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Biomedical subjects

F S Silverstein

Publications and source records attributed to F S Silverstein.

At least 73 records · Page 4Linked to original sources
PubMed1988

Perinatal hypoxic-ischemic brain injury enhances quisqualic acid-stimulated phosphoinositide turnover.

In an experimental model of perinatal hypoxic-ischemic brain injury, we examined quisqualic acid (Quis)-stimulated phosphoinositide (PPI) turnover in hippocampus and striatum. To produce a unilateral forebrain lesion in 7-day-old rat pups, the right carotid artery was ligated and animals were then exposed to moderate hypoxia (8% oxygen) for 2.5 h. Pups were killed 24 h later and Quis-stimulated PPI turnover was assayed in tissue slices obtained from hippocampus and striatum, target regions for hypoxic-ischemic injury. The glutamate agonist Quis (10(-4) M) preferentially stimulated PPI hydrolysis in injured brain. In hippocampal slices of tissue derived from the right cerebral hemisphere, the addition of Quis stimulated accumulation of inositol phosphates by more than ninefold (1,053 +/- 237% of basal, mean +/- SEM, n = 9). In contrast, the addition of Quis stimulated accumulation of inositol phosphates by about fivefold in the contralateral hemisphere (588 +/- 134%) and by about sixfold in controls (631 +/- 177%, p less than 0.005, comparison of ischemic tissue with control). In striatal tissue, the corresponding values were 801 +/- 157%, 474 +/- 89%, and 506 +/- 115% (p less than 0.05). In contrast, stimulation of PPI turnover elicited by the cholinergic agonist carbamoylcholine, (10(-4) or 10(-2) M) was unaffected by hypoxia-ischemia. The results suggest that prior exposure to hypoxia-ischemia enhances coupling of excitatory amino acid receptors to phospholipase C activity. This activation may contribute to the pathogenesis of irreversible brain injury and/or to mechanisms of recovery.

Animals↗
PubMed1987

Hypoxia-ischemia produces focal disruption of glutamate receptors in developing brain.

We examined the impact of a perinatal hypoxic-ischemic insult on the distribution of glutamate receptors in developing brain. We used a well characterized rodent model for perinatal hypoxic-ischemic encephalopathy, unilateral carotid artery occlusion followed by exposure to 8% oxygen for 2.5 h in 7-day-old rat pups. This preparation results in focal neuronal damage in striatum, hippocampus, and cortex ipsilateral to ligation. Alterations in the regional distribution of glutamate binding in the first 24 h after the insult were assessed with quantitative in vitro [3H]glutamate autoradiography. In lesioned animals, we found progressive selective reductions in [3H]glutamate binding in forebrain ipsilateral to ligation in regions destined for neuronal damage. The earliest and most prominent unilateral reductions in binding were noted in the dentate gyrus of hippocampus (-45 +/- 9%, compared with contralateral hemisphere at 24 h). Acute reductions in specific glutamate binding appear to be a sensitive marker for hypoxic-ischemic neuronal damage in the immature brain. These observations suggest that neurons bearing glutamate receptors may be particularly susceptible to hypoxic-ischemic injury.

Age Factors↗
PubMed1987

Risks of neuroleptic drugs in children.

We surveyed members of the Child Neurology Society to examine their attitudes about use of neuroleptic drugs in children and their experiences with neuroleptic-induced movement disorders. Sixty percent of the membership responded to our questionnaire. Of these responders, over 99% agreed that there were clinical indications for neuroleptics in children, but their criteria varied. Only a minority of the responders routinely incorporated drug holidays in the therapeutic plans of children treated with neuroleptics. The majority had not had clinical experience with patients who developed chronic movement disorders associated with neuroleptic treatment, but 35% (140/410) had encountered patients whose symptoms they considered typical of tardive dyskinesia. However, some of these patients did not meet strict criteria for diagnosis of this movement disorder. The results suggest that neuroleptic-induced movement disorders occur with significant frequency in children and that more detailed prospective studies of the risks and benefits of these drugs in children are warranted.

Antipsychotic Agents↗
PubMed1987

Evidence for transient perinatal glutamatergic innervation of globus pallidus.

