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Biomedical subjects

G S Hamilton

Publications and source records attributed to G S Hamilton.

At least 19 recordsLinked to original sources
PubMed2004

Obstructive sleep apnoea and cardiovascular disease.

Obstructive sleep apnoea (OSA) leads to both acute and chronic physiological effects on the cardiovascular system. There is now a large amount of evidence showing that OSA is independently associated with a wide spectrum of clinical cardiovascular disease (CVD). Evidence for a causative effect of OSA is strongest for hypertension, but is weaker for other cardiovascular disorders. Large prospective trials are ongoing and when results become available the link between OSA and CVD is likely to be strengthened. Treatment of OSA with continuous positive airway pressure has been shown to improve blood pressure, particularly in those with hypertension, and also left ventricular ejection fraction in those with congestive heart failure. Given the high prevalence of OSA in the community and its effects on the cardiovascular system, symptoms of this disorder should be sought in patients being investigated or treated for CVD.

Age Distribution↗
PubMed2002

The non-immunosuppressive immunophilin ligand GPI-1046 potently stimulates regenerating axon growth from adult mouse dorsal root ganglia cultured in Matrigel.

We used explant cultures of adult mouse dorsal root ganglia with spinal nerve attached growing in Matrigel to assess the effects of the non-immunosuppressive immunophilin ligand GPI-1046 [Snyder et al. (1998) TIPS 19, 21-26] on the growth rate of regenerating sensory axons and found a potent stimulation of axon growth. In these explant cultures, naked, unfasciculated axons emerge from the cut end of the spinal nerve and continue to grow in the Matrigel for up to eight days [Tonge et al. (1996) Neuroscience 73, 541-551]. Some axons are entirely smooth whilst others show prominent varicosities. Some of the former express the phosphorylated neurofilament epitope recognised by monoclonal antibody RT97, a marker for large calibre, myelinated axons, whilst the latter express calcitonin gene-related peptide, predominantly a marker for unmyelinated, and small diameter myelinated sensory axons. Many of the axons in these cultures also express the low-affinity neurotrophin receptor p75. GPI-1046 has been shown to have striking stimulatory effects on embryonic primary sensory axons growing in vitro and it was therefore of interest to see whether it could also enhance regenerating sensory axon growth from the adult ganglia in our cultures. GPI-1046 potently stimulated axon growth in our cultures in a dose-dependent manner. The stimulatory effect was not dependent on the class of sensory axon. These observations show that GPI-1046 is a potent stimulator of regenerating axons from adult, primary sensory neurones. The cellular site of action of GPI-1046 is unknown. To distinguish between a direct effect of the drug on neurones and an indirect effect we compared the effects of GPI-1046 on explant and dissociated cultures. In confirmation of previous results, we found that GPI-1046 potently stimulated axon outgrowth from explants of embryonic chick dorsal root ganglia. However, the drug was without effect on dissociated embryonic dorsal root ganglion neurones, suggesting that non-neuronal cells are important for axon growth stimulation.

Animals↗
PubMed2001

Regeneration of dopaminergic function in 6-hydroxydopamine-lesioned rats by neuroimmunophilin ligand treatment.

Nonimmunosuppressant immunophilin ligands have been found previously to stimulate neurite growth in culture and to promote regeneration of peripheral and central nerve fibers in vivo. To further characterize the effectiveness of these ligands, we have investigated the effect of the immunophilin ligand GPI-1046 in 6-hydroxydopamine (6-OHDA)-lesioned rats. In unlesioned rats, tetanic stimulation of the white matter induced long-term potentiation (LTP) of corticostriatal synaptic transmission as indicated by a 40-100% increase in the field potential amplitudes recorded in striatal brain slices. Unilateral microinjection of 6-OHDA into the substantia nigra resulted in a loss of corticostriatal LTP and in significant abnormality of motor behavior as assessed by amphetamine-induced ipsilateral rotations. Daily treatment of 6-OHDA-lesioned rats with GPI-1046 (10 mg/kg, s.c.) for 1 week reduced amphetamine-induced rotations by 75% and greatly restored the striatal tyrosine hydroxylase immunostaining. In addition, GPI-1046 almost completely restored corticostriatal LTP in 6-OHDA-lesioned animals. LTP in normal animals and that restored by GPI-1046 in lesioned animals were both blocked by the NMDA receptor antagonist APV, suggesting mediation by NMDA receptors. Both LTPs were sensitive to dopamine (DA) receptor antagonists. The nonselective DA receptor antagonist chlorpromazine and the selective D1-D5 receptor antagonist SCH23390 reduced the LTP by 90%. These results demonstrate that the immunophilin ligand GPI-1046 can reverse the abnormalities in the substantia nigra-striatal dopaminergic system that are caused by 6-OHDA, thus providing a potential therapeutic agent for Parkinson's disease.

