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J H Weiss

Publications and source records attributed to J H Weiss.

At least 37 records · Page 2Linked to original sources
PubMed1995

Zn(2+) permeates Ca(2+) permeable AMPA/kainate channels and triggers selective neural injury.

Brief exposures of cortical cultures to kainate (100 mu M) plus Zn(2+) (300 mu M) cause fluorescence of the Zn(2+) sensitive dye, TS-Q, to appear in virtually all neurons, probably reflecting depolarization and secondary Zn(2+) permeation through voltage-sensitive Ca(2+) channels. However, if Na+ ions are removed from the media (to prevent depolarization), prominent TS-Q fluorescence is still observed in the small subset of neurons labeled by kainate stimulated Co(2+) uptake (Co(2+)(+) neurons), a histochemical technique that identifies neurons expressing Ca(2+) permeable AMPA/kainate receptor-gated channels. Kainate/Zn(2+) exposures in Na+ containing media with lower (50-100 mu M) Zn(2+) concentrations resulted 24 h later in selective loss of the Co(2+)(+) neurons, suggesting that these channels may permit particularly high rates of Zn(2+) passage. Thus, direct permeation of synaptically released Zn(2+) through Ca(2+) permeable AMPA/kainate channels could contribute to selective degeneration of neurons in disease as well as subserving physiological signaling functions.

Animals↗
PubMed1995

Spinal cord neurons are vulnerable to rapidly triggered kainate neurotoxicity in vitro.

Initial studies found glutamate injury to murine spinal cultures (14-17 days in vitro) to reflect contributions of both NMDA and AMPA/kainate receptors. Subsequent experiments found the spinal cultures to be more sensitive than cortical cultures to injury from prolonged low level kainate exposures, and, unlike cortical cultures, to be significantly damaged by relatively brief (30-60 min) kainate exposures. This rapidly triggered kainate damage to spinal neurons is Ca(2+)-dependent. Also, more than 40% of spinal neurons (in comparison to about 15% of cortical neurons) are subject to kainate-activated Co2+ uptake (Co2+(+) neurons), a histochemical technique that labels neurons with Ca(2+)-permeable AMPA/kainate channels. These spinal Co2+(+) neurons are very sensitive to Ca(2+)-dependent kainate injury, and show greater kainate-induced elevations in intracellular Ca2+ concentrations ([Ca2+]i) than other spinal neurons during low level kainate exposures. Thus, the heightened vulnerability of spinal neurons to kainate toxicity may at least in part reflect the large proportion that possess Ca2+ permeable AMPA/kainate channels, permitting receptor activation to trigger rapid Ca2+ influx and overwhelm the cells Ca2+ homeostatic capabilities.

Animals↗
PubMed1995

Ca2+ permeable AMPA/kainate channels permit rapid injurious Ca2+ entry.

Small subsets of central neurons possessing Ca2+ permeable AMPA/kainate channels can be identified by a histochemical stain based on kainate-stimulated Co2+ uptake (Co2+(+)neurons) and are unusually vulnerable to AMPA/kainate receptor-mediated injury. Using brief kainate exposures (which selectively destroy Co2+(+) neurons) along with kainate triggered 45Ca2+ influx measurements, we estimate kainate to cause an unusually high rate of Ca2+ influx into Co2+(+) neurons. Also, while fura-2 Ca2+ imaging revealed low (10 microM) kainate exposures to preferentially induce intracellular free Ca2+ ([Ca2+]i) elevations in Co2+(+) neurons, intense (100 microM) kainate exposures used in the 45Ca2+ influx studies triggered comparable [Ca2+]i rises in all neurons. These findings suggest that the exceptional vulnerability of Co2+(+) neurons to AMPA/kainate receptor-mediated injury reflects a high rate of agonist triggered Ca2+ influx, and that [Ca2+]i rises may only poorly reflect influx rate.

Animals↗
PubMed1995

In vitro kainate injury to large, SMI-32(+) spinal neurons is Ca2+ dependent.

The non-phosphorylated neurofilament marker, SMI-32, identifies ventral horn motor neurons in spinal cord slice. We show here that SMI-32 marks a subset of spinal cord neurons in culture. Many of these neurons ('large SMI-32(+) neurons') have morphological characteristics of identified motor neurons in vitro: large cell body size (> 20 microns), extensive neuritic arborization and, generally, one particularly long process. These neurons are preferentially injured by brief (40 min) kainate exposures, but not by NMDA exposures. This rapidly triggered damage to large SMI-32(+) neurons is Ca2+ dependent. In addition, most of the SMI-32(+) neurons exhibit kainate-stimulated Co2+ uptake, a histochemical technique which marks neurons possessing Ca(2+)-permeable AMPA/kainate receptor-gated channels. The unusual vulnerability of large SMI-32(+) spinal neurons to kainate toxicity may result from rapid Ca2+ entry through Ca(2+)-permeable AMPA/kainate channels.

