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A C Scallet

Publications and source records attributed to A C Scallet.

At least 37 records · Page 2Linked to original sources
PubMed1997

The 139H scrapie agent produces hypothalamic neurotoxicity and pancreatic islet histopathology: electron microscopic studies.

Neuronal degeneration, along with astrocytosis, spongiform vacuolation, and amyloid (PrPSc) formation, have long been regarded as neuropathological hallmarks of transmissible spongiform encephalopathies (TSEs). In animals, these diseases include; scrapie, transmissible mink encephalopathy, chronic wasting disease, bovine and feline spongiform encephalopathies, and in humans; kuru, Creutzfeldt-Jakob disease (CJD), and Gerstmann-Sträussler-Scheinker syndrome (GSS). The abnormal amyloid protein, (PrPSc) is toxic to neurons. Our previous studies showed that hamsters treated with 139H scrapie strain developed obesity, and generalized endocrinopathy, including lesions in hypothalamus, pituitary and pancreas. Histochemical and immunocytochemical studies revealed extensive pathological changes in the islets of Langerhans in 139H-infected hamsters, but not in hamsters infected with 263K scrapie strain. Using routine electron microscopy (EM), we have observed more details of lesions in the beta cells of islets of Langerhans in these animals. Cytoplasmic vacuolation occurred, cytoplasmic organelles were found damaged and disrupted, and membranes were occasionally ruptured. The width of endoplasmic reticulum (ER) lumina were 50-150 nm in controls, whereas in 139H-infected hamsters, they wee occasionally increased up to 4000 nm in diameter. Most beta cells showed degranulation. These EM observations suggest that the cellular death seen in the islets of Langerhans in 139H-infected hamsters is due to necrosis, not apoptosis. Since there were no amyloid deposits found in the islet of Langerhans at the EM level, and there were extremely low scrapie infectivity levels and PrPSc levels in pancreas, it is suggested that the changes noted in pancreas were not a direct toxic effect of PrPSc. Instead, our study suggests that scrapie prion protein PrPSc, acting as a neurotoxicant, alters the hypothalamic neuroendocrine regulation of the pancreas.

Animals↗
PubMed1996

Parenterally administered 3-nitropropionic acid and amphetamine can combine to produce damage to terminals and cell bodies in the striatum.

The combined effects of amphetamine (AMPH) and 3-nitropropionic acid (3-NPA) were investigated to determine how the energy depletion proposed to be produced by AMPH interacts with an inhibitor of mitochondrial respiration to produce striatal neurotoxicity. Neither two doses (2 h apart) of 3.75 mg/kg AMPH alone nor a single dose of 30 mg/kg 3-NPA i.p. produced neurotoxicity in the striatum or lowered striatal dopamine content in rat. Administration of 40 mg/kg of 3-NPA alone almost invariably produced either lethality or did not produce neurotoxicity in the striatum of surviving animals. However, 30 mg/kg of 3-NPA administered along with 2 doses of 3.75 mg/kg AMPH to 47 animals produced striatal damage in the 31 survivors with 15 of the surviving rats showing muscle rigidity/catatonia for several days after dosing, along with decreased food consumption. Thirteen of these 15 rats showed degeneration of axons and cell bodies in the medial caudate-putamen with minimal damage to the globus pallidus. However, two rats exhibited hindlimb paralysis and signs of axonal and neuronal soma degeneration in the thalamus and cerebellar nuclei as well as striatum. Sixteen of the rats given both AMPH and 3-NPA exhibited only torpidity and loss of muscle tone 1-3 h after dosing. Such rats showed no signs of neuronal cell degeneration in the striatum, but did show significant dopamine depletions (60% of control) and reductions in tyrosine hydroxylase immunoreactivity at 14 days postexposure. The mitochondrial dysfunction produced by 3-NPA combined with activation of neuronal pathways by AMPH may have predisposed terminals, axons and cell bodies in striatum to degeneration.

Amphetamine↗
PubMed1996

Neonatal MSG reduces hypothalamic DA, beta-endorphin, and delays weight gain in genetically obese (A viable yellow/alpha) mice.