Amphetamine↗
PubMed2001

The small molecule FKBP ligand GPI 1046 induces partial striatal re-innervation after intranigral 6-hydroxydopamine lesion in rats.

Extensive unilateral striatal deafferentation was produced by intranigral 6-hydroxydopamine (6-OHDA) in rats. Beginning 60 days after 6-OHDA injection animals received a 14-day course of treatment with either the small molecule FKBP ligand GPI 1046 (10 mg/kg) or its vehicle alone. Striatal dopaminergic innervation density was determined from high power image analysis of striatal tyrosine hydroxylase (TH) immunohistochemistry. GPI 1046 treatment did not alter TH fiber density in the contralateral striatum but did produce significantly higher striatal TH fiber density in the ipsilateral caudate-putamen. This striatal re-innervation occurred in the absence of increased nigral sparing, and appears to reflect the GPI 1046 induced sprouting of residual TH+ fibers spared by the 6-OHDA lesion.

Animals↗
PubMed1999

Systemic treatment with GPI 1046 improves spatial memory and reverses cholinergic neuron atrophy in the medial septal nucleus of aged mice.

Systemic treatment with GPI 1046, a non-immunosuppressive ligand of the immunophilin FKBP12 (FK-506-binding protein 12 kDa), has previously been shown to promote morphological recovery of the nigrostriatal dopaminergic projection after MPTP lesion in mice, and of lesioned sciatic nerve fibres after nerve crush in rats. In the present study, we investigated whether chronic systemic treatment with GPI 1046 could affect the decline of spatial learning and memory, and the atrophy of medial septal cholinergic neurons, associated with late senescence in C57 black mice. Three-month old (young) and 18-19-month old (aged) male C57BL/6N-Nia mice were first trained in a place learning task in the Morris water maze. Based on their performance relative to young controls, aged animals were then allocated to treatment groups (10 mg/kg GPI 1046, or vehicle). Retention of the spatial platform location was assessed after 3 weeks of dosing. We found that aged animals that had been dosed with GPI 1046 now performed at a significantly better level than their vehicle control group. Aged animals that had shown the greatest degree of impairment during training in the place learning task showed the greatest relative degree of improvement under treatment and were statistically indistinguishable from young, or aged unimpaired control animals. Cell volumes of cholinergic cells in the medial septal nucleus were assessed after an additional 10 months of dosing at 30 months of age, using stereological methods. We found that aged animals displayed a significant 34% decrease in volume of these cells relative to young controls. This atrophy was significantly reversed in aged GPI 1046-treated animals (13% shrinkage). We conclude that chronic systemic treatment with GPI 1046 positively affects memory mechanisms in the aged mouse, possibly by acting on the septohippocampal cholinergic system.

Aging↗
PubMed1998

Autocrine-paracrine regulation of human trophoblast invasiveness by insulin-like growth factor (IGF)-II and IGF-binding protein (IGFBP)-1.

Trophoblast growth and invasion of the uterus are tightly regulated by locally produced factors. Since insulin-like growth factor (IGF)-II is produced by the invasive human extravillous trophoblast (EVT) cells and IGF-binding protein (IGFBP)-1 by the decidual cells in situ that are in proximity to each other, we examined the possible influence of these molecules on proliferation, migration, and invasiveness of first-trimester EVT cells in culture. These EVT cell functions were respectively measured by 3H-TdR uptake, in vitro migration, and invasion assays. Secretion of invasion-associated enzymes was assessed by zymography, and IGF-binding moieties on the EVT cell were examined by affinity cross-linking. Proliferation of serum-starved EVT cells was stimulated by addition of serum but unaffected by a wide range of IGF-I, IGF-II, and IGFBP-1 concentrations. IGF-II and IGFBP-1 or their combination stimulated EVT cell invasiveness and migration, when assays were conducted in serum-reduced media. Affinity cross-linking studies failed to detect the type 1 IGF receptor, although several IGF-II-specific and IGF-II-preferring binding molecules including type 2 IGF receptor were identified on the EVT cell surface. IGF-II enhancement of invasion was unaffected in the presence of IGF-1 receptor-blocking antibody and IGF-1 failed to influence EVT cell invasion, indicating that type 1 IGF receptor was not responsible for the IGF-II effects. Secretion of gelatinases or plasminogen activators was unaltered by IGF-II or IGFBP-1. We conclude that trophoblast-derived IGF-II and decidua-derived IGFBP-1 provide autocrine/paracrine enhancement of trophoblast invasiveness largely by stimulating migration, an essential step in invasion.

