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Biomedical subjects

A S Basile

Publications and source records attributed to A S Basile.

At least 55 records · Page 3Linked to original sources
PubMed1996

Early increases in TNF-alpha, IL-6 and IL-1 beta levels following transient cerebral ischemia in gerbil brain.

The effects of transient global ischemia using bilateral carotid artery occlusion on regional cytokine levels in gerbil brain were investigated using enzyme-linked immunoassay techniques. Brain concentrations of interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha) were increased during the early recirculation period ( < 6 h) after 10 min of ischemia, with lesser degrees of elevation following only 5 min of ischemia. TNF-alpha levels in the hippocampus and striatum were significantly increased as early as 1 h after recirculation, declining sharply to control levels by 12 h, then transiently increasing at 24 h. Elevated levels of IL-1 beta and IL-6 were not seen until 3-6 h post-occlusion. No significant increases in cytokine concentrations were observed in the cerebellum or thalamus. These results suggest that regionally selective increases in cytokines may be involved in the pathophysiological changes in hippocampus and striatum following transient cerebral ischemia.

Analysis of Variance↗
PubMed1996

N-methyl-D-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss.

The use of aminoglycoside antibiotics is limited by ototoxicity that can produce permanent hearing loss. We report that concurrent administration of N-methyl-D-aspartate (NMDA) antagonists markedly attenuates both the hearing loss and destruction of cochlear hair cells in guinea pigs treated with aminoglycoside antibiotics. These findings indicate that aminoglycoside-induced hearing loss is mediated, in part, through an excitotoxic process. The high correlation (Spearman correlation coefficient: 0.928; P < 0.01) obtained between the relative cochleotoxicities of a series of aminoglycosides in humans and the potencies of these compounds to produce a polyamine-like enhancement of [3H]dizocilpine binding to NMDA receptors is consistent with this hypothesis, and provides a simple in vitro assay that can predict this aspect of aminoglycoside-induced ototoxicity.

Animals↗
PubMed1996

Increased brain levels of platelet-activating factor in a murine acquired immune deficiency syndrome are NMDA receptor-mediated.

Mice infected with the LP-BM5 murine leukemia virus (MuLV) develop an immunodeficiency syndrome (murine AIDS) and an encephalopathy characterized by impaired spatial learning and memory. Because platelet-activating factor (PAF) has been implicated in the pathogenesis of HIV-associated dementia complex, brain PAF levels were measured in LP-BM5 MuLV-infected mice. PAF levels in cerebral cortex and hippocampus were significantly increased at 6 and 12 weeks after LP-BM5 MuLV inoculation, whereas significant increases in striatal and cerebellar PAF levels were observed only at 12 weeks after inoculation. Administration of the NMDA antagonist MK-801 significantly reduced the increased PAF levels in the cerebral cortex and hippocampus of LP-BM5 MuLV-infected mice. These results indicate that the LP-BM5 MuLV-induced increases in brain PAF levels are the results of NMDA receptor activation and are consistent with the hypothesis that elevated CNS PAF levels contribute to the behavioral deficits observed in LP-BM5 MuLV-infected mice.

AIDS Dementia Complex↗
PubMed1996

Altered brain fyn kinase in a murine acquired immunodeficiency syndrome.

Mice infected with the replication-defective virus (BM5def) in the LP-BM5 murine leukemia virus (MuLV) mixture develop an immune deficiency syndrome and encephalopathy characterized by impaired spatial learning and memory as demonstrated in the Morris water maze. However, the molecular mechanism (or mechanisms) underlying this cognitive deficit remains unknown. Here we report that brain fyn kinase, which has been proposed to be involved in spatial learning and memory, was unresponsive to glutamatergic stimulation in mice with MAIDS. Thus, whereas application of glutamate to hippocampal slices from control mice increased fyn protein tyrosine kinase (PTK) activity more than 2.5-fold, these changes were significantly impaired in LP-BM5 MuLV-infected mice. Moreover, mice with MAIDS exhibited an abnormal histological distribution of fyn PTK in the hippocampus. These findings suggest that virus-associated disruption of fyn kinase-mediated signaling contributes to the cognitive deficits observed in mice with MAIDS and other retrovirus-induced encephalopathies.