There is no known glutamatergic innervation of globus pallidus (GP) in adult mammals, but we report that during postnatal development of the GP there are large, transient increases in both presynaptic high-affinity glutamate uptake and postsynaptic Na+-independent glutamate receptor binding. These glutamatergic markers increase rapidly in rat GP after birth and then decrease to adult levels over a period of weeks. A similar developmental pattern of pallidal glutamate binding was found in human brains. In contrast, binding in rat caudate-putamen (CPu) increases after birth, reaches a peak, and remains constant into adulthood. The results suggest that a glutamatergic pathway transiently innervates the globus pallidus during the perinatal period. Because glutamate is an excitotoxin, this pathway may account, in part, for the basal ganglia damage seen in some forms of cerebral palsy after perinatal hypoxia/ischemia.

Adult↗
PubMed1986

The glutamate analogue quisqualic acid is neurotoxic in striatum and hippocampus of immature rat brain.

To assess the neurotoxic properties of the glutamate agonist quisqualic acid (QA) in immature brain, we injected this compound (100 nmol QA/1 microliter) directly into the striatum of 7-day-old rats. QA produced neuronal necrosis and glial infiltration in 14 pups and reduced the size of the striatum and hippocampus on the side of injection. Intracerebral injection of QA provides a new method for producing neuronal lesions in the developing brain.

Animals↗
PubMed1986

Perinatal hypoxia-ischemia disrupts striatal high-affinity [3H]glutamate uptake into synaptosomes.

We examined the impact of hypoxia-ischemia on high-affinity [3H]glutamate uptake into a synaptosomal fraction prepared from immature rat corpus striatum. In 7-day-old pups the right carotid artery was ligated, and pups were exposed to 8% oxygen for 0, 0.5, 1, or 2.5 h, and allowed to recover for up to 24 h before they were killed. High-affinity glutamate uptakes in striatal synaptosomes derived from tissue ipsilateral and contralateral to ligation were compared. After 1 h of hypoxia plus ischemia, high-affinity glutamate uptake in the striatum was reduced by 54 +/- 13% compared with values from the opposite (nonischemic) side of the brain (p less than 0.01, t test versus ligates not exposed to hypoxia). There were similar declines after 2.5 h of hypoxia-ischemia. Activity remained low after a 1 h recovery period in room air, but after 24 h of recovery, high-affinity glutamate uptake was equal bilaterally. Kinetic analysis revealed that loss of activity could be attributed primarily to a 40% reduction in the number of uptake sites. Hypoxia alone had no effect on high-affinity glutamate uptake although it reduced synaptosomal uptake of [3H]3,4-dihydroxyphenylethylamine. Addition of 1 mg/ml of bovine serum albumin to the incubation medium preferentially stimulated high-affinity glutamate uptake in hypoxic-ischemic brain compared with its effects in normal tissue. These studies demonstrate that hypoxia-ischemia reversibly inhibits high-affinity glutamate uptake and this occurs earlier than the time required to produce neuronal damage in the model.

Animals↗
PubMed1986

A model of methotrexate encephalopathy: neurotransmitter and pathologic abnormalities.

Methotrexate may cause seizures, dementia, and leukoencephalopathy when given in toxic doses to children with leukemia or solid tumors. Even in therapeutic doses, treatment with this drug is associated with an increased incidence of seizures in children with leukemia. To study mechanisms of injury, juvenile rats were given multiple intraventricular injections of methotrexate and the brains were analyzed for histopathology and biogenic amine metabolites of dopamine and serotonin. Disruption of monoamine metabolism has been proposed as a cause of brain dysfunction from this chemotherapy. Multiple injections (1 or 2 mg/kg) produced convulsions in an increasingly larger percentage of animals at higher cumulative doses, and five doses produced the neuropathological changes seen in human leukoencephalopathy. A single dose reduced the concentration of brain metabolites of dopamine, but not serotonin, six hours later. The effect was less pronounced after five doses. This rodent model should be useful for studying the metabolic basis of methotrexate encephalopathy.

Animals↗
PubMed1986

Cerebrospinal fluid biogenic amine metabolites in children during treatment for acute lymphocytic leukemia.