Antibodies↗
PubMed1998

SV40 Tag transformation of the normal invasive trophoblast results in a premalignant phenotype. I. Mechanisms responsible for hyperinvasiveness and resistance to anti-invasive action of TGFbeta.

Invasion of the uterus by first trimester human placental extravillous trophoblast (EVT) cells depends on mechanisms shared by malignant cells. However, unlike tumor invasion, trophoblast invasion of the uterus is stringently controlled in situ by local molecules such as transforming growth factor (TGF)beta. Since EVT cells possess active invasion-associated genes but are nontumorigenic, our objective was to induce premalignant and then malignant phenotype into a normal EVT cell line in order to identify the molecular basis of tumor progression. Simian virus 40 large T antigen (SV40 Tag) was introduced into a normal human first trimester invasive EVT cell line, HTR8, established in our laboratory. Since the HTR8 line has a limited in vitro lifespan of 12-15 passages, SV40 Tag-transformed cells were selected on the basis of extended lifespan. A long-lived line, RSVT-2, was produced and an immortalized subclone, RSVT2/C, was further derived under a forced crisis regimen. We examined transformation-induced alterations in proliferative and invasive abilities, responses to the invasion and proliferation-regulating growth factor TGFbeta and changes in gene expression for invasion-associated enzymes or enzyme inhibitors. RSVT-2 and RSVT2/C cell lines were hyperproliferative and hyperinvasive when compared with the parental HTR8 cell line. They were also variably resistant to the anti-proliferative and anti-invasive signals from TGFbeta. Since both cell lines remained non-tumorigenic in nude mice, these properties indicate that they attained a premalignant phenotype. Both cell lines showed reduced expression of tissue inhibitor of metalloproteases (TIMP)-1, while TIMP-2 and plasminogen activator inhibitor (PAI)-I expression was was also reduced in RSVT2/C cells, thus contributing to their hyperinvasiveness. Their resistance to the anti-invasive action of TGFbeta was explained by the failure of TGFbeta to upregulate TIMPs and PAI-I, in contrast to the TGFbeta-induced upregulation noted in parental HTR8 cells.

Animals↗
PubMed1998

Neural actions of immunophilin ligands.

Immunophilins, protein receptors for immunosuppressant drugs such as cyclosporin A and FK506, are enriched far more in the brain than in the immune system. Drug-immunophilin complexes bind to calcineurin, inhibiting its phosphatase activity and leading to immunosuppressant effects. The immunophilin FKBP-12 (FK506 binding protein, 12 kDa) forms a complex with the ryanodine and inositol (1,4,5) trisphosphate (IP3) receptors to regulate their physiological release of intracellular Ca2+. Here, Solomon Snyder and colleagues describe how non-immunosuppressant as well as immunosuppressant immunophilin ligands are neurotrophic for numerous classes of damaged neurones, both in culture systems and intact animals. Their ability to stimulate functional regrowth of damaged sciatic, cortical cholinergic, dopamine and 5-HT neurones may have therapeutic relevance.

Animals↗
PubMed1998

Vascular endothelial growth factor stimulates proliferation but not migration or invasiveness in human extravillous trophoblast.

Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein that promotes angiogenesis and vascular hyperpermeability and interacts with two receptors, fms-like tyrosine kinase (Flt-1) and kinase domain-containing region (KDR). In situ localization in the pregnant human uterus revealed that VEGF mRNA is expressed primarily by the maternal decidua, whereas the receptor Flt-1 is expressed primarily by chorionic vascular endothelium and trophoblast cells-in particular, the extravillous trophoblast (EVT). We examined whether the mRNA and protein of VEGF and its receptors are expressed by invasive human first-trimester EVT cells propagated in culture and whether VEGF influences EVT cell proliferation, migration, and invasiveness. Proliferation was assessed by the uptake of [3H]thymidine. Invasion and migration across transwells were assessed by the degree of cellular transgression of a Millipore membrane coated, respectively, with and without Matrigel. Results of immunocytochemical and reverse transcription-polymerase chain reaction analysis revealed that both protein and mRNA of VEGF, Flt-1, and KDR were expressed by cultured normal EVT cells as well as their premalignant derivative produced by SV-40 Tag-immortalization, and BeWo choriocarcinoma cells. Under serum-free conditions, exogenous VEGF121 (the non-heparin-binding isoform) stimulated proliferation of all three cell lines in a concentration-dependent manner. The effects were abolished with a VEGF-neutralizing antibody. The same stimulatory effects on EVT cells were also seen with exogenous VEGF165 (a heparin-binding isoform), only after a cleaving of the heparin-binding domain with plasmin or a blocking of heparin binding sites with excess soluble heparan sulphate proteoglycans (HSPGs), suggesting a regulatory role of HSPGs. However, VEGF121 and VEGF165 (with and without the HSPG pretreatment) had no effect on normal EVT cell migration or invasiveness. Thus, VEGF may provide a dual role in angiogenesis and EVT cell proliferation during normal placental development.

Cell Division↗
PubMed1998

Effects of colony stimulating factor-1 on human extravillous trophoblast growth and invasion.

Colony stimulating factor (CSF)-1 has been localized in a variety of tissues and shown to influence proliferation and differentiation of numerous cell types. Messenger RNA and protein products of CSF-1 and its receptor (c-fms) have been identified in the human placenta and decidua. We examined whether CSF-1 and c-fms mRNA and protein are expressed by normal human first trimester invasive extravillous trophoblast (EVT) cells propagated in culture and whether CSF-1 influences proliferation and/or invasion of these cells. CSF-1 mRNA and protein expression was determined by RT-PCR and immunofluorescence microscopy. Proliferation was assessed by the cellular uptake of tritiated thymidine and invasion was evaluated by Matrigel invasion assay as well as Northern blot analysis of mRNA expression for invasion-associated enzymes and their inhibitors. Results revealed that normal invasive EVT cells in culture express both CSF-1 and c-fms mRNA and protein. Under serum-free conditions, exogenous CSF-1 greatly stimulated the proliferation of these cells. CSF-1 neutralizing and c-fms receptor blocking antibody (Ab) each abolished the growth stimulatory effects of CSF-1, indicating that CSF-1 and c-fms interaction was responsible for these effects. In fact, c-fms Ab alone reduced proliferation to below background levels. While exogenous CSF-1 failed to influence EVT cell invasiveness, Northern blot analysis of mRNA indicated a slight upregulation of the invasion-associated enzyme 72 kDa type IV collagenase as well as its natural inhibitor tissue inhibitor of metalloprotease (TIMP)-1, so that the balance between the two remained unaltered. These findings suggest that CSF-1 may represent an autocrine (and possibly paracrine) growth stimulatory factor for the invasive trophoblast cells in situ with no net effect on their invasiveness.

Analysis of Variance↗
PubMed1997

Neurotrophic immunophilin ligands stimulate structural and functional recovery in neurodegenerative animal models.

Although immunosuppressant immunophilin ligands promote neurite outgrowth in vitro, their neurotrophic activities are clearly independent of their immunosuppressive activity. In the present report, a novel nonimmunosuppressive immunophilin ligand, GPI-1046 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate+ ++) is described. In vitro, GPI-1046 bound to FK506 binding protein-12 and elicited neurite outgrowth from sensory neuronal cultures with picomolar potency with maximal effects comparable to nerve growth factor. In vivo, GPI-1046 stimulated the regeneration of lesioned sciatic nerve axons and myelin levels. In the central nervous system, GPI-1046 promoted protection and/or sprouting of serotonin-containing nerve fibers in somatosensory cortex following parachloroamphetamine treatment. GPI-1046 also induced regenerative sprouting from spared nigrostriatal dopaminergic neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice or 6-hydroxydopamine (6-OHDA) toxicity in rats. The rotational abnormality in 6-OHDA treated rats was alleviated by GPI-1046. These neurotrophic actions in multiple models suggest therapeutic utility for GPI-1046 in neurodegenerative diseases.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin A.

