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F S Silverstein

Publications and source records attributed to F S Silverstein.

At least 55 records · Page 3Linked to original sources
PubMed1992

Excitatory amino acids contribute to the pathogenesis of perinatal hypoxic-ischemic brain injury.

A large body of experimental evidence indicates that over-activation of excitatory amino acid (EAA) receptors may mediate irreversible neuronal injury in a variety of pathologic settings including cerebral ischemia, and that the developing brain may be particularly susceptible to the adverse effects of EAA receptor overactivation. In this article, we review current information about EAA receptor pharmacology and EAA neurotoxicity in the immature brain, and summarize recent experimental data indicating that EAA contribute to the pathogenesis of perinatal hypoxic-ischemic brain injury.

Amino Acids↗
PubMed1991

Effect of depolarization on striatal amino acid efflux in perinatal rats: an in vivo microdialysis study.

We used in vivo microdialysis to determine if infusion of depolarizing concentrations of potassium stimulated striatal excitatory amino acid (EAA) efflux in post-natal day (PND) 7 rats. Dialysis probes were perfused with 100 mM KCl for 60 min (n = 6); EAA efflux was unaffected until 40-60 min after onset of the infusion, when a trend towards increased EAA efflux was observed (glutamate 284 +/- 56% of baseline). In animals exposed to 8% oxygen (n = 7) before a more prolonged (100 min) KCl infusion, again over the first 40 min of KCl there were no changes in EAA efflux; subsequently, glutamate, aspartate and taurine efflux increased (peak values 682 +/- 187%, 228 +/- 32%, and 1208 +/- 437% of baseline). These data suggest that in PND 7 rats a substantial contribution to basal striatal EAA efflux may be derived from non-neurotransmitter pools.

Amino Acids↗
PubMed1991

Excitotoxic brain injury suppresses striatal high-affinity glutamate uptake in perinatal rats.

In immature rodent brain, the glutamate receptor agonist N-methyl-D-aspartate (NMDA) is a potent neurotoxin. In postnatal day (PND)-7 rats, intrastriatal injection of 25 nmol of NMDA results in extensive ipsilateral forebrain injury. In this study, we examined alterations in high-affinity [3H]glutamate uptake (HAGU) in NMDA-lesioned striatum. HAGU was assayed in synaptosomes, prepared from lesioned striatum, the corresponding contralateral striatum, or unlesioned controls. Twenty-four hours after NMDA injection (25 nmol), HAGU declined 44 +/- 8% in lesioned tissue, compared with the contralateral striatum (mean +/- SEM, n = 6 assays, p less than 0.006, paired t test). Doses of 5-25 nmol of NMDA resulted in increasing suppression of HAGU (5 nmol, n = 3; 12.5 nmol, n = 3; and 25 nmol, n = 5 assays; p less than 0.01, regression analysis). The temporal evolution of HAGU suppression was biphasic. There was an early transient suppression of HAGU (-28 +/- 4% at 1 h; p less than 0.03, analysis of variance, comparing changes at 0.5, 1, 2, and 3 h after lesioning); 1 or 5 days postinjury there was sustained loss of HAGU (at 5 days, -56 +/- 11%, n = 3, p less than 0.03, paired t test, lesioned versus contralateral striata).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Effects of perinatal stroke on striatal amino acid efflux in rats studied with in vivo microdialysis.

