Biomedical subjects

H A Gelbard

Publications and source records attributed to H A Gelbard.

5 recordsLinked to original sources

PubMed1992

Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease.

Human immunodeficiency virus (HIV) infection of brain macrophages and astroglial proliferation are central features of HIV-induced central nervous system (CNS) disorders. These observations suggest that glial cellular interactions participate in disease. In an experimental system to examine this process, we found that cocultures of HIV-infected monocytes and astroglia release high levels of cytokines and arachidonate metabolites leading to neuronotoxicity. HIV-1ADA-infected monocytes cocultured with human glia (astrocytoma, neuroglia, and primary human astrocytes) synthesized tumor necrosis factor (TNF-alpha) and interleukin 1 beta (IL-1 beta) as assayed by coupled reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and biological activity. The cytokine induction was selective, cell specific, and associated with induction of arachidonic acid metabolites. TNF-beta, IL-1 alpha, IL-6, interferon alpha (IFN-alpha), and IFN-gamma were not produced. Leukotriene B4, leukotriene D4, lipoxin A4, and platelet-activating factor were detected in large amounts after high-performance liquid chromatography separation and correlated with cytokine activity. Specific inhibitors of the arachidonic cascade markedly diminished the cytokine response suggesting regulatory relationships between these factors. Cocultures of HIV-infected monocytes and neuroblastoma or endothelial cells, or HIV-infected monocyte fluids, sucrose gradient-concentrated viral particles, and paraformaldehyde-fixed or freeze-thawed HIV-infected monocytes placed onto astroglia failed to induce cytokines and neuronotoxins. This demonstrated that viable monocyte-astroglia interactions were required for the cell reactions. The addition of actinomycin D or cycloheximide to the HIV-infected monocytes before coculture reduced, > 2.5-fold, the levels of TNF-alpha. These results, taken together, suggest that the neuronotoxicity associated with HIV central nervous system disorders is mediated, in part, through cytokines and arachidonic acid metabolites, produced during cell-to-cell interactions between HIV-infected brain macrophages and astrocytes.

Animals↗

PubMed1991

Dopamine D1 autoreceptor function: possible expression in developing rat prefrontal cortex and striatum.

Synthesis-modulating dopamine (DA) autoreceptor function was studied in vivo using gamma-butyrolactone (GBL) to block propagation along DA axons. DA synthesis was measured by the accumulation of L-3,4-dihydroxyphenylalanine (L-DOPA) after inhibition of aromatic L-amino acid decarboxylase. GBL treatment markedly increased DOPA accumulation in both the striatum and prefrontal cortex of developing rats. The selective DA partial D1 agonist SKF-38393 inhibited this GBL-induced rise in DA synthesis in both the striatum and prefrontal cortex of 15- and 22-day-old rats, but not in adults. The effects of SKF-38393 in developing rats were mimicked by the non-catechol D1 partial agonist CY-208-243, and were blocked by the D1 antagonist SCH-23390, suggesting receptor mediation. The mixed D2/D3 agonist quinpirole attenuated DA synthesis in striatum of both two-week-old and adult rats, but failed to inhibit the GBL-induced increase in DA synthesis in the developing prefrontal cortex. These findings suggest that synthesis-modulating D1-like receptor function may emerge transiently in the developing mammalian forebrain. In the adult striatum these functions appear to be subsumed by D2-like receptors, whereas all synthesis-modulating DA receptor function in prefrontal cortex appears to be essentially lost with maturation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1991

Excitotoxicity and dopaminergic dysfunction in the acquired immunodeficiency syndrome dementia complex. Therapeutic implications.

Human immunodeficiency virus infection is frequently complicated by a syndrome of central nervous system dysfunction known as the acquired immunodeficiency syndrome dementia complex (ADC). The ADC is characterized by abnormalities in cognition, motor performance, and behavior, and it produces serious morbidity in a significant number of patients with acquired immunodeficiency syndrome. The pathogenesis of ADC is unclear, but appears to be caused by the human immunodeficiency virus itself, rather than by a secondary opportunistic process. Herein, we review the data regarding the pathogenesis of ADC and hypothesize a mechanism involving excitotoxicity and dopaminergic dysfunction. N-methyl-D-aspartate receptor antagonists may be of therapeutic benefit, as these agents may both limit glutamate-mediated neuronal dysfunction and improve dopaminergic neuronal function.

AIDS Dementia Complex↗

PubMed1990

Dopamine D1 receptor development depends on endogenous dopamine.

Profound depletion of forebrain dopamine by 6-hydroxydopamine in neonatal rats (day 3) was associated with up to 82% loss of D1 receptor sites labeled with [3H]SCH-23390 at day 21. Administration of the selective D1 agonist SKF-38393 (days 6-18) abolished the correlation between D1 receptor density and DA concentrations, even with greater than 99% depletion of DA. In intact control animals, there was an inverse correlation between spontaneous variation in levels of DA and D1 receptor site density in forebrain tissue (r = -0.79) which also was abolished by treatment with the D1 agonist. Thus, D1 receptor density may be regulated by reciprocal regulatory processes during normal development, but may fail to develop in the absence of an adequate level of stimulation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1989

Postnatal development of dopamine D1 and D2 receptor sites in rat striatum.

Tissue was obtained from corpus striatum of maturing rats at representative postnatal ages of 8-120 days for evaluation of D1 and D2 dopamine (DA) receptor sites in radioreceptor assays based on use of 0.05-2.5 nM concentrations of [3H]SCH-23390 or [3H]domperidone, respectively. Pharmacologic selectivity was verified by high rank-correlations (rs greater than 0.90) of Ki values for representative test agents in both assays (vs 0.3 nM ligand), using striatal tissue obtained at ages 20 and 120 days. Data from repeated (3-5x) six-concentration isotherm experiments involving a wide range of D1 or D2 radioligand concentrations were analyzed by linear regression of specific binding (B) vs free ligand concentration (F) in linearized form (B/F vs B) for each replicate assay and for pooled values, as well as by curve-fitting all available raw data (B vs F) using the LIGAND program adapted to microcomputer. Values for apparent ligand affinity (Kd = 0.15-0.35 nM) failed to show a consistent change with age, while values for apparent receptor site density (Bmax) followed a similar developmental course with both methods of analysis (between methods: r = 0.99 and 0.89 for D1 and D2 assays, respectively, across all ages tested).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