We show that the nonimmunosuppressive analogues of the immunosuppressive drugs FK506, rapamycin and cyclosporin A promote neurite outgrowth both in PC12 cells and sensory neuronal cultures of dorsal root ganglia with potencies resembling their immunosuppressive homologues. Neurotrophic potencies of the immunophilin ligands resemble their potencies in binding to and inhibiting the rotamase activity of FKBP-12 of cyclophilin. Since nonimmunosuppressive immunophilin ligands, which are devoid of calcineurin inhibitory activity, are equally neurotrophic, inhibition of calcineurin activity is not the mediator of the neurotrophic effects. The immunophilin ligands are neurotrophic in intact animals. FK506 and L-685,818 (the C18-hydroxy, C21-ethyl derivative of FK506) treatment of rats with crushed sciatic nerves enhances both functional and morphologic recovery. The striking potency of these agents, their bioavailability and the dissociation of neurotrophic from immunosuppressant actions argue for their therapeutic relevance in the treatment of neurodegenerative diseases.

Animals↗
PubMed1996

Novel anti-inflammatory compounds prevent CD11b/CD18, alpha M beta 2 (Mac-1)-dependent neutrophil adhesion without blocking activation-induced changes in Mac-1.

Leumedins are small organic molecules with anti-inflammatory properties in vivo. We report here that leumedins inhibit the CD11b/CD18 alpha M beta 2 (Mac-1)-dependent adherence of neutrophils to serum proteins. The activation of neutrophils leading to adherence via Mac-1 is associated with an increase in cell surface Mac-1 level, and with an increased affinity of Mac-1 for adhesion partners. Inhibition of neutrophil adherence by leumedins does not require blocking the recruitment of Mac-1 from intracellular granules to the cell surface. Furthermore, leumedins do not block the expression on Mac-1 of the epitope for an "activation-specific" antibody (CBRM1/5). Time course studies show that leumedins inhibit adherence by targeting an event which occurs concurrently with changes in Mac-1 level and induction of the CBRM1/5 epitope. Therefore, leumedins block an unknown process which is permissive for Mac-1-dependent adherence.

Amino Acid Sequence↗
PubMed1995

Fluorenylalkanoic and benzoic acids as novel inhibitors of cell adhesion processes in leukocytes.

A series of fluoren-9-ylalkanoic and alkylbenzoic acids was prepared as simplified analogues of a previously reported series of antiinflammatory agents which act to inhibit neutrophil recruitment into inflamed tissue. The previous compounds ("leumedins") contained (alkoxycarbonyl)amino or benzoic acid moieties tethered to a fluorene ring. This functionality was replaced with simple structural elements. The new compounds were, in general, found to be more potent than the earlier series at inhibiting adherence of neutrophils to serum-coated wells or endothelial cells in vitro. Compound 9 was approximately 10-fold more potent than the previously reported FMOC-phenylalanine, of which it is an analogue. Similarly, compound 19 was superior in potency to its first generation progenitor, NPC 16570. The new compounds were shown to inhibit neutrophil adherence under conditions in which adherence is mediated by Mac-1 (CD11b/CD18) and LFA-1 (CD11a/CD18); they thus appear to target beta 2-integrins in their antiadhesion activity. These compounds provide a departure point for the further development of new cell adhesion inhibitors which should exhibit enhanced potency and a more selective mode of action.

Benzoates↗
PubMed1994

Uterine vascular changes after unilateral intrauterine infusion of indomethacin and prostaglandin E2 to rats sensitized for the decidual cell reaction.

Uterine extracellular fluid volume (ECFV), vascular permeability (VP), and blood flow (BF) were assessed after unilateral infusion of PBS, 0.05 mM indomethacin (IM), or IM plus 1 mg/ml prostaglandin (PG) E2 (PGE2) into uteri of rats sensitized for decidualization. The study was intended to determine the importance of PGE2 in mediating uterine vascular changes during early decidualization. Uterine ECFV was assessed by the uterine volume of distribution of 51Cr-EDTA, and uterine VP by the rate of change of the uterine volume of distribution of 125I-albumin, after i.v. injection of the respective tracers. Uterine BF was determined by the radioactive microsphere technique. ECFV and VP were significantly higher in infused than in control horns after both 10 and 20 h of PBS infusion (p < 0.05). Infusion of IM abolished these vascular changes while coinfusion of PGE2 with IM returned ECFV and VP to levels not significantly different from those associated with PBS infusion. Infusion of PBS resulted in proportionate increases in both uterine weight and total uterine BF for infused horns (p < 0.05) whereas neither of these variables changed after infusion of IM. Infusion of IM+PGE2 resulted in significantly reduced tissue BF (in microliter/min/mg) to infused horns because increases in uterine weights were not matched by proportionate increases in total BF. We conclude that PGs are essential for the increