min were reached. Concentrations of the excitatory amino acid neurotransmitters increased most (aspartate 10-fold, glutamate 30-fold, and -y-aminoburyric acid 300-fold compared with control values) below a blood flow threshold of 20 ml/100 g/min. The total power of the electrocorticogram and the amplitude of the auditory evoked potentials were affected below the same blood flow threshold. In contrast, concentrations of the nontransmitter amino acids taurine, alanine, asparagine, serine, and glutamine increased 1.5-5-fold as blood flow decreased, while concentrations of the essential amino acids phenylalanine, valine, leucine, and isoleucine did not change during cerebral ischemia. The great increases in concentrations of the excitatory amino acid neurotransmitters below a blood flow threshold close to that for functional disturbance is in accordance with the role of these amino acids in ischemic cell damage. Their release at blood flow levels compatible with cell survival and the increase in their concentrations with severity and duration of cerebral ischemia imply that excitotoxic antagonists may have potential as therapeutic agents. (Stroke

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Effects of Anoxia on the Stimulated Release of Amino Acid Neurotransmitters in the Cerebellum In Vitro

Cited by 130 publications

References 35 publications

AMPA receptors undergo channel arrest in the anoxic turtle cortex

AMPA receptors undergo channel arrest in the anoxic turtle cortex

Interaction between free radicals and excitatory amino acids in the formation of ischemic brain edema in rats.

Differences in ischemia-induced accumulation of amino acids in the cat cortex.

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