Ketamine-induced neuronal cell death in the perinatal rhesus monkey.

Ketamine is widely used as a pediatric anesthetic. Studies in developing rodents have indicated that ketamine-induced anesthesia results in brain cell death. Additional studies are needed to determine if ketamine anesthesia results in brain cell death in the nonhuman primate and if so, to begin to define the stage of development and the duration of ketamine anesthesia necessary to produce brain cell death.

Blockade of N-methyl-D-aspartate receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is used as a general pediatric anesthetic. Recent data suggest that anesthetic drugs may cause neurodegeneration during development. The purpose of this study was to determine the robustness of ketamine-induced developmental neurotoxicity using rhesus monkey frontal cortical cultures and also to determine if dysregulation of NMDA receptor subunits promotes ketamine-induced cell death.

Neurohistochemical biomarkers of the marine neurotoxicant, domoic acid.

Domoic acid and its potent excitotoxic analogues glutamic acid and kainic acid, are synthesized by marine algae such as seaweed and phytoplankton. During an algal bloom, domoic acid may enter the food web through its consumption by a variety of marine organisms held in high regard as seafoods by both animals and humans. These seafoods include clams, mussels, oysters, anchovies, sardines, crabs, and scallops, among others.

The role of the N-methyl-D-aspartate receptor in ketamine-induced apoptosis in rat forebrain culture.

Recent data suggest that anesthetic drugs may cause widespread and dose-dependent apoptotic neurodegeneration during development. The window of vulnerability to this neurotoxic effect, particularly with N-methyl-D-aspartate (NMDA) antagonists such as ketamine, is restricted to the period of synaptogenesis. The purposes of this study are to determine whether treatment of forebrain cultures with ketamine results in a dose-related increase in neurotoxicity and whether upregulation of NMDA receptor subunit NR1 promotes ketamine-induced apoptosis.

Fluoro-Jade C results in ultra high resolution and contrast labeling of degenerating neurons.

The causes and effects of neuronal degeneration are of major interest to a wide variety of neuroscientists. Paralleling this growing interest is an increasing number of methods applicable to the detection of neuronal degeneration. The earliest methods employing aniline dyes were methodologically simple, but difficult to interpret due to a lack of staining specificity.

Sex differences in cytochrome P450 1B1, an estrogen-metabolizing enzyme, in the rhesus monkey telencephalon.

The metabolic enzyme CYP1B1 is a recently cloned member of the cytochrome P450 superfamily, expressed widely throughout primate tissue, including the CNS. Although CYP1B1 protein is known to metabolize estradiol to catecholestrogens in the uterus, its localization and function in brain have not yet been described. To better understand CYP1B1 distribution, we have combined in situ hybridization (ISH) for its mRNA with immunohistochemistry (IHC) for the CYP1B1 protein in selected brain regions of male and female adult rhesus monkeys (Macaca mulatta).

Increased volume of the calbindin D28k-labeled sexually dimorphic hypothalamus in genistein and nonylphenol-treated male rats.

The adult rat brain develops through an interplay of neuronal proliferation and programmed cell death. Steroid hormones and growth factors may alter the balance between these competing processes. "Endocrine disrupters" (EDs) may also alter brain development, by mimicry or modulation of endogenous hormone systems.

Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons.

Ketamine is a widely used pediatric anesthetic recently reported (C. Ikonomidou et al., 1999, Science 283, 70-74) to enhance neuronal death in neonatal rats.

Electroencephalographic, behavioral, and c-fos responses to acute domoic acid exposure.

Domoic acid, a potent excitotoxic analogue of glutamate and kainate, may cause seizures, amnesia, and sometimes death in humans consuming contaminated shellfish. Continuous behavioral observations and recordings of the electrocorticogram (ECoG, via bipolar, epidural electrodes) were obtained from nonanesthetized rats for 2 h after intraperitoneal injection with either saline, 2.2, or 4.

3-nitropropionic acid inhibition of succinate dehydrogenase (complex II) activity in cultured Chinese hamster ovary cells: antagonism by L-carnitine.

3-Nitropropionic acid (3-NPA) is an inhibitor of the mitochondrial enzyme succinate dehydrogenase (SDH, a part of complex II) that links the tricarboxylic acid (TCA) cycle to the respiratory electron transport chain. 3-NPA inactivates SDH by covalently and irreversibly binding to its active site. We previously examined the effects of 3-NPA on the histochemical activity of SDH in vivo, by using the reduction of a yellow tetrazolium dye (nitro blue tetrazolium) to a blue formazan as an indicator.

Dietary exposure to genistein increases vasopressin but does not alter beta-endorphin in the rat hypothalamus.

Genistein is a plant-derived estrogenic isoflavone commonly found in soy-based products such as soymilk and soy-based dietary supplements for treating menopausal symptoms, for example. Vasopressin is a neurosecretory nonapeptide synthesized primarily in neurons of the hypothalamus and secreted into the bloodstream from the posterior lobe of the pituitary. The endogenous opiate peptide beta-endorphin is synthesized both in neurons of the hypothalamus and in pituitary cells, primarily of the neurointermediate lobe.

Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity.

The NMDA receptor has been widely investigated in recent years as a target for the pharmacological management of seizures, pain and a variety of neurological disorders. Its role in normal central nervous system (CNS) activity and development, as well as in the development of CNS abnormalities and neurodegeneration has also been of interest. The NMDA receptor is one of three pharmacologically distinct subtypes of ionotropic receptor channels that are sensitive to the endogenous excitatory amino acid, L-glutamate.