Neonatal treatment with monosodium glutamate (MSG) decreases proopiomelanocortin (POMC) peptides and results in obesity. The yellow mouse is a model of obesity induced by the viable yellow (Avy) gene at the agouti locus on Chromosome 2, which results in overproduction of a POMC receptor antagonist. Thus we hypothesized that MSG, when imposed on the genetically susceptible model, would alter the development of obesity. Both yellow obese (Avy) and black lean (alpha/alpha) males were injected on Postnatal Days 1, 3, 5, 7, and 9 with 2.0 mg/g body weight MSG or saline SC. Their food intake, growth parameters, and neurochemical status were examined. Paradoxically, MSG interacted with the yellow phenotype to delay the rapid rate of weight gain characteristic of this model (p < 0.05). Food intake was decreased (p < 0.05) in both phenotypes treated with MSG, as was hypothalamic content of dopamine (p < 0.05) and of the POMC peptide, beta-endorphin (p < 0.001). The yellow obese phenotype was more sensitive than the black lean phenotype to the neurochemical effect of early postnatal MSG administration. Recent reports suggest the agouti locus protein is an antagonist of the receptor for another POMC peptide, melanocyte-stimulating hormone (MSH). Therefore, the balance of functional activity between various POMC peptides appears to be an important factor in the development of both acquired and genetic obesity.

Animals↗
PubMed1995

Domoic acid-induced neuronal degeneration in the primate forebrain revealed by degeneration specific histochemistry.

Domoic acid is a potent excitotoxin produced by diatoms which is subsequently passed along the marine food chain. Its chemical structure and toxicological properties are similar to kainic acid. Like kainic acid, exposure results in extensive hippocampal degeneration. The effect of domoic acid on other primate brain structures, however, is less resolved. In an attempt to clarify this issue, the present study applied a degeneration specific histochemical technique (de Olmos' cupric-silver method) to reveal degeneration within the brains of domoic acid-dosed cynomolgus monkeys. Degenerating neuronal cell bodies and terminals were found not only within the hippocampus, but also within a number of other 'limbic' structures including the entorhinal cortex, the subiculum, the piriform cortex, the lateral septum, and the dorsal lateral nucleus of the thalamus. Although the hippocampus is a component of the original limbic circuit of Papez, other components such as the mammillary bodies, the anterior nucleus of the thalamus and the cingulate cortex contained no degeneration, while a number of more recently documented efferent targets of the hippocampal formation revealed extensive degeneration. The pattern of degeneration generally correlated with those regions containing high densities of kainate receptors.

Animals↗
PubMed1995

Quantitative histological evaluation of neuroprotective compounds.

The application of quantitative morphometric methods to neurotoxicology is a relatively recent endeavor, and appropriate techniques are still evolving. However, such methods are essential for subsequent use of neurohistological data in mathematical representations of the risk of exposure to neurotoxicants. It can be predicted that the same methods will also be of great utility in studies of the efficacy of neuroprotective drugs. When the neuropathological conditions to be prevented or reversed are best monitored by neurohistology, quantitative morphometry should be considered as the most direct means to demonstrate the efficacy of a neuroprotective agent. Initially, a decision to choose the most appropriate histological procedure must be made. The rationale for such decisions with regard to several common histochemical techniques was discussed. The appropriate stereological and statistical considerations to be addressed by the sampling strategy were also presented. It is anticipated that quantitative morphometric methods will play an increasingly important role in the evaluation of the efficacy and toxicity of neuroactive compounds.

Analysis of Variance↗
PubMed1995

Comparison of glutamine-enhanced glutamate release from slices and primary cultures of rat brain.

Increased extracellular glutamate has been associated with a wide range of effects including production of neurotoxicity. Glutamine has previously been shown to cause increased release of glutamate from a variety of preparations. Extracellular central nervous system (CNS) glutamine levels are known to increase with neurotoxin exposures, hepatic failure, renal failure, head trauma or stroke. However, the action of glutamine to enhance the release of glutamate under nondepolarizing conditions has not been well studied. Since glutamine-mediated increases in extracellular glutamate are potentially of significance in cellular damage as a result of CNS insult, further examination of this phenomenon is important. Striatal and hippocampal slices or virtually neuron-free primary striatal glial cultures were employed in studies to further elucidate the mechanism(s) of glutamine-enhanced glutamate release. Elevated extracellular glutamine caused increased glutamate release in all three preparations. In hippocampal and striatal slices elevated glutamine caused an enhancement of N-methyl-D-aspartate (NMDA) receptor-mediated [3H]catecholamine release equivalent to that produced by high concentrations (up to 100 microM) of exogenous glutamate. In both striatal slices and primary cultures kynurenate increased glutamate release in the presence of 500 microM glutamine, while kainate either had no effect or decreased glutamate levels in the presence of glutamine. Since several presynaptic modulators of release did not affect the glutamate release produced by glutamine in slices, vesicular release of glutamate from nerve terminals was probably not involved in the effects of the exogenous glutamine. The similarities between striatal slices and primary striatal cultures indicate that enzymatic conversion of glutamine to glutamate within glia may be an important factor in the glutamine-mediated elevation of extracellular glutamate levels.