Animals↗
PubMed1995

Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy.

Benzodiazepine receptor (BZR) ligands are elevated in animals and humans with fulminant hepatic failure (FHF) and contribute to the pathogenesis of the associated hepatic encephalopathy (HE). As gut factors are proposed to play a role in the pathogenesis of HE, we investigated gut flora as a source of BZR ligands. Rats received daily oral neomycin, vancomycin and metronidazole (AB +) or saline (AB -) before and concurrent with the induction of FHF with thioacetamide. BZR ligands were extracted from brain and plasma and quantified using radiometric techniques. Plasma BZR ligand concentrations in AB(+) and AB(-) rats with HE were higher than AB(+) and AB(-) control rats. Brain BZR ligand concentrations increased in AB(+) and AB(-) rats with HE. Stool cultures from antibiotic treated rats with HE indicated the presence of multidrug resistant Acinetobacter lwoffii. Although no significant concentrations of BZR ligands were detected in culture media inoculated with A. lwoffii, administering A. lwoffii to normal rats significantly elevated BZR ligand levels in brain, but not plasma. Thus, antibiotic treatment of rats is associated with the growth of a resistant strain of bacterium which produces an inactive BZR ligand precursor. BZR ligands may be synthesized from these precursors in the brain and efficiently cleared by a normal liver following brain-to-plasma transfer. Impairment of this clearance process in FHF facilitates their accumulation, enabling agonist BZR ligands to contribute to the pathogenesis of HE by further enhancing GABAergic neurotransmission.

Analysis of Variance↗
PubMed1995

The relationship between plasma and brain quinolinic acid levels and the severity of hepatic encephalopathy.

BACKGROUND/AIMS: Quinolinic acid is an endogenous neuroexcitant derived from tryptophan. Brain quinolinic acid concentrations are reportedly elevated in chronic liver failure. The aim of this study was to determine if brain quinolinic acid levels correlate with the severity of hepatic encephalopathy. METHODS: Postmortem samples of selected brain regions and plasma samples taken at several stages of encephalopathy were obtained from patients with acute and chronic liver failure. Quinolinic acid levels were measured by mass spectroscopy using [18O]quinolinic acid. RESULTS: Plasma quinolinic acid levels were significantly increased by stage I encephalopathy in patients with acute liver failure and by stages II and III in patients with chronic liver failure. Brain quinolinic acid levels were elevated only in patients with acute liver failure and were uniformly distributed at concentrations below those observed in plasma. CONCLUSIONS: The uniform distribution of quinolinic acid at subplasma concentrations in the brains of patients with acute liver failure suggests that it is synthesized peripherally and enters the brain across a permeabilized blood-brain barrier. Whereas the elevation of brain quinolinic acid levels in patients who died of acute but not chronic liver failure suggests that the involvement of quinolinic acid in the pathogenesis of hepatic encephalopathy is minimal, it could predispose these patients to seizures.

Acute Disease↗
PubMed1995

Striatal met-enkephalin and substance P levels are decreased in mice infected with the LP-BM5 murine leukemia virus.

Mice infected with the LP-BM5 murine leukemia virus mixture develop severe immunosuppression and an encephalopathy characterized by spatial learning deficits. Twelve weeks after infection of C57BL/6J mice with LP-BM5, significant (50-60%) reductions in Met-enkephalin and substance P levels were observed in the striatum, whereas somatostatin levels were unchanged. In addition, a 39% decrease in hypothalamic substance P concentrations was observed, with no alteration in Metenkephalin levels. The apparent selectivity of the decrease in neuropeptide concentrations indicates that a functional alteration of the primary striatal efferent neurons occurs in this infection, which may contribute to the impairment of spatial learning observed in these mice. Moreover, this decrease in striatal neuropeptide levels is similar to the neuropathological changes in basal ganglia observed in HIV-infected individuals and is consistent with previous studies suggesting that the LP-BM5-infected mouse may serve as a useful model of AIDS dementia.

