Ionic requirements for neurotoxic effects of excitatory amino acid analogues in rat cerebellar slices

Garthwaite, G.; Hajós, F.; Garthwaite, John

doi:10.1016/0306-4522(86)90164-8

Cited by 145 publications

(38 citation statements)

References 15 publications

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“…Studies in mammalian culture systems indicate that lowering extracellular Ca2+ concentrations can protect cortical neurons normally susceptible to the delayed form of glutamate-induced death (24)(25)(26). These findings, and those reported here for high extracellular Ca2", suggest that Ca2+ influx might play a role in glutamate-induced neurotoxicity.…”

Section: Discussionsupporting

confidence: 66%

Central mammalian neurons normally resistant to glutamate toxicity are made sensitive by elevated extracellular Ca2+: toxicity is blocked by the N-methyl-D-aspartate antagonist MK-801.

Hahn

Aizenman

Lipton

1988

Proc. Natl. Acad. Sci. U.S.A.

127

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It Is widely held that a glutamate-like toxin that resembles N-methyl-D-aspartate may be responsible for the death of nerve cells seen after severe neurological Insults including stroke, seizures, and degenerative disorders, such as Huntington disease, Alzheimer disease, and the amyotrophic lateral sclerosis-parkinsonism-dementia complex found on Guam. One puzzling fact about these maladies is the differential vulnerability of specific groups of neurons peculiar to each condition. We report here that an identified population of central neurons, rat retinal ganglion cells, are resistant to the neurotoxic effects of millimolar concentrations of glutamate under otherwise normal culture conditions. Patch-clamp experiments show that this resistance is associated with a very small ionic current response to N-methyl-D-aspartate. These rmdings strongly suggest that Ca2`entry through N-methyl-D-aspartate-activated channels is responsible for this type of neuronal death and suggest strategies that may be clinically useful in the treatment of various neurological disorders.In the mammalian central nervous system glutamate is thought to be the major excitatory neurotransmitter that acts at three major receptor subtypes. Excessive stimulation of one of these subtypes, selective for the glutamate analog N-methyl-D-aspartate (N-Me-D-Asp), has been implicated in the pathophysiology of neuronal degeneration caused by a variety of conditions; these include anoxia, ischemia, hypoglycemia, seizures, and several neurodegenerative diseases (1-3). Nevertheless, certain groups of neurons appear to be resistant to toxicity mediated through the N-Me-D-Asp receptor (3, 4). The mammalian retina was the first preparation in which central neurons were shown to be vulnerable to glutamate toxicity (5). Since then, however, the effect of glutamate analogs on the vertebrate retina has been studied repeatedly but sometimes with conflicting results regarding toxicity to the ganglion cells, the neurons that link the retina to deeper centers of the brain (6-9). These observations gave rise to the hypothesis that variations in the extracellular environment of the neurons might render them vulnerable or resistant to the toxic effects ofglutamate. To define a possible ionic basis for the selective toxicity of some populations of central mammalian neurons and to develop a preventative treatment, we examined the effects of glutamate on rat postnatal retinal ganglion cells under the precisely controlled ionic conditions that can only be afforded by tissue culture. Here, we report that this population of central neurons is resistant to glutamate-induced cell death; however, increasing the extracellular Ca2+ concentration above normal levels resulted in a strikingly increased vulnerability of the retinal ganglion cells. Even then, only relatively high levels (1 mM) of glutamate produced toxic effects. MATERIALS AND METHODSRetinal ganglion cells (RGCs) from postnatal rats were identified with fluorescent labels, as developed in this laboratory (16)....

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Section: Discussionsupporting

confidence: 66%

Central mammalian neurons normally resistant to glutamate toxicity are made sensitive by elevated extracellular Ca2+: toxicity is blocked by the N-methyl-D-aspartate antagonist MK-801.

Hahn

Aizenman

Lipton

1988

Proc. Natl. Acad. Sci. U.S.A.

127

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“…These data can be interpreted as reduction in damage by reduction in metabolic stress. A related proposal is that increase in intracellular Ca2+ concentration mediates cytotoxicity of excitatory amino acids (27).…”

Section: Resultsmentioning

confidence: 99%

Superoxide dismutase protects cultured neurons against death by starvation.