We used in vivo microdialysis to determine the impact of a focal hypoxic-ischemic insult on striatal amino acid efflux in the immature brain. Microdialysis probes were inserted into the right striatum of postnatal day 7 rats. To induce hypoxic-ischemic injury, the right carotid artery was ligated and the animals were exposed to 8% oxygen for 2.5 hours (n = 22). Rats exposed to ligation alone (n = 10) or hypoxia alone (n = 8) and untreated controls (n = 17) were also studied. Two hours after probe insertion, a 30-minute baseline microdialysis sample was obtained. After arterial ligation, two additional baseline samples were collected. Five more samples were collected over the next 2.5 hours (in 8% oxygen or room air). Eight amino acids (glutamate, aspartate, taurine, glutamine, alanine, serine, glycine, and asparagine) were consistently detected in dialysates using a high-performance liquid chromatography assay with electrochemical detection. In untreated controls, amino acid efflux did not change over 4 hours. During hypoxia-ischemia, efflux values fluctuated widely, with marked intra-animal and interanimal variability. Efflux peaks for each amino acid were defined as values greater than the highest control mean value plus two standard deviations. Glutamate efflux peaks (greater than 7 pmol/min compared with 2 pmol/min at baseline) were detected in no controls and in eight hypoxic-ischemic rats (p = 0.006, Fisher's two-tailed exact test). Taurine efflux peaks (greater than 75 pmol/min compared with 10 pmol/min for controls at baseline) were detected in 10 hypoxic-ischemic rats and one control (p = 0.01) and in seven of the eight animals in which glutamate efflux peaks occurred (p = 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1991

Hypoxia-ischemia stimulates hippocampal glutamate efflux in perinatal rat brain: an in vivo microdialysis study.

We used in vivo microdialysis to determine the impact of a focal hypoxic-ischemic insult on hippocampal amino acid efflux in the immature brain. Microdialysis probes were inserted into the right hippocampus of postnatal d 7 rats. To induce hypoxic-ischemic injury, the right carotid artery was ligated and animals were exposed to 8% oxygen for 2 h (n = 6, histologically verified). Ten 20-min dialysis fractions were collected from each animal: three sequential 20-min baseline samples, six samples during hypoxia, and a recovery sample in room air. Eight amino acids were detected in dialysates with a HPLC assay. There was marked intra- and interanimal variation in glutamate efflux; mean glutamate efflux increased from 17 pmol/min in baseline samples to 51 in the 2nd h of hypoxia (p = 0.002, Kruskal Wallis test). There was a concurrent decline in glutamine efflux (310 to 207 pmol/min, p = 0.0005). Alanine efflux doubled during hypoxia (p = 0.015). There were no changes in efflux of the other five amino acids analyzed. In this experimental model of perinatal stroke, during the acute evolution of hypoxic-ischemic brain injury, transient large increases in glutamate efflux and corresponding declines in glutamine efflux were detected. These data support the hypothesis that synaptic concentrations of the endogenous excitatory amino acid glutamate increase during the evolution of hippocampal ischemic injury.

Amino Acids↗
PubMed1990

Magnesium reduces N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats.

We evaluated the neuroprotective effects of systemically administered magnesium against N-methyl-D-aspartate (NMDA)-mediated brain injury in perinatal rats. Postnatal day (PND) 7 rats received unilateral intrastriatal injections of 25 nmol NMDA followed 15 min later by single or multiple doses of magnesium intraperitoneally (i.p.). Animals were sacrificed five days later and the severity of brain injury was assessed by comparison of the weights of the injected and contralateral cerebral hemispheres. NMDA injection reduced the weight of the injected cerebral hemisphere by 31 +/- 3%. Single doses of magnesium reduced the severity of NMDA-induced brain injury in a dose-dependent fashion (2 mmol/kg, 29 +/- 11% protection; 3 mmol/kg, 52 +/- 12% protection; 4 mmol/kg, 62 +/- 7% protection). Multiple doses of magnesium reduced brain injury by 65 +/- 4%. These data demonstrate that systemically administered magnesium antagonizes the neurotoxic effects of NMDA in vivo in perinatal rats.

Animals↗
PubMed1990

Hypoglycemia alters striatal amino acid efflux in perinatal rats: an in vivo microdialysis study.

