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J A Yergey

Publications and source records attributed to J A Yergey.

35 records · Page 2Linked to original sources
PubMed1991

Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status.

Quinolinic acid is an "excitotoxic" metabolite and an agonist of N-methyl-D-aspartate receptors. Of patients infected with human immunodeficiency virus type 1 (HIV-1) who were neurologically normal or exhibited only equivocal and subclinical signs of the acquired immunodeficiency syndrome (AIDS) dementia complex, concentrations of quinolinic acid in cerebrospinal fluid (CSF) were increased twofold in patients in the early stages of disease (Walter Reed stages 1 and 2) and averaged 3.8 times above normal in later-stage patients (Walter Reed stages 4 through 6). However, in patients with either clinically overt AIDS dementia complex, aseptic meningitis, opportunistic infections, or neoplasms, CSF levels were elevated over 20-fold and generally paralleled the severity of cognitive and motor dysfunction. CSF concentrations of quinolinic acid were significantly correlated to the severity of the neuropsychological deficits. After treatment of AIDS dementia complex with zidovudine and treatment of the opportunistic infections with specific antimicrobial therapies, CSF levels of quinolinic acid decreased in parallel with clinical neurological improvement. By analysis of the relationship between levels of quinolinic acid in the CSF and serum and integrity of the blood-brain barrier, as measured by the CSF:serum albumin ratio, it appears that CSF levels of quinolinic acid may be derived predominantly from intracerebral sources and perhaps from the serum. While quinolinic acid may be another "marker" of host- and virus-mediated events in the brain, the established excitotoxic effects of quinolinic acid and the magnitude of the increases in CSF levels of the acid raise the possibility that quinolinic acid plays a direct role in the pathogenesis of brain dysfunction associated with HIV-1 infection.

AIDS Dementia Complex↗
PubMed1991

Stable isotope-labeled tryptophan as a precursor for studying the disposition of quinolinic acid in rabbits.

The utility of stable isotope-labeled tryptophan as a precursor for studying the disposition of quinolinic acid was investigated. TRP-D5 at doses of 50, 25 or 10 mg/kg was administered to rabbits. Blood and CSF samples were taken for up to 6 hours. There was no loss of deuterium from the tryptophan and the specifically tri-deuterated quinolinic acid measured in plasma and CSF. CSF levels of QUIN-D3 remained elevated 6 hours following TRP-D5 administration. Further studies of the CNS disposition of quinolinic acid and other metabolites of the kynurenine pathway employing stable isotope-labeled tryptophan as precursor at appropriate doses and with extended sampling are in progress.

Animals↗
PubMed1990

Sustained increases in cerebrospinal fluid quinolinic acid concentrations in rhesus macaques (Macaca mulatta) naturally infected with simian retrovirus type-D.

Sustained increases in CSF concentrations of the excitotoxin quinolinic acid (QUIN) occur in patients with AIDS and have been implicated in the pathogenesis of the AIDS dementia complex. Macaques in captivity may also develop immunodeficiency syndromes caused by retrovirus infection, including simian retrovirus type-D. In the present study, CSF QUIN concentrations were moderately increased in retrovirus type-D-positive/antibody-negative macaques (163.8 +/- 35.1 nmol/l; P less than 0.0001, n = 21) but not virus-negative/antibody-positive macaques (27.4 +/- 9.4 nmol/l, n = 8) compared to uninfected control macaques (23.0 +/- 1.6 nmol/l; n = 22). CSF QUIN concentrations in virus-positive/antibody-negative macaques tended to remain elevated over a 4-20 month period. Post-mortem studies of 9 virus-positive/antibody-negative macaques and 6 virus-negative/antibody-positive macaques revealed inflammatory responses in the brains of 6 of 9 virus-positive/antibody negative macaques, including lymphocytic infiltrates of the choroid plexus in 3 macaques, glial nodules in 3 macaques and perivascular infiltrates in 1 macaque. These lesions were not extensive and no evidence of brain atrophy was observed. No lesions were observed in the 6 antibody-positive/virus-negative macaques. Small increases in plasma L-kynurenine in virus-positive/antibody-negative macaques are consistent with activation of indoleamine-2,3-dioxygenase, the first enzyme in the kynurenine pathway. We conclude that sustained moderate increases in CSF QUIN occur in viremic simian retrovirus type-D macaques. The increases in CSF QUIN may reflect inflammatory responses within the brain or synthesis of QUIN precursors in systemic tissues, their entry into brain and subsequent conversion to QUIN. The neuropathologic significance of these increases in CSF QUIN remains to be determined.

Animals↗
PubMed1990

Brain eicosanoid formation following acute penetration injury as studied by in vivo microdialysis.

Formation of eicosanoids has been implicated in the pathological changes that follow brain injuries. In the present study, we used a microdialysis probe to both induce acute penetration injury and also sample extracellular fluid concentrations of eicosanoids. Formation of prostaglandin (PG) D2, PGF2 alpha, and thromboxane B2 was highest in the first hour following introduction of the probe into rat striatum. In contrast, the level of PGE2 was highest during the sixth hour of collection, while 6-keto-PGF1 alpha remained stable throughout the sampling period. We conclude that in vivo microdialysis may be useful in the evaluation of the time course of the effects of acute penetration injury of the brain on the local production of eicosanoids.