Sáez¹,

Kessler²,

Bennett³

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

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Brief substrate deprivation resulted in high mortality of superior cervical ganglion neurons in culture, assayed 2 hr later by trypan blue exclusion. Involvement of superoxide anions was indicated by several observations. Survival was increased significantly by prior treatment that induced cells to take up superoxide dismutase. During starvation, neurons reduced nitroblue tetrazolium to form the blue precipitate formazan, and the color change was blocked in neurons preloaded with superoxide dismutase. The incidence of staining was comparable to the mortality. In many cells, brief starvation caused the appearance of fluorescence due to oxidation of 2',7'-dichlorofluorescin to dichlorofluorescein, which indicates that oxidants were generated intracellularly. In some cells fluorescence was transient, as would be caused by membrane breakdown, and these cells were then shown to be dead. Superoxide generation caused by substrate deprivation may contribute importantly to cell damage in a variety of pathological conditions. products because of the large ratio of solution to tissue volume.Earlier studies with whole animals indicated that intravenous superoxide dismutase (SOD; superoxide:superoxide oxidoreductase, EC 1.15.1.1) protected beagle puppies from intraventricular hemorrhage after a hemorrhagic hypotension/volume expansion insult (13) and prevented death in gerbils due to seizures induced by cerebral ischemia (8). We wished to analyze the role of O°-at a cellular level. Since generation of O°-is the result of univalent reduction of oxygen, we did not expect generation of 02-during anoxia.Thus, we focused our interest on Oy-formation and protection against it during starvation. Our data indicate that neuronal death caused by starvation involves generation of O°-, since the cytotoxicity can be markedly reduced by SOD.Cytochemical procedures also indicate production of Oj-or other oxidants. Preliminary accounts of this work have appeared (14,15).Substrate deprivation occurs in brain during ischemia due to stroke, cardiac arrest, and trauma and under severe hypoglycemic conditions such as insulin shock. Biochemical changes that accompany ischemia include formation of free radicals such as the superoxide anion 0,-, and these highly reactive substances may be an important cause of neuronal damage (1). In support of this hypothesis, tissue concentrations of nonspecific free-radical scavengers (e.g., reduced glutathione, ascorbic acid, a-tocopherol, and ubiquinone) decrease significantly during partial ischemia or reperfusion after total ischemia (1-4). Also, reversible global ischemia induces lipid peroxidation (5), which is a reaction initiated by free radicals. Moreover, pretreatment with free-radical scavengers or blockers of metabolic reactions that yield free radicals protects against damage due to concussive injury or brain ischemia (6-8). In these studies, protection was attributed mainly to action at the level of the vascular endothelium, and it was unclear whether free radicals were generated in dying n...

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“…Excitotoxic neuronal injury is proposed to result from intense and prolonged glutamatergic excitation that produces excessive elevation of intracellular calcium, leading to activation of multiple calcium-dependent enzymes that damage cellular constituents (Olney et al, 1971;Olney, 1978;Garthwaite et al, 1986;Choi, 1987Choi, , 1988Siman and Noszek, 1988). Activation of Purkinje cells by climbing fibers can lead to elevation of cytosolic calcium levels by several mechanisms.…”

Section: Discussionmentioning

confidence: 99%

The Olivocerebellar Projection Mediates Ibogaine-Induced Degeneration of Purkinje Cells: A Model of Indirect, Trans-Synaptic Excitotoxicity

1997

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Ibogaine, an indole alkaloid that causes hallucinations, tremor, and ataxia, produces cerebellar neurotoxicity in rats, manifested by degeneration of Purkinje cells aligned in narrow parasagittal bands that are coextensive with activated glial cells. Harmaline, a closely related alkaloid that excites inferior olivary neurons, causes the same pattern of Purkinje cell degeneration, providing a clue to the mechanism of toxicity. We have proposed that ibogaine, like harmaline, excites neurons in the inferior olive, leading to sustained release of glutamate at climbing fiber synapses on Purkinje cells. The objective of this study was to test the hypothesis that increased climbing fiber activity induced by ibogaine mediates excitotoxic Purkinje cell degeneration. The inferior olive was pharmacologically ablated in rats by a neurotoxic drug regimen using 3-acetylpyridine, and cerebellar damage attributed to subsequent administration of ibogaine was analyzed using immunocytochemical markers for neurons and glial cells. The results show that ibogaine administered after inferior olive ablation produced little or no Purkinje cell degeneration or glial activation. That a lesion of the inferior olive almost completely prevents the neurotoxicity demonstrates that ibogaine is not directly toxic to Purkinje cells, but that the toxicity is indirect and dependent on integrity of the olivocerebellar projection. We postulate that ibogaine-induced activation of inferior olivary neurons leads to release of glutamate simultaneously at hundreds of climbing fiber terminals distributed widely over the surface of each Purkinje cell. The unique circuitry of the olivocerebellar projection provides this system with maximum synaptic security, a feature that confers on Purkinje cells a high degree of vulnerability to excitotoxic injury.

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Ionic requirements for neurotoxic effects of excitatory amino acid analogues in rat cerebellar slices

Cited by 145 publications

References 15 publications

Central mammalian neurons normally resistant to glutamate toxicity are made sensitive by elevated extracellular Ca2+: toxicity is blocked by the N-methyl-D-aspartate antagonist MK-801.

Central mammalian neurons normally resistant to glutamate toxicity are made sensitive by elevated extracellular Ca2+: toxicity is blocked by the N-methyl-D-aspartate antagonist MK-801.

Superoxide dismutase protects cultured neurons against death by starvation.

The Olivocerebellar Projection Mediates Ibogaine-Induced Degeneration of Purkinje Cells: A Model of Indirect, Trans-Synaptic Excitotoxicity

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