In adult brain, during insulin-induced hypoglycemia, striatal extracellular fluid concentrations of the excitatory amino acids glutamate and aspartate rise markedly (fourfold to tenfold). In this study, we used in vivo microdialysis to determine if insulin-induced hypoglycemia altered striatal amino acid efflux in similar fashion in the immature brain. Microdialysis probes were inserted into the right striatum of rats on postnatal day 7. After a 2-hour recovery period, in each animal a 30-minute baseline sample was obtained. Then insulin (0.6 mu/kg, intraperitoneal injection) was administered (n = 6) and dialysate sampling was continued over the next 210 minutes (terminal blood glucose level less than 5 mg/dl). Untreated control rats (n = 6) were sampled over the same time interval. After pre-column derivatization with o-phthaldialdehyde, dialysate samples were assayed by high-pressure liquid chromatography with electrochemical detection to measure their amino acid content; eight amino acids (glutamate, aspartate, taurine, glutamine, alanine, serine, glycine, and asparagine) were consistently detected. In controls, amino acid efflux did not change over 4 hours. In hypoglycemic animals, glutamate efflux increased (peak: 238 +/- 85% of baseline, p = 0.02, repeated measures analysis of variance [ANOVA]), glutamine efflux declined (to 44 +/- 5% of baseline, p = 0.002, ANOVA), and taurine efflux increased (up to 310 +/- 120% of baseline; p less than 0.06, ANOVA). In contrast with 9- to 12-fold increases in aspartate efflux reported in adult striatum, aspartate efflux increased only slightly (to 174 +/- 69% of baseline; not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1990

Systemic administration of MK-801 protects against N-methyl-D-aspartate- and quisqualate-mediated neurotoxicity in perinatal rats.

MK-801, a non-competitive antagonist of N-methyl-D-aspartate-type glutamate receptors, was tested for its ability to antagonize excitotoxic actions of N-methyl-D-aspartate or quisqualic acid injected into the brains of seven-day-old rats. Stereotaxic injection of N-methyl-D-aspartate (25 nmol/0.5 microliters) or quisqualic acid (100 nmol/1.0 microliter) into the corpus striatum under ether anesthesia consistently produced severe unilateral neuronal necrosis in the basal ganglia, dorsal hippocampus and overlying neocortex. The distribution of the damage corresponded to the topography of glutamate receptors in the vulnerable regions demonstrated by previous autoradiographic studies. N-Methyl-D-aspartate produced severe, confluent neuronal destruction while quisqualic acid typically caused more selective neuronal necrosis. Intraperitoneal administration of MK-801 (0.1-1.0 mg/kg) 30 min before N-methyl-D-aspartate injection had a prominent dose-dependent neuroprotective effects as assessed morphometrically by comparison of bilateral striatal, hippocampal and cerebral hemisphere cross-sectional areas five days later. A 1 mg/kg dose of MK-801 given as pre-treatment completely protected the infant brain. The same dose of MK-801 was also completely protective when administered 30 or 40 min after N-methyl-D-aspartate and afforded partial protection when given 2 h later. MK-801 pre-treatment also prevented the electrically confirmed behavioral seizures induced by N-methyl-D-aspartate. The drug significantly reduced striatal but not hippocampal or neocortical injury when given as two doses (1 mg/kg) 30 min prior to and immediately following quisqualic acid injection. The data indicate that systemic administration of MK-801 can prevent N-methyl-D-aspartate-induced neuronal injury in perinatal rat brain even when administered after the initial insult. MK-801 also partially antagonized quisqualic acid-mediated neurotoxicity, suggesting that quisqualic acid-induced toxicity is, in part, mediated through N-methyl-D-aspartate receptor activation. The sensitivity of the developing brain to the toxicity of N-methyl-D-aspartate provides a sensitive and reproducible in vivo model for exploring these issues and for screening prospective neuroprotective drugs that act at the N-methyl-D-aspartate receptor-channel complex.

Animals↗
PubMed1990

MK-801 pretreatment enhances N-methyl-D-aspartate-mediated brain injury and increases brain N-methyl-D-aspartate recognition site binding in rats.