Analysis of Variance↗
PubMed1995

The effects of perinatal hypoxia on the behavioral, neurochemical, and neurohistological toxicity of the metabolic inhibitor 3-nitropropionic acid.

3-nitropropionic acid (3-NPA) neurotoxicity and long-term effects of perinatal hypoxia were evaluated in 18 adult rats. Hypoxia-insulted (I) and noninsulted (NI) rats were delivered by cesarean section. Hypoxic insult was effected by submerging dissected uterine horns in warmed saline for 15 min. NI rats were delivered from the adjacent nonsubmerged horns. At postnatal day 90, I and NI rats were trained to perform tasks thought to measure behaviors dependent upon aspects of time estimation (TE), motivation, and learning. At 12 months of age, rats were injected i.p. with escalating doses of 3-NPA (5 mg/kg/day to a maximum of 30 mg/kg/day) immediately after each test session and sacrificed at the end of treatment. Additional male rats were used as untreated controls. Although 3-NPA produced a dose-dependent impairment of performance in each task, the effects were qualitatively similar for each group. A significant difference between I and NI rats was, however, observed in the TE task where NI rats completed less of the task at high doses of 3-NPA compared to I rats. Compared to untreated controls, dopamine concentrations were decreased in caudate nucleus of both I and NI rats after 3-NPA. Specific areas most frequently damaged included cerebral cortex, hippocampal subfield CA1, thalamus, caudate nucleus, and the cerebellum. Lesions usually were less extensive in the I rather than NI members of a littermate pair, suggesting a possible protective effect of perinatal hypoxia against subsequent 3-NPA neurotoxicity.

Animals↗
PubMed1995

Postnatal MSG treatment attenuates angiotensin II (AII) induced drinking in rats.

Exogenous angiotensin II (AII) administration produces a robust drinking response, even in water-satiated rats. All receptors are located in the hypothalamus and circumventricular organs (CVOs). Early postnatal administration of monosodium glutamate (MSG) produces hypothalamic/CVO damage. Therefore MSG might damage hypothalamic/CVO neurons important for producing the drinking response to AII. Few noninvasive procedures or tests exist to indicate the presence of a MSG lesion. Thus, the present study sought to determine whether altered water consumption after AII administration would signify the presence of a MSG lesion, as well as to demonstrate hypothalamic/CVO involvement in AII-induced drinking. Adult rats (dosed as neonates with MSG or saline) were given various doses of AII and the beta-adrenergic agonist isoproterenol. MSG-treated rats drank significantly less water after 100 ug/kg, sc AII than control rats. MSG-treated rats also had an unexpectedly high mortality after 100 ug/kg, sc isoproterenol. Thus, measurement of the drinking response may be a sensitive, noninvasive method for detecting neurotoxic damage to hypothalamic/CVO sites critical for the central action of AII.

Angiotensin II↗
PubMed1994

The effects of reduced perfusion and reperfusion on c-fos and HSP-72 protein immunohistochemistry in gestational day 21 rat brains.

Metabolic stressors such as hyperthermia, seizures and ischemic hypoxia result in the induction of c-fos and heat-shock proteins (HSP) in affected brain cells of the adult rodent, especially within the hippocampal region, which normally has high metabolic demands. Here we ligated the uterine vessels of gestational day (GD) 21 rat pups to produce ischemic hypoxia. We confirmed that HSP-72 protein, as previously reported, was activated in the perinatal rat pup, especially in the hippocampal CA3 region. However, the capability of hippocampal cells to produce c-fos protein following drug-induced seizures has been reported to develop only after postnatal day 13. Here, ischemic hypoxia caused CA1 hippocampal cells to produce immunohistochemically detectable c-fos protein in GD-21 rats. These results seem to contradict the previous reports of no c-fos induction in rats this young by demonstrating a functional c-fos translational mechanism by GD-21. However, seizure vs ischemic hypoxia-induced c-fos expression may involve several different pre-translational pathways. A delayed development of a receptor, second messenger, or genomic element for regulating c-fos transcription remain as possible explanations for the late maturity of responsivity to seizures.