Animals↗
PubMed1995

Ca2+ and in vitro kainate damage to cortical and hippocampal SMI-32(+) neurons.

SMI-32 is a monoclonal antibody to non-phosphorylated neurofilament epitopes, which labels subsets of pyramidal neurons prone to degeneration in Alzheimer's disease. We found SMI-32 to identify a small minority of neurons in dissociated cultures of murine cortex and hippocampus (SMI-32(+) neurons). Labeled neurons, which were larger than average and were often immunoreactive for GABA, were preferentially destroyed by brief kainate exposures. This rapidly triggered kainate damage to SMI-32(+) neurons was dependent upon the presence of Ca2+ in the media during the toxic exposure. Furthermore, most SMI-32(+) neurons in both cortex and hippocampus were subject to kainate-activated cobalt uptake, a histochemical procedure that marks cells with Ca2+ permeable AMPA/kainate channels. The unusual vulnerability of cortical and hippocampal SMI-32(+) neurons to AMPA/kainate receptor-mediated injury may result from rapid Ca2+ entry through Ca2+ permeable AMPA/kainate receptor-gated channels.

Animals↗
PubMed1994

Kainate injury to cultured basal forebrain cholinergic neurons is Ca2+ dependent.

WHILE exposure times of several hours or more are needed for kainate to induce widespread degeneration of most cortical or basal forebrain neurons, basal forebrain cholinergic neurons, as identified by choline acetyltransferase immunocytochemistry, were substantially damaged by brief (45 min) kainate exposures. This rapidly triggered damage to basal forebrain cholinergic neurons is Ca2+ dependent. Also, basal forebrain cholinergic neurons have unusually large elevations in intracellular Ca2+ concentration in response to kainate, and generally exhibit kainate-activated Co2+ uptake, suggesting that they possess Ca(2+)-permeable AMPA/kainate receptor-gated channels. The heightened vulnerability of basal forebrain cholinergic neurons to kainate toxicity may reflect rapid Ca2+ entry through Ca(2+)-permeable AMPA/kainate channels.

Animals↗
PubMed1994

AMPA/kainate receptor-mediated damage to NADPH-diaphorase-containing neurons is Ca2+ dependent.

While exposure times of several hours or more are needed for AMPA or kainate to induce widespread cortical neurodegeneration, the small subset of cortical neurons that contain high concentrations of the enzyme, NADPH-diaphorase (NADPH-d(+) neurons) were destroyed by brief (15-30 min) exposures. AMPA or kainate-induced degeneration of NADPH-d(+) neurons was decreased by removal of extracellular Ca2+ and increased by augmentation of extracellular Ca2+. More than 90% of NADPH-d(+) neurons exhibited kainate-activated Co2+ uptake, suggesting that they possess Ca(2+)-permeable AMPA/kainate receptor-gated channels. The heightened vulnerability of NADPH-d(+) neurons to AMPA or kainate toxicity may reflect rapid Ca2+ entry through these Ca(2+)-permeable channels.

Animals↗
PubMed1994

Cortical neurones with Ca2+ permeable AMPA/kainate channels display distinct receptor immunoreactivity and are GABAergic.

A minority subset of cortical neurones exhibit kainate-activated Co2+ uptake, a marker for AMPA/kainate receptor gated Ca2+-permeable channels. Consistent with enhanced Ca2+ influx through these channels, Co2+-positive neurones are unusually vulnerable to death induced by exposure to either AMPA or kainate. Here we show that Co2+-positive cortical neurones express a distinctive profile of AMPA receptor subunits as determined by immunostaining. Co2+-positive neurones were much less likely to express GluR2/GluR3, and much more likely to express GluR1 or GluR4, than the general cortical neuronal population. Thus expression of AMPA receptors lacking the GluR2 subunit may explain the Co2+ staining, and selective vulnerability to kainate exhibited by Co2+-positive cells. Almost all GABAergic neurones, identified by immunostaining for glutamic acid decarboxylase, were Co2+-positive. The widespread presence of Ca2+-permeable AMPA/kainate receptor-gated channels on cortical GABAergic neurones may have important implications for the fate of cortical inhibition in disease states associated with the excitotoxic overstimulation of glutamate receptors.

Animals↗
PubMed1994

Cortical neurones exhibiting kainate-activated Co2+ uptake are selectively vulnerable to AMPA/kainate receptor-mediated toxicity.