Direct intracerebral administration of N-methyl-D-aspartate typically produces focal brain injury. (+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-immi ne maleate (MK-801), a non-competitive N-methyl-D-aspartate antagonist, can protect against N-methyl-D-aspartate-mediated brain injury when administered shortly before or after an intracerebral injection of N-methyl-D-aspartate. However, in this study we report that in perinatal rats if MK-801 (1 mg/kg) is administered intraperitoneally 24 h prior to a unilateral intrastriatal N-methyl-D-aspartate injection, N-methyl-D-aspartate-mediated brain injury is paradoxically enhanced. The severity of resulting brain injury is 15-25% greater in groups that received MK-801 in comparison with saline-treated controls (P less than 0.001, linear regression analysis). In contrast, the severity of brain injury resulting from intrastriatal injection of the glutamate agonist quisqualate is not altered by a similar 24 h MK-801 pretreatment. Furthermore, the enhanced toxicity of N-methyl-D-aspartate produced by a 24 h pretreatment with MK-801 is completely blocked if a second dose of MK-801 is administered 15 min after the intrastriatal injection of N-methyl-D-aspartate. To determine if MK-801 produced alterations in glutamate receptor pharmacology co-incident with the enhanced toxicity of N-methyl-D-aspartate, in vitro quantitative autoradiography for excitatory amino acid receptor subtypes was performed with [3H]glutamate and [3H]N-1-(2-thienyl)cyclohexyl-3,4-piperidine in seven-day-old rats killed 2 or 24 h after MK-801 (1 mg/kg) administration. A 2 h MK-801 pretreatment produced a 30-50% increase in [3H]glutamate binding at N-methyl-D-aspartate preferring recognition sites in all four brain regions examined (areas CA1 and CA3 of the hippocampus, corpus striatum, cingulate cortex) in comparison with saline-treated controls (P less than 0.05, ANOVA). [3H]N-1-(2-Thienyl)cyclohexyl-3,4-piperidine binding to the phencyclidine site associated with the N-methyl-D-aspartate receptor was reduced by 60-80% in all brain regions examined (P less than 0.001). Quisqualate-sensitive [3H]glutamate binding was not altered by a 2 h MK-801 pretreatment. In animals that received a 24 h MK-801 pretreatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Transient hypoxia alters striatal catecholamine metabolism in immature brain: an in vivo microdialysis study.

Microdialysis probes were inserted bilaterally into the striatum of 7-day-old rat pups (n = 30) to examine extracellular fluid levels of dopamine, its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA). The dialysis samples were assayed by HPLC with electrochemical detection. Baseline levels, measured after a 2-h stabilization period, were as follows: dopamine, not detected; DOPAC, 617 +/- 33 fmol/min; HVA, 974 +/- 42 fmol/min; and 5-HIAA, 276 +/- 15 fmol/min. After a 40-min baseline sampling period, 12 animals were exposed to 8% oxygen for 120 min. Hypoxia produced marked reductions in the striatal extracellular fluid levels of both dopamine metabolites (p less than 0.001 by analysis of variance) and a more gradual and less prominent reduction in 5-HIAA levels (p less than 0.02 by analysis of variance), compared with controls (n = 12) sampled in room air. In the first hour after hypoxia, DOPAC and HVA levels rose quickly, whereas 5-HIAA levels remained suppressed. The magnitude of depolarization-evoked release of dopamine (elicited by infusion of potassium or veratrine through the microdialysis probes for 20 min) was evaluated in control and hypoxic animals. Depolarization-evoked dopamine efflux was considerably higher in hypoxic pups than in controls: hypoxic (n = 7), 257 +/- 32 fmol/min; control (n = 12), 75 +/- 14 fmol/min (p less than 0.001 by analysis of variance). These data demonstrate that a brief exposure to moderate hypoxia markedly disrupts striatal catecholamine metabolism in the immature rodent brain.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Effects of hypoxia-ischemia and MK-801 treatment on the binding of a phencyclidine analogue in the developing rat brain.