Animals↗
PubMed1993

Domoic acid-treated cynomolgus monkeys (M. fascicularis): effects of dose on hippocampal neuronal and terminal degeneration.

Domoic acid is a tricarboxylic amino acid (structurally related to kainic acid and glutamic acid) that is found in the environment as a contaminant of some seafood. To determine the nature of any neurological damage caused by domoate, as well as the minimum neurotoxic dose, juvenile and adult monkeys were dosed intravenously with domoate at one of a range of doses from 0.25 to 4 mg/kg. When animals were perfused one week later, histochemical staining using a silver method to reveal degenerating axons and cell bodies showed two distinct types of hippocampal lesions. One lesion, termed 'Type A', was a small focal area of silver grains restricted to CA2 stratum lucidum, the site of greatest kainic acid receptor concentration in the brain. Type A lesions occurred over a dose range of 0.5 to 2.0 mg/kg in juvenile animals and 0.5 to 1.0 mg/kg in adult animals. No mortality occurred in any of the juvenile monkeys, but one juvenile animal that received 4.0 mg/kg sustained a second type of lesion, termed 'Type B', characterized by widespread damage to pyramidal neurons and axon terminals of CA4, CA3, CA2, CA1, and subiculum subfields of the hippocampus. Doses of more than 1.0 mg/kg in the adult monkeys either proved lethal or resulted in Type B lesions. Induction of c-fos protein had occurred in the hippocampal dentate gyrus and CA1 regions of moribund animals perfused within hours of their initial dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

No increase in carcinogen-DNA adducts in the lungs of monkeys exposed chronically to marijuana smoke.

Rhesus monkeys exposed to marijuana smoke either 7 or 2 days/weeks (HI and LO groups, respectively), or ethanol-extracted marijuana smoke for 7 days/week (EM) or sham treatment (SH) for 1 year were sacrificed 7 months following the last exposure. Pulmonary levels of carcinogen-DNA adducts were determined. Although mean or median adduct levels were not statistically different, 15 of 22 adduct measures were highest in the EM group and lowest 12 of 22 times in the SH group. The levels of aromatic carcinogen-DNA adducts seem no higher in the lungs of animals exposed to marijuana smoke than in untreated animals. Ethanol-extracted marijuana may have effects greater than marijuana itself.

Animals↗
PubMed1992

Chronic marijuana smoke exposure in the rhesus monkey. II: Effects on progressive ratio and conditioned position responding.

Sixty-two male rhesus monkeys were trained to respond in an operant test battery that included tasks thought to allow measurement of aspects of motivation and color and position discrimination. Subjects were assigned to eight treatment groups (n = 7-8) based upon behavioral performance. There were two behavioral groups: ACTIVE = behavior assessed throughout the 365 days of active exposure and beyond, and RESIDUAL = behavior assessed beginning 2 months after the last exposure. Each behavioral group had four dose groups: HI = smoke from one marijuana (MJ) cigarette/day 7 days/week; LO = MJ smoke only on weekends; EX = smoke from one extracted MJ (placebo) cigarette/day 7 days/week; SH = sham exposure 7 days/week. For the motivation task, both HI and LO ACTIVE groups earned significantly fewer reinforcers than did both ACTIVE control groups during the last several months of exposure. These effects disappeared within 2 to 3 months of cessation of treatment, and no similar effect was present when RESIDUAL groups were tested. Performance of the color and position discrimination task was adversely affected in one of eight HI ACTIVE subjects throughout most of the chronic exposure, and there was a trend toward residual deficits in performance of this task in the HI RESIDUAL group compared to both SH and EX RESIDUAL controls. These data could be interpreted to mean that during periods of chronic use, MJ produces an amotivational-like syndrome in rhesus monkeys and that this syndrome disappears only several weeks to months after the last exposure.

Animals↗
PubMed1991

Chronic exposure to delta 9-tetrahydrocannabinol fails to irreversibly alter brain cannabinoid receptors.

The effects of chronic delta 9-tetrahydrocannabinol (delta 9-THC) and marijuana administration on the properties of brain cannabinoid receptor populations of the rat and monkey, respectively, were examined in this study. It was determined that the properties of the cannabinoid receptors in the striatum, cerebral cortex, cerebellum, hippocampus, and brainstem/spinal cord of the rat do not appear to be irreversibly altered by chronic exposure to delta 9-THC. Similarly, the cannabinoid receptors in the caudate, prefrontal cortex, and cerebellum of the monkey do not appear to be irreversibly altered by chronic exposure to marijuana smoke.

Analgesics↗