Animals↗
PubMed1995

The relationship between plasma and brain quinolinic acid levels and the severity of hepatic encephalopathy in animal models of fulminant hepatic failure.

Quinolinic acid is an excitatory, neurotoxic tryptophan metabolite proposed to play a role in the pathogenesis of hepatic encephalopathy. This involvement was investigated in rat and rabbit models of fulminant hepatic failure at different stages of hepatic encephalopathy. Although plasma and brain tryptophan levels were significantly increased in all stages of hepatic encephalopathy, quinolinic acid levels increased three-to sevenfold only in the plasma, CSF, and brain regions of animals in stage IV hepatic encephalopathy. Plasma-CSF and plasma-brain quinolinic acid levels in rats and rabbits with fulminant hepatic failure were strongly correlated, with CSF and brain concentrations approximately 10% those of plasma levels. Moreover, there was no significant regional difference in brain quinolinic acid concentrations in either model. Extrahepatic indoleamine-2,3-dioxygenase activity was not altered in rats in stage IV hepatic encephalopathy, but hepatic L-tryptophan-2,3-dioxygenase activity was increased. These results suggest that quinolinic acid synthesized in the liver enters the plasma and then accumulates in the CNS after crossing a permeabilized blood-brain barrier in the end stages of liver failure. Furthermore, the observation of low brain concentrations of quinolinic acid only in stage IV encephalopathy suggests that the contribution of quinolinic acid to the pathogenesis of hepatic encephalopathy in these animal models is minor.

Animals↗
PubMed1995

Brain and plasma levels of opioid peptides are altered in rats with thioacetamide-induced fulminant hepatic failure: implications for the treatment of hepatic encephalopathy with opioid antagonists.

Although plasma levels of Met-enkephalin and beta-endorphin are elevated in patients suffering from liver failure, it is not known whether central nervous system (CNS) opioidergic neurotransmission is altered in these patients. Such changes may contribute to the motor dysfunction, psychiatric abnormalities and CNS depression observed in hepatic encephalopathy (HE). Therefore, Met- and Leu-enkephalin, dynorphin A and beta-endorphin levels were measured in discrete brain regions and plasma from thioacetamide-treated rats in Stages II to IV of HE. Pituitary and plasma beta-endorphin, Met- and Leu-enkephalin concentrations increased with the severity of HE by 50 to 290%. Pituitary and brainstem dynorphin A levels increased whereas plasma levels decreased in rats with thioacetamide-induced fulminant hepatic failure. Both striatal Met- and Leu-enkephalin levels increased and hypothalamic concentrations decreased in HE. Concurrent with the increase in striatal Met-enkephalin levels was a 26 to 48% decrease in the density of striatal and hypothalamic delta receptors. No change in either the density or affinity of radioligand binding to mu or delta receptors was observed in the CNS. Finally, administering (+/-)-naloxone (5 and 10 mg/kg) or (+/-)-naltrexone (5-15 mg/kg), but not (+)-naloxone (10 mg/kg), significantly increased the motor activity of rats with Stage III HE. Whereas elevated plasma levels of opioid peptides may play a role in the peripheral manifestations of hepatic failure (ascites and hypotension), increased CNS levels of these peptides may be involved in the neuropsychiatric abnormalities characteristic of HE. Thus, opioid antagonists may be effective in ameliorating some of the neurological manifestations of HE.

Animals↗
PubMed1995

Sustained exposure to 1-aminocyclopropanecarboxylic acid, a glycine partial agonist, alters N-methyl-D-aspartate receptor function and subunit composition.

Partial agonists at the strychnine-insensitive glycine sites coupled to N-methyl-D-aspartate (NMDA) receptors reduce both glutamate-induced neurotoxicity in vitro and ischemia-induced neurodegeneration in vivo. Paradoxically, sustained exposure of cultured cerebellar granule cell neurons to glycinergic ligands, including glycine and the glycine partial agonists (+/-)-3-amino-1-hydroxy-2-pyrrolidone, 1-aminocyclopropanecarboxylic acid (ACPC), and D-cycloserine, attenuates the neuroprotective effects of (+/-)-3-amino-1-hydroxy-2-pyrrolidone and ACPC. In the present study, we investigated the mechanisms responsible for this attenuated neuroprotection. Three NMDA receptor-mediated responses were examined after sustained exposure to ACPC: glutamate-induced neurotoxicity, NMDA-stimulated increases in cGMP levels, and NMDA-stimulated increases in [Ca+2]i. Consistent with previous findings, coincubation with ACPC blocked glutamate-induced neurotoxicity, whereas sustained (24 hr) exposure to ACPC attenuated its protective effects. Moreover, sustained exposure to ACPC caused an apparent approximately 2-fold increase in the potency of both glutamate to act as neurotoxin and NMDA to stimulate cGMP formation. Sustained exposure to ACPC also increased NMDA-stimulated [Ca+2]i approximately 3-fold compared with control granule cell cultures but did not affect basal [Ca+2]i. This apparent increase in glutamate sensitivity may be attributable to a change in NMDA receptor subunit composition as sustained ACPC exposure resulted in a approximately 2.5-fold increase in NMDA receptor 2C RNA levels, without concomitant changes in the amounts of RNA encoding the NMDA receptor 2A, 2B, or 1 subunit. This is the first demonstration that sustained exposure to a glycinergic ligand can alter the expression of RNAs encoding NMDA receptor subunits. Because glycinergic ligands are potential clinical candidates, these results may have important implications for the treatment of neurodegenerative disorders.

Amino Acids↗
PubMed1994

The protective effects of stress control may be mediated by increased brain levels of benzodiazepine receptor agonists.

Control over stress protects against many of the deleterious effects of stress exposure, but the endogenous mediators responsible for these prophylactic effects have remained elusive. Using behavioral pharmacology, in vitro radioligand binding and neurochemical analyses, we demonstrate that exposure to escapable stress results in brain and behavior changes reminiscent of benzodiazepine administration. The stress control group shows significant protection against picrotoxinin-induced seizures, reductions in [35S]t-butylbicyclophosphorothionate (TBPS) binding and a 3-fold increase of benzodiazepine-like substances in brain in comparison to both yoked-inescapable shock and non-shock controls. These observations suggest that coping behavior leads to the release of endogenous benzodiazepine-like compounds in brain which protect the organism from stress pathology.

Analysis of Variance↗
PubMed1994

Volatile anesthetics bidirectionally and stereospecifically modulate ligand binding to GABA receptors.

Pharmacologically relevant concentrations of volatile anesthetics can bidirectionally modulate radioligand binding to GABAA receptors. In mouse cerebral cortex, halothane (a prototypic volatile anesthetic) increased [3H]muscimol (a GABA receptor agonist) binding while inhibiting the binding of a GABA receptor antagonist ([3H]SR 95531). These bidirectional effects of inhalational anesthetics on ligand binding to GABA receptors are effected through changes in the Bmax with no significant alterations in the KD of these radioligands. Moreover, the concentration dependent, bidirectional modulation of radioligand binding to GABA receptors by volatile anesthetics exhibited stereoselectivity. Thus, (+)-isoflurane was about twice as potent as the (-)-enantiomer in enhancing [3H]muscimol binding and approximately 50% more potent as an inhibitor of [3H]SR 95531 binding, respectively. The demonstration of a bidirectional, stereospecific modulation of radioligand binding to GABA receptors by inhalational agents is consistent with the presence of specific recognition sites for inhalational anesthetics on the GABAA receptor complex.