The phencyclidine analogue [3H](1-[2-thienyl]cyclohexyl)piperidine (3H-TCP) binds to the ion channel associated with the N-methyl-D-aspartate receptor channel complex. In vitro autoradiography indicates that the distribution of 3H-TCP binding in brain closely parallels that of [3H]glutamate binding to the N-methyl-D-aspartate receptor. In nine 7-day-old rats, an acute focal hypoxic-ischemic insult produced by unilateral carotid artery ligation and subsequent exposure to 8% oxygen acutely reduced 3H-TCP binding ipsilateral to the ligation by 30% in the CA1, by 27% in the CA3, by 26% in the dentate gyrus, and by 17% in the striatum compared with values from the contralateral hemisphere. In 10 littermates that received 1 mg/kg of the neuroprotective noncompetitive N-methyl-D-aspartate antagonist MK-801 immediately before hypoxic exposure, the regional distribution of 3H-TCP binding in hypoxic-ischemic brain was relatively preserved and there were no interhemispheric asymmetries in 3H-TCP binding densities. In addition, in three unoperated rats decapitated 24 hours after MK-801 treatment, 3H-TCP binding was reduced by 15-35%; similar bilateral suppression of 3H-TCP binding was detected in MK-801-treated ligates. Our data indicate that 3H-TCP autoradiography can be used to assay the efficacy of neuroprotective agents in this experimental model of perinatal stroke.

Animals↗
PubMed1989

Effect of glycine and glycine receptor antagonists on NMDA-induced brain injury.

In postnatal day 7 rats, a unilateral intrastriatal injection of 12.5 nmol of N-methyl-D-aspartate (NMDA) reproducibly injures the ipsilateral striatum, adjacent hippocampus and overlying cortex. The severity of injury can be quantified by comparing cerebral hemisphere weights in animals sacrificed 5 days after the injection. Co-injection of NMDA and the glycine receptor antagonists kynurenic acid (KYN) or 7-chlorokynurenic acid (7-CKA) reduced the severity of NMDA-induced damage in a dose-dependent fashion. One hundred nmol of KYN with 12.5 nmol of NMDA reduced average % damage from 19.3 +/- 0.9% (n = 9) to 2.3 +/- 0.5% (n = 6), P less than 0.001, ANOVA. Co-injection of 40 nmol of 7-CKA with 12.5 nmol of NMDA (n = 6) reduced average % damage from 17.1 +/- 1.6% (n = 15) to 3.0 +/- 0.6%, P less than 0.001, ANOVA. Concurrent injection of 1000 nmol glycine with 5 nmol NMDA did not increase the extent of NMDA-induced damage. Our results demonstrate that glycine receptor antagonists attenuate NMDA-induced brain injury in vivo.

Animals↗
PubMed1989

HA-966 (1-hydroxy-3-aminopyrrolidone-2) selectively reduces N-methyl-D-aspartate (NMDA)-mediated brain damage.

The neuroprotective effects of the strychnine-insensitive glycine receptor antagonist, HA-966, against N-methyl-D-aspartate (NMDA)- and quisqualate (QA)-mediated brain injury were determined in perinatal rats. Postnatal day (PND) 7 rats received intrastriatal injections of NMDA (25 nmol) or QA (100 nmol) and then were administered intraperitoneal (i.p.) injections of varying doses of HA-966 or vehicle 15 min later. Animals were sacrificed 5 days later and the degree of brain injury was calculated by comparison of the weights of injected and contralateral cerebral hemispheres. HA-966 selectively reduced the degree of NMDA-mediated brain injury in a dose-dependent manner. However, HA-966 did not attenuate QA-mediated brain injury.

Animals↗
PubMed1989

Neuroprotective effects of MK-801, TCP, PCP and CPP against N-methyl-D-aspartate induced neurotoxicity in an in vivo perinatal rat model.