Acute Disease↗
PubMed1989

Prostaglandins in cerebrospinal fluid of healthy human volunteers, abstinent alcoholics and rhesus monkeys.

A sensitive and selective assay for measuring prostaglandins in cerebrospinal fluid has been developed, based on the selected-ion-monitoring, electron-capture negative ionization GC/MS detection for the MO-PFB-TMS derivatives of prostaglandins E2, E1, F2 alpha, F1 alpha, and 6-keto-F1 alpha. Improvements over previously published assay procedures have been made, and the new assay has been applied to measurement of prostaglandin concentrations in lumbar CSF of healthy human volunteers, abstinent alcoholic patients, in cisternal CSF of Rhesus monkeys, and continuously sampled lumbar CSF of awake Rhesus monkeys. Results indicated that the concentrations of PGE2, PGE1, PGF1 alpha, and 6-keto-PGF1 alpha were below 15 pg/mL CSF in lumbar CSF of healthy humans and abstinent alcoholics, and in cisternal CSF of Rhesus monkeys. In contrast, continuously sampled lumbar CSF of awake Rhesus monkeys contained more than 200 pg/mL of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha, probably present as a result of local production.

Alcoholism↗
PubMed1988

GC/MS assay of prostaglandins in cerebrospinal fluid from humans and monkeys.

The objective of this project has been to develop a sensitive and specific assay for prostaglandins in human cerebrospinal fluid (CSF) from patients with alcoholism and appropriate controls using gas chromatography/mass spectrometry. This study was initiated because numerous literature reports strongly suggest that a relationship exists between ethanol's central nervous system effects and the central production of prostaglandins. In both human and animal studies, administration of prostaglandin synthesis inhibitors prior to administration of ethanol attenuated central nervous system effects of ethanol. Samples from alcoholics after a three week period of abstinence and normals contained none of the measured prostaglandins (PGE2, PGE1, PGF1a, PGF2a, 6-keto-PGF1a) at a concentration more than twice the limit of quantification (3 pg/mL CSF). Comparison of GC/MS and radioimmunoassay methods provided further validation for these results. Literature reports of much higher levels of prostaglandins in normal controls, i.e., tens to hundreds of pg/mL CSF, appear to be incorrect. Examination of monkey CSF provided a positive control, since several of the prostaglandins were easily quantifiable in these samples.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Discovery of novel brain lipoxygenase products formed from docosahexaenoic acid (22:6w3).

It is known that alcohol exposure leads to a decline in brain docosahexaenoate (22:6w3). We hypothesized that alcohol could stimulate the metabolism of this polyunsaturated fatty acid to bioactive products. Several oxidized products of 22:6w3 were indeed observed when rat brain homogenate was incubated with 14C22:6w3 in vitro. A similar group of metabolites was formed in vivo from 14C-22:6w3 injected into the lateral ventricle. These metabolites were characterized by thermospray- and GC/MS as well as by the synthesis of standards using purified enzymes. Platelet lipoxygenase also proved useful in identifying one of the brain metabolites and served as a source of enzyme for preparative studies. Their physiological effects on smooth muscle tone and platelet aggregation will be presented.

Animals↗
PubMed1988

Smooth muscle effects of hydroxylated docosahexaenoates produced from human platelet.

Washed platelets (10(8)cells/ml) are capable of metabolizing docosahexaenoic acid (22:6w3, DHE) to 12-lipoxygenase derivatives. The two major metabolites of the DHE thus formed were collected and derivatized for analysis by GC/MS/EI. The structures assigned were 14(S) and 11(S) hydroxy-docosahexenoate (HDHE). 12-lipoxygenase inhibitors such as ETYA inhibited the production of HDHE. The metabolites formed are biologically active as they are capable of inducing a weak contraction in airway but not vascular smooth muscle preparations; a thromboxane-agonist (U46619) was 10 to 20-fold more efficacious than HDHE in the guinea pig lung parenchymal strip. HDHE may act in part through stimulation of leukotriene production as increased peptidyl-leukotriene levels were associated with the HDHE-induced contraction in this preparation and a lipoxygenase inhibitor (NDGA) was capable of a partial blockade of this response. In addition, HDHE antagonizes the contractile effects of the thromboxane-agonist, U46619, especially in vascular smooth muscle. Stimulation of the sulfidopeptido leukotrienes and thromboxane antagonism may therefore be important aspects of the biological function of HDHE.

Animals↗
PubMed1987

Determination of eicosanoids, phospholipids and related compounds by thermospray liquid chromatography-mass spectrometry.

Thermospray mass spectrometry has proven to be a useful technique for analyzing various biological compounds including eicosanoids and phospholipids. Molecular ions as well as fragment ions which reveal useful structural information are produced for underivatized eicosanoids and phospholipids using filament-off or filament-on thermospray mass spectrometry, respectively. In conjunction with on-line chromatographic separation, complex mixtures of biological samples can be rapidly analyzed with great reliability. Data will be presented concerning the analysis of prostaglandins, other eicosanoids and molecular species of phospholipids as well as the application of these methodologies to complex biological samples.