Kainate-activated Co2+ uptake, a histochemical method that identifies cells bearing Ca2+-permeable AMPA/kainate receptors, labels approximately 15% of murine cortical neurones in cell culture. While exposure times exceeding several hours were needed for AMPA or kainate to destroy most cultured cortical neurones, the subpopulation exhibiting kainate-activated Co2+ uptake was selectively destroyed after AMPA or kainate exposures of only 10-60 min. No selective loss was seen after exposure to NMDA. Kainate toxicity on Co2+ uptake-positive neurones was dependent on extracellular Ca2+ concentration, and associated with an increase in intracellular free Ca2+ even in the absence of extracellular Na+. These results suggest that a distinct subpopulation of cortical neurones expresses AMPA/kainate receptors linked to Ca2+-permeable channels, and that this characteristic conveys enhanced vulnerability to kainate-induced, Ca2+-mediated, damage.

Animals↗
PubMed1994

Basal forebrain cholinergic neurons are selectively vulnerable to AMPA/kainate receptor-mediated neurotoxicity.

We exposed murine basal forebrain neuronal cultures for 24 h to defined concentrations of N-methyl-D-aspartate, kainate or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, and assessed the resultant degeneration of the cholinergic neuronal subpopulation, as identified by choline acetyltransferase immunocytochemistry and acetylcholinesterase histochemistry. Cholinergic neurons, representing about 0.5% of the total neuronal population, were atypically vulnerable to excitotoxins. Compared to most basal forebrain neurons, they were more vulnerable to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate receptor-mediated injury and slightly less vulnerable to N-methyl-D-aspartate receptor-mediated injury. The present findings provide quantitative demonstration of a mechanism that preferentially injures basal forebrain cholinergic neurons, and may thus suggest candidate factors pertaining to their loss in disease states like Alzheimer's disease.

Acetylcholine↗
PubMed1994

Ca2+ channel blockers attenuate beta-amyloid peptide toxicity to cortical neurons in culture.

Deposit of beta-amyloid protein (A beta) in Alzheimer's disease brain may contribute to the associated neurodegeneration. We have studied the neurotoxicity of A beta in primary cultures of murine cortical neurons, with the aim of identifying pharmacologic ways of attenuating the injury. Exposure of cultures to A beta (25-35 fragment; 3-25 microM) generally triggers slow, concentration-dependent neurodegeneration (over 24-72 h). With submaximal A beta-(25-35) exposure (10 microM), substantial (> 40% within 48 h) degeneration often occurs and is markedly attenuated by the presence of the Ca2+ channel blockers nimodipine (1-20 microM) and Co2+ (100 microM) during the A beta exposure. However, A beta neurotoxicity is not affected by the presence of glutamate receptor antagonists. We suggest that Ca2+ influx through voltage-gated Ca2+ channels may contribute to A beta-induced neuronal injury and that nimodipine and Co2+, by attenuating such influx, are able to attenuate A beta neurotoxicity.

Amyloid beta-Peptides↗
PubMed1993

AMPA receptor activation potentiates zinc neurotoxicity.

Extracellular Zn2+ attenuates NMDA receptor-mediated neurotoxicity and increases AMPA receptor-mediated toxicity. Known electrophysiological effects of Zn2+ predict only the former. We considered the possibility that the latter rather reflects AMPA potentiation of Zn2+ toxicity, perhaps mediated by neuronal depolarization and Zn2+ entry through voltage-gated Ca2+ channels. High K+ or kainate also potentiated Zn2+ toxicity, and AMPA plus Zn2+ toxicity was attenuated by raising extracellular Ca2+, or by Ca2+ channel blockers. AMPA plus Zn2+ exposure induced an increase in fluorescence from neurons loaded with the Zn(2+)-sensitive dye TS-Q and increased subsequent 45Ca2+ accumulation. The ability of AMPA receptor activation to potentiate Zn2+ toxicity may be relevant to neuronal death associated with intense activation of glutamatergic pathways.

Animals↗
PubMed1993

Secobarbital attenuates excitotoxicity but potentiates oxygen-glucose deprivation neuronal injury in cortical cell culture.

We examined the effects of secobarbital and other sedative-hypnotic barbiturates on the neuronal death induced by exposure to excitatory amino acids or deprivation of oxygen or glucose in mouse cortical cell cultures. N-Methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate, and kainate toxicities were attenuated in a concentration-dependent fashion by high concentrations of secobarbital or thiopental. Antagonism of NMDA toxicity was not overcome by increasing NMDA concentration and not mimicked by gamma-aminobutyrate. Despite these antiexcitotoxic actions, secobarbital exacerbated the neuronal death induced by deprivation of either glucose alone or oxygen and glucose together; death induced by oxygen deprivation alone was little affected. Thiopental and methohexital also increased oxygen-glucose deprivation injury. A possible explanation for this injury potentiation was provided by the observation that secobarbital enhanced the cellular ATP depletion induced by combined oxygen-glucose deprivation. Deleterious effects on ATP production may counterbalance the protective effects of barbiturates under some conditions.