Quantitative three-dimensional reconstruction: feasibility for studies of sexually dimorphic hypothalamic development in rats.

The adult rat brain develops through an interplay of neuronal proliferation with programmed cell death. Sensory stimulation, as well as growth factors and steroids, may alter the balance between these competing processes. "Endocrine disrupters" (EDs) may do the same by mimicry or modulation of endogenous hormones.

Fluoro-Jade and silver methods: application to the neuropathology of scrapie, a transmissible spongiform encephalopathy.

Traditional methods for evaluating neurodegeneration include variations of Nauta's selective silver-staining techniques. The Fluoro-Jade (FJ) method applies a novel fluorescent, anionic stain for localizing degenerating neurons. FJ has produced comparable results to the silver methods, when both have been applied to detect neurodegeneration in animals treated acutely with a variety of neurotoxins, including kainic acid (KA), ibogaine (IBO), 3-nitropropionic acid (3-NPA), domoic acid and others.

Comparison of NADPH diaphorase activity in the brains of hamsters infected with scrapie strains 139H or 263K or with normal hamster brain homogenate.

Previous studies showed that the histopathological changes found in the brains of scrapie-infected animals included amyloid plaque formation, vacuolation, gliosis and neuronal and neurite degeneration. There were differences in the histopathological findings as a function of the scrapie strain-host combination. NADPH-diaphorase (NADPH-d) has been shown to be a selective histochemical marker for neurons containing nitric oxide (NO) synthase.

Evaluation of neurodegeneration in scrapie-infected animals by selective methods that detect cellular degeneration.

Scrapie is a fatal neurodegenerative disease of sheep and goats. The precise details of neuronal and neurite degeneration in scrapie-infected animals remain unknown. Using specific silver staining methods, we compared the neurodegeneration caused by treatment of rats with kainic acid (KA) or ibogaine (IBO) to the neuropathology observed in mice infected with the C602 strain of scrapie.

Gender-based differences in rats after chronic dietary exposure to genistein.

Gender-based differences can be observed from pharmacokinetic, behavioral, or anatomical assessments. No single assessment tool will provide a complete answer, but the use of a variety of indices, each with known gender-related outcome differences, can reveal agent-induced gender-based alterations. In a series of initial range-finding studies in rats conducted at the National Center for Toxicological Research (NCTR), the effects of dietary exposure to the weak estrogen, genistein, have been assessed using a number of techniques with validated gender-related outcome measures.

Biomarkers of 3-nitropropionic acid (3-NPA)-induced mitochondrial dysfunction as indicators of neuroprotection.

In humans or animals, symptoms of mitochondrial energy dysfunction may be produced by mutations or inborn errors of the necessary enzymes, as well as by enzyme inhibitors or uncouplers of the oxidative phosphorylation process. 3-Nitropropionic acid (3-NPA) is a toxin that is sometimes produced on moldy crops (sugarcane, peanuts, etc.) in amounts sufficient to cause severe neuromuscular disorders when consumed by humans.

Effect of L-carnitine pretreatment on 3-nitropropionic acid-induced inhibition of rat brain succinate dehydrogenase activity.

L-Carnitine (LC) plays an important regulatory role in the mitochondrial transport of long chain free fatty acids (FFA). 3-Nitropropionic acid (3-NPA) is known to induce cellular energy deficit and oxidative stress-related neurotoxicity via an irreversible inhibition of mitochondrial succinate dehydrogenase (SDH). In the present study, activity of SDH was measured in order to evaluate neuroprotective effects of LC against the 3-NPA-induced neurotoxicity.

Developmental neurotoxicity of endocrine disrupters: focus on estrogens.

A number of different environmental compounds are proposed to interact with the endocrine system (i.e., endocrine disrupters).

A practical three-dimensional reconstruction method to measure the volume of the sexually-dimorphic central nucleus of the medial preoptic area (MPOC) of the rat hypothalamus.

Published estimates of the volume of the sexually-dimorphic central nucleus of the medial preoptic area (MPOC) have been quite variable both within and between laboratories. To obtain MPOC volume, most experimenters began with a two-dimensional (2-D) approach. They outlined the MPOC on each of several individual sections; then they added up the area contained on each section and multiplied the total by the section thickness.

A dose-response study of ibogaine-induced neuropathology in the rat cerebellum.

Ibogaine (IBO) is an indole alkaloid from the West African shrub, Tabernanthe iboga. It is structurally related to harmaline, and both these compounds are rigid analogs of melatonin. IBO has both psychoactive and stimulant properties.

Quantitating silver-stained neurodegeneration: the neurotoxicity of trimethlytin (TMT) in aged rats.

This report describes the development of a histoanalytical procedure to measure the degree of neurodegeneration produced by the organometal toxicant trimethyltin (TMT). Based on a previous, non-quantitated experiment we hypothesized that the same dose of TMT would produce greater damage in animals of increasing age. Male rats aged 6, 12, 18, or 24 months at the time of dosing were given either 4.

Systemic administration of domoic acid-induced spinal cord lesions in neonatal rats.

Domoic acid (Dom) is a glutamate analog and a seafood toxin that has caused neurological disturbance and death in humans. Brain lesions caused by Dom have been documented in the literature, but the effect of Dom on the spinal cord has not been investigated as extensively. Systemic administration of glutamate agonists (i.