Animals↗
PubMedDate not supplied

Quinolinic acid concentrations in brain and cerebrospinal fluid of patients with intractable complex partial seizures.

Quinolinic acid (QUIN) is a neurotoxin and convulsant when injected directly into the brains of experimental animals and as such has been implicated in the etiology of human seizure disorders. In the present study, we quantified QUIN in cerebrospinal fluid (CSF) and in spiking (focus) and nonspiking (nonfocus) regions of surgically resected human temporal neocortex. L-tryptophan (L-TRP), the putative precursor of QUIN, was also measured in brain, along with CSF concentrations of L-TRP, 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA). In brain tissue, no differences were found in the concentrations of QUIN and L-TRP between focus and nonfocus regions in 15 pairs of samples. No differences were found in CSF, L-TRP, 5-HIAA, or HVA concentrations between 11 neurologically normal controls and 15 interictal (no seizures for greater than 24 h) and 20 postictal (within 50 min of seizure) samples from epileptic patients. However, CSF QUIN concentrations were significantly lower (32%) in the epileptic patients as compared with controls, which may indicate a generalized disturbance in brain QUIN metabolism or perhaps a response to antiepileptic drugs.

Adolescent↗
PubMedDate not supplied

Characterization of verlukast metabolites arising from an epoxide intermediate produced with hepatic microsomes from beta-naphthoflavone-treated rodents (P-4501A1).

Verlukast, (R)3-((((3-(2-(7-chloroquinolin-2-yl)-(E)-ethenyl)phenyl)-3- dimethylamino-3-oxopropylthio)methyl)thio)-propionic acid (also known as MK-0679 and L-668,019), is a potent leukotriene D4 antagonist. Verlukast was incubated with hepatic microsomes from beta-naphthoflavone (beta NF) or isosafrole-treated rodents to evaluate whether P-4501A1 or 1A2 mediated biotransformations could occur. With beta NF-induced mouse or rat microsomes, in which the induction of P-4501A1 had been proven by Western blot analysis, incubations produced new metabolites that were separated by reversed-phase HPLC and were initially characterized by UV (photodiode array). Metabolites were subsequently isolated and characterized by NMR and MS, and were assigned as the 5",6"-dihydrodiol and 6"-phenol (on the quinoline ring). The presumed 5",6"-epoxide intermediate was also detected and was characterized by UV (photodiode array) and MS. Microsomes from isosafrole-treated rodents produced the dihydrodiol to a much lesser extent and did not yield any other new metabolites. alpha-Naphthoflavone inhibited the dihydrodiol formation in incubations with microsomes from isosafrole- and beta NF-treated rats. In incubations with microsomes from beta NF-treated rats, to which the epoxide hydrolase inhibitor 3,3,3-trichloropropene 1,2-oxide had been added, the formation of dihydrodiol was inhibited, consistent with a microsomal epoxide hydrolase hydrolysis of the epoxide intermediate. When glutathione was added to incubations with microsomes from beta NF-treated rats, the dihydrodiol, phenol, and epoxide peaks were reduced in size and a new material, the glutathione adduct, was formed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

CYP1A1 specificity of Verlukast epoxidation in mice, rats, rhesus monkeys, and humans.

It has previously been shown that Verlukast is converted to Verlukast dihydrodiol in microsomes from beta-naphthoflavone (BNF)-treated, but not uninduced Swiss Webster mice and Sprague-Dawley rats. We have examined the involvement of CYP1A1 in this reaction in more detail. It is concluded that this reaction is catalyzed exclusively by CYP1A1 in rats, mice, and humans based on the following criteria: 1) the epoxidation of Verlukast is negligible in uninduced rats, which express CYP1A2 but not CYP1A1; 2) Verlukast epoxidation is highly inducible by BNF treatment (60- to 200-fold); 3) Verlukast epoxidation in BNF-treated rat microsomes was inhibited by alpha-naphthoflavone (ANF) treatment, indicating that this activity was mediated by the CYP1A subfamily; 4) > 95% of Verlukast epoxidation in BNF-treated rat microsomes was inhibited by antibodies raised against CYP1A1; and 5) Verlukast was epoxidized by human CYP1A1 but not CYP1A2. Thus, Verlukast epoxidation appears to be specific for rat, mouse, and human CYP1A1. Additional studies showed that Verlukast was metabolized to Verlukast dihydrodiol in microsomes from uninduced rhesus monkeys. This reaction was inhibited by nanomolar concentrations of ANF in rhesus monkey microsomes implicating the involvement of the CYP1A subfamily. In addition, the 8-hydroxylation of R-warfarin, a pathway that is selective for rodent and human CYP1A1 activity, was also catalyzed at significant rates by rhesus monkey microsomes. These findings indicate that, unlike rats, mice, and humans, which have very low constitutive levels of hepatic CYP1A1 activity, the uninduced rhesus monkey is able to catalyze reactions specific to CYP1A1 in rodents and humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