To learn more about the impact of intrathecal methotrexate and cytosine arabinoside therapy on neuronal metabolism, we measured serial cerebrospinal fluid concentrations of homovanillic acid and 5-hydroxyindoleacetic acid, major metabolites of the neurotransmitters dopamine and serotonin, in children with acute lymphocytic leukemia. Multiple sequential cerebrospinal fluids were obtained from 30 children with acute lymphocytic leukemia evaluated prospectively from the time of diagnosis. We focused on the period of induction and intensification when children received weekly intrathecal chemotherapy. Paired cerebrospinal fluid specimens were also obtained at 3-month intervals from 60 children with acute lymphocytic leukemia in remission. Homovanillic acid and 5-hydroxyindoleacetic acid were measured using high performance liquid chromatography with electrochemical detection. We found that pretreatment metabolite values were no different from those in age-matched subjects in remission. In the first 5 wk of treatment, there were no significant changes in metabolite levels in patients treated exclusively with methotrexate. There was a transient decrease in homovanillic acid (-28 +/- 10%, p less than 0.001, Student's t test) and 5-hydroxyindoleacetic acid (-28 +/- 12%, p less than 0.05) in five of six patients after a single intrathecal dose of cytosine arabinoside. In the next 4 wk there was a gradual rise in levels of homovanillic acid (p = 0.001, by analysis of variance) and 5-hydroxyindoleacetic acid (p = 0.029, analysis of variance); this pattern did not correlate with administration of cranial irradiation. In children in remission, there were no significant changes in metabolite levels over a 3-month period.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1986

Effects of intraventricular methotrexate on cerebrospinal fluid monoamine metabolites in rhesus monkeys.

Previous work suggested that methotrexate (MTX) may cause encephalopathy by inhibiting biosynthetic pathways for dopamine and serotonin in the brain. We examined this issue by measuring the neurotransmitter metabolites homovanillic acid and 5-hydroxyindoleacetic acid in the lumbar CSF of rhesus monkeys receiving continuous intracerebroventricular infusions of MTX or dichloromethotrexate. Infusion of the lowest dose (0.05 mg/day) produced a large (300%) rise in homovanillic acid levels and a modest elevation in 5-hydroxy-indoleacetic acid. During higher dose infusion, which was associated with clinical encephalopathy, the biogenic amine metabolites fell from their previous elevated levels. In one encephalopathic monkey, an injection of 1 mg of leucovorin produced a marked elevation in CSF monoamine metabolites within 1 hour and rapid clinical recovery. In contrast, leucovorin produced no change in monoamine metabolites in control animals. The data suggest that MTX may block egress of monoamine metabolites from CSF at the lower doses and suppress neurotransmitter turnover at toxic doses which cause encephalopathy. Serial measurements of CSF monoamine metabolites deserve further investigation as biochemical markers for toxic effects of MTX on neuronal metabolism in the CNS.

Animals↗
PubMed1985

Muscarinic cholinergic receptors in human infant forebrain: [3H]quinuclidinyl benzilate binding in homogenates and quantitative autoradiography in sections.

The ontogeny of muscarinic receptors in human brain was studied by comparing [3H]quinuclidinyl benzilate [( 3H]QNB) binding in postmortem tissue from infants 1 week to 3 months of age with binding in adult specimens. Saturation analysis with [3H]QNB and displacement studies with muscarinic antagonists and agonists in tissue homogenates demonstrated that binding sites in the infants' forebrain regions were present in adult or higher than adult concentrations (Bmax). Binding affinity (Kd) and pharmacological characteristics were nearly identical at the two ages. Quantitative receptor autoradiography demonstrated more [3H]QNB binding in the gray matter of infants than adults and revealed a marked difference between the two ages in the laminar distribution of binding sites in neocortex. In contrast to the adult pattern with higher binding in superficial layers 1-3 than in layers 4-6, the distribution in the immature cortex was inverted. These results suggest that muscarinic receptors in infants resemble closely those in mature brain. However, the topography of receptors in the immature neocortex is distinct and they are redistributed in a gradient from inside outward during postnatal development.

Adult↗
PubMed1985

Lesch-Nyhan syndrome: CSF neurotransmitter abnormalities.

Serial determinations of spinal fluid homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were made in four patients with the Lesch-Nyhan syndrome over a 5-year period. Control spinal fluids for age-matched comparison were obtained from 194 neurologic and nonneurologic pediatric patients. A rapid decline in control spinal fluid HVA and 5-HIAA occurs over the first 3 years of life (50 and 60%, respectively), and a more gradual decline persists throughout adolescence. The Lesch-Nyhan subjects have similar age-related changes in their spinal fluid neurotransmitter levels. Sequential 5-HIAA determinations from the four Lesch-Nyhan boys fall within the control range. The Lesch-Nyhan HVA levels are lower than the mean value for the age-matched control group in 18 of 19 samples. Ten of 19 determinations fell below the control range. Our findings provide evidence for altered CNS dopamine metabolism in the Lesch-Nyhan syndrome.

Adolescent↗
PubMed1984

Concentrations of homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid from human infants in the perinatal period.