Three non-competitive antagonists (MK-801, TCP, PCP) and one competitive antagonist (CPP) of N-methyl-D-aspartate (NMDA) receptors, were compared for their ability to antagonize neurotoxic actions of NMDA injected into the brains of 7-day-old rats. Unilateral intracerebral injection of NMDA (25 nmol/0.5 microliters) into the corpus striatum of pups consistently produced severe confluent neuronal necrosis in the striatum extending into the dorsal hippocampus and overlying neocortex. The distribution of damage corresponded to the topography of NMDA type glutamate receptors in the vulnerable regions. With this lesion in developing brain, the weight of the injected hemisphere 5 days later can be used as a quantitative measure of brain injury. Intraperitoneal administration of MK-801 (0.02-42.0 mumol/kg), TCP (3.5-54.0 mumol/kg), PCP (1.0-41.0 mumol/kg), and CPP (1.0-60.0 mumol/kg) 15 min after NMDA injection had prominent dose-dependent neuroprotective effects. MK-801 was 14 times more potent than other compounds tested and the 50% protective dose (PD50, that dose which reduced damage by 50% relative to untreated NMDA-injected controls) was 0.63 mumol/kg. Corresponding values for CPP, PCP, and TCP were 8.84, 10.85, and 24.05 mumol/kg respectively. The lowest dose of MK-801 that provided significant protection was 0.2 mumol/kg (0.04 mg/kg, 37.9 +/- 4.6% protection). Four mumol/kg (0.8 mg/kg) of MK-801 completely protected against NMDA-mediated damage. The study provides the first direct in vivo comparison of the neuroprotective abilities of these compounds. Systemic administrations of MK-801, TCP, PCP, and CPP all limit NMDA-induced neuronal injury in this model. The susceptibility of the immature brain to the neurotoxicity of NMDA provides a sensitive, reproducible, and quantitative in vivo system for comparing the effectiveness of drugs with protective actions against excitotoxic neuronal injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Quantitative assessment of neuroprotection against NMDA-induced brain injury.

In immature rodent brain, unilateral intrastriatal injections of selected excitatory amino acid (EAA) receptor agonists, such as N-methyl-D-aspartate (NMDA), produce prominent ipsilateral forebrain lesions. In Postnatal Day (PND) 7 rats that receive a right intrastriatal injection of NMDA (25 nmol) and are sacrificed 5 days later, there is a considerable and consistent reduction in the weight of the injected cerebral hemisphere relative to that of the contralateral side (-28.5 +/- 1.9%, n = 6). In animals treated with specific NMDA receptor antagonists, the severity of NMDA-induced damage is markedly reduced. We have previously reported that the efficacy of potential neuroprotective drugs in limiting NMDA-induced lesions can be assessed quantitatively by comparison of hemisphere weights after a unilateral NMDA injection. In this study, we compared three quantitative methods to evaluate the severity of NMDA-induced brain injury and the degree of neuroprotection provided by NMDA receptor antagonists. We characterized the severity of brain injury resulting from intrastriatal injections of 1-50 nmol NMDA in PND 7 rats sacrificed on PND 12 by (i) comparison of cerebral hemisphere weights; (ii) assay of the activity of the cholinergic neuronal marker, choline acetyltransferase (ChAT) activity; and (iii) measurement of regional brain cross-sectional areas. The severity of the resulting brain injury as assessed by comparison of hemisphere weights increased linearly with the amount of NMDA injected into the striatum up to 25 nmol NMDA. The magnitude of injury was highly correlated with the degree of reduction in ChAT activity (r2 = 0.97).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Neurotoxicity of N-methyl-D-aspartate is markedly enhanced in developing rat central nervous system.

The neurotoxic lesion produced by direct injection of 25 nmol of N-methyl-D-aspartate (NMDA) into the corpus striatum of 7-day-old rats was compared to the effects of injecting 75 nmol into the striatum or hippocampus of adults. The area of histopathology in the immature striatum was 21 X larger than the striatal lesion in adults. Damage from NMDA injected into the immature striatum also extended into the dorsal hippocampus and produced an area of destruction which was 16 X larger than observed after direct injection into the adult hippocampus. Several studies have implicated excessive N-methyl-D-aspartate receptor activation in the pathogenesis of hypoxic-ischemic and hypoglycemic injury and our results suggest that this neurotoxic mechanism is extremely active in the immature brain.

Aging↗
PubMed1988

Glutamate recognition sites in human fetal brain.

We used in vitro autoradiography with [3H]glutamate to examine the distribution of glutamate recognition sites in 18 and 21 week gestation human fetal brains. We found a wide distribution of [3H]glutamate binding in both specimens, in a pattern distinct from that reported in adult brain using the same autoradiographic methods. In fetal brain, prominent [3H]glutamate binding was evident in hippocampal formation, caudate-putamen, globus pallidus, subthalamic nucleus, reticular nucleus of thalamus and substantia innominata.

Autoradiography↗