Animals↗
PubMed1994

Internucleosomal DNA fragmentation in gerbil hippocampus following forebrain ischemia.

Internucleosomal DNA fragmentation, the characteristics feature of programmed cell death, was demonstrated in gerbil hippocampus following 10 min of forebrain ischemia. Quantitative analysis revealed the presence of DNA fragments as early as 12 h after ischemia, reaching a maximum at 48 h. Measurable DNA fragmentation was still present in 3/3 subjects 96 h after the ischemic insult. In situ staining of hippocampus demonstrated pronounced DNA fragmentation that was localized in the CA1 region. The localization of fragmented DNA to the CA1 is consistent with the vulnerability of this layer to ischemic insult, and indicates that DNA fragmentation may be associated with the delayed loss of CA1 neurons in this model of forebrain ischemia.

Animals↗
PubMed1994

Multiple [3H]DTG binding sites in guinea pig cerebellum: evidence for the presence of non-specific binding.

The characteristics of the low affinity component of 1,3-di(2-[5-3H]tolyl)guanidine binding to the guinea pig cerebellum were investigated. Saturation binding assays where sigma 1 receptors were masked with dextrallorphan indicated that 1,3-di(2-[5-3H]tolyl)guanidine bound to cerebellar membranes in a fashion best described by a 1 site+non-specific binding model with a low density of specific binding sites (Bmax approximately 200 fmol/mg protein). Boiling the cerebellar membranes before addition to the saturation assay had no effect on the density of 1,3-di(2-[5-3H]tolyl)guanidine binding. In contrast, both the Kd and Bmax for 1,3-di(2-[5-3H]tolyl)guanidine binding to liver membranes was significantly reduced by boiling, as was the density of [3H](+)-pentazocine binding to cerebellum and liver. Thus, a substantial component of 1,3-di(2-[5-3H]tolyl)guanidine binding in the guinea pig cerebellum is to non-specific, proteinaceous binding sites with some of the pharmacological characteristics of the sigma 2 binding site.

Animals↗
PubMed1994

Relationship between plasma benzodiazepine receptor ligand concentrations and severity of hepatic encephalopathy.

Levels of benzodiazepine receptor ligands were measured in plasma samples from 25 patients in various stages of hepatic encephalopathy due to fulminant liver failure who were not exposed to pharmaceutical benzodiazepines immediately before or during hospitalization. Chromatographic analysis of extracted plasma samples revealed one to nine fractions containing material that competitively inhibited [3H]flumazenil binding to benzodiazepine receptors with the pharmacological properties of benzodiazepine receptor agonists. Two of these peaks were positively identified as the 1,4-benzodiazepines diazepam and N-desmethyldiazepam on the basis of chromatographic, ultraviolet and mass spectral evidence. The plasma levels of diazepam and N-desmethyldiazepam were significantly increased above control values in stage 4 hepatic encephalopathy, whereas total benzodiazepine receptor ligand concentrations were increased above control in stages 1 through 4. A significant but weak linear correlation was found between the relative increase in the levels of diazepam, N-desmethyldiazepam and total benzodiazepine receptor ligands and the severity of hepatic encephalopathy. Thus increased concentrations of benzodiazepine receptor ligands appear to contribute to the enhancement of GABAergic neurotransmission in hepatic encephalopathy, particularly in stage 4. These results constitute further support for a role for benzodiazepine receptor ligands in the pathogenesis of hepatic encephalopathy associated with acute liver failure.

Adult↗
PubMed1993

Structure-activity relationship studies at the benzodiazepine receptor (BZR): a comparison of the substitutent effects of pyrazoloquinolinone analogs.

The synthesis of a series of 2-phenylpyrazolo[4,3-c]quinolin-3-one derivatives and their in vitro biological evaluation as ligands for the benzodiazepine receptor are described. The in vitro activities, as determined by an analysis of GABA shift ratios, and binding affinities of these compounds to BZR are compared in terms of the electronic, lipophilic, and steric effect changes of their substituents.

Animals↗