Adenosine Triphosphate↗
PubMed1993

Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration.

Murine neuronal and glial cell cultures exposed briefly to glutamate accumulated large amounts of 45Ca2+ from the extracellular medium during the exposure. Most of the accumulation likely reflected influx into neurons, as little accumulation was observed in similarly treated glial cultures. When the concentration of glutamate was varied between 10 and 1000 microM, or exposure duration was varied between 0 and 10 min, the amount of 45Ca2+ accumulation correlated closely with the amount of neuronal death 24 hr later. Both 45Ca2+ accumulation and cell death could be attenuated in a dose-dependent manner by the competitive NMDA antagonist D-aminophosphonovalerate or the noncompetitive antagonist dextrorphan, with IC50 values of approximately 100 microM and 15 microM, respectively. In contrast, neither 45Ca2+ accumulation nor cell death was blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the presence of high glycine. With brief exposure, high concentrations of AMPA, kainate, or K+ produced much less death or 45Ca2+ accumulation than produced by glutamate, especially if 10 microM MK-801 was included in the exposure medium to block NMDA receptor activation. Kainate- or AMPA-induced 45Ca2+ accumulation or neuronal cell death was blocked with CNQX. However, high K(+)-triggered 45Ca2+ accumulation was only partially blocked with CNQX plus MK-801, consistent with mediation by voltage-gated Ca2+ channels. In addition to measuring the accumulation of 45Ca2+ occurring during agonist exposure, we also assessed accumulation during the 30 min immediately following completion of a 3-5 min exposure to 500 microM NMDA.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

Extracellular alkalinity exacerbates injury of cultured cortical neurons.

BACKGROUND AND PURPOSE: We have previously shown that extracellular acidity protects cultured fetal murine neocortical neurons from glutamate toxicity and combined oxygen-glucose deprivation injury, an action at least in part mediated by reduction in N-methyl-D-aspartate receptor activation. We now investigate the effect of extracellular alkalinity on both glutamate neurotoxicity and injury due to combined oxygen-glucose deprivation. METHODS: The effects of extracellular alkalinity during injury induced by exposure of murine neocortical cultures to glutamate (0.5 mM for 5 minutes) or oxygen-glucose deprivation are characterized morphologically and quantitated by efflux of lactate dehydrogenase from both neurons and glia to the bathing medium. Calcium accumulation is measured with calcium-45. RESULTS: Moderate extracellular alkalinity is well tolerated by cortical cells but significantly potentiates both glutamate neuronal toxicity and oxygen-glucose deprivation neuronal injury. In contrast, glial viability in the face of combined oxygen-glucose deprivation is little affected by extracellular alkalinity. Increased accumulation of calcium-45 during oxygen-glucose deprivation in alkalotic medium and blockade of this increase by MK-801 is demonstrated. CONCLUSIONS: These observations suggest that alkaline pH can exacerbate excitotoxic neuronal injury, most likely because of increased N-methyl-D-aspartate receptor activation. Metabolic alkalosis of any etiology may sensitize neurons to ischemic injury and potentiate reperfusion injury.

Alkalies↗
PubMed1991

Differential vulnerability to excitatory amino acid-induced toxicity and selective neuronal loss in neurodegenerative diseases.

Neurodegenerative diseases are characterized by selective degeneration of certain biochemically distinct subpopulations of central neurons. Studies of the intrinsic vulnerability of such neurons to injury by excitatory amino acids in vitro, as well as study of neurologic syndromes produced in animals or humans by ingestion of environmental excitatory amino acid neurotoxins may suggest a link between excitotoxicity, and the pathogenesis of certain neurodegenerative diseases.

Amino Acids↗
PubMed1991

HTLV-I-associated myelopathy in a Californian: diagnosis by reactivity to a viral recombinant antigen.

A male patient developed leg numbness and weakness, and bowel, bladder, and erectile dysfunction. Examination revealed an isolated thoracic myelopathy, with lower-extremity spasticity, decreased vibration and position sense, hyperreflexia, and Babinski's signs. Serum and CSF showed antibody reactivity to human T-cell lymphotropic virus type I or II (HTLV-I/II), suggesting HTLV-I-associated myelopathy. Antibody reactivity to a unique HTLV-I recombinant protein provided definitive diagnosis of HTLV-I infection.

Antigens, Viral↗