To assess maturation of central serotonin and catecholamine pathways at birth, we measured lumbar CSF homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), stable acid metabolites of dopamine and serotonin, using HPLC with electrochemical detection. CSFs from 57 neonates (38 premature and 19 at term) and 13 infants 1-6 months old were studied. HVA levels increased with maturity (p less than 0.05; ANOVA), whereas 5-HIAA levels were similar in all these subjects. HVA/5-HIAA ratios increased markedly from 1 +/- 0.12 in the most premature neonates to 1.98 +/- 0.17 in the older infants (p less than 0.01; t test). There were no sex differences for these values.

Aging↗
PubMedDate not supplied

The glutamate uptake inhibitor L-trans-2,4-pyrrolidine dicarboxylate is neurotoxic in neonatal rat brain.

High-affinity glutamate uptake (HAGU) transporters rapidly remove released glutamate from the synaptic cleft. If HAGU is suppressed, neurotoxic concentrations of excitatory amino acids may accumulate. To seek further evidence in support of the neurotoxicity of endogenous glutamate in the developing brain, we assessed the neurotoxicity of the selective HAGU inhibitor L-trans-2,4-pyrrolidine dicarboxylate (L-PDC) in postnatal day 7 (PND 7) rats. The hippocampus of PND 7 rats is susceptible to EAA agonist-mediated injury; features of injury include atrophy and neuronal loss. Since HAGU is energy-dependent, we hypothesized that moderate hypoxia would increase L-PDC-mediated injury by further suppressing HAGU. L-PDC was stereotaxically injected into dorsolateral hippocampus of PND 7 rats (568 nmol, n = 20). Prior to return to the dam, rats were divided into two groups, one of which was subjected to moderate hypoxia (3 h, FiO2 = 0.08) (n = 11; 2 died acutely). On PND 12, hippocampal neuropathology was assessed by a blinded observer using a five-point scale and also by measuring hippocampal cross-sectional areas with computerized image analysis. Three brains were excluded from analysis, since markedly asymmetric tissue sectioning precluded valid side-to-side comparison of hippocampal areas. Injection of L-PDC alone elicited focal pyramidal cell loss (6/7); in the (L-PDC + hypoxia) group, injury was significantly increased (median scores: L-PDC = 2; [L-PDC + hypoxia] = 3.5; p < 0.005). Hippocampal atrophy was noted only after L-PDC + hypoxia (4/8) (percent right-left difference in mean hippocampal area [+/- SE]: L-PDC = 2.5% [+/- 2.6]; [L-PDC + hypoxia] = 8.9% [+/- 3.2]; p < 0.02). In tissue from PND 7 rats, L-PDC (10 microM) inhibited hippocampal synaptosomal HAGU by > 85%; at the same concentration, L-PDC did not displace [3H]glutamate from NMDA- or AMPA-sensitive hippocampal binding sites. These results support the hypothesis that increased synaptic accumulation of endogenous excitatory amino acid neurotransmitters may produce hippocampal injury in perinatal rodents.

Animals↗
PubMedDate not supplied

Cytokines and perinatal brain injury.

A rapidly expanding body of data provides support for the hypothesis that pro-inflammatory cytokines including interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) are expressed acutely in injured brain and contribute to progressive neuronal damage. Little is known about the pathogenetic role of these cytokines in perinatal brain injury. Recent experimental studies have incorporated two closely related in vivo perinatal rodent brain injury models to evaluate the role(s) of pro-inflammatory cytokines in the progression of neuronal injury: a perinatal stroke model, elicited by unilateral carotid artery ligation and subsequent timed exposure to 8% oxygen in 7-day-old rats, and a model of excitotoxic injury, elicited by stereotactic intra-cerebral injection of the selective excitatory amino acid agonist NMDA. Each of these lesioning methods results in reproducible, quantifiable focal forebrain injury at this developmental stage. Acute brain injury, evoked by cerebral hypoxia-ischemia or excitotoxin lesioning, results in transient marked increases in expression of IL-1 beta, and TNF-alpha mRNA in brain regions susceptible to irreversible injury, and there is evidence that pharmacological antagonism of IL-1 receptors can attenuate injury in both models. Recent studies also suggest that complementary strategies, based on pharmacological antagonism of platelet activating factor and on neutrophil depletion can also limit the extent of irreversible injury. In summary, current data suggest that pro-inflammatory cytokines contribute to the progression of perinatal brain injury, and that these mediators are important targets for neuroprotective interventions in the acute post-injury period.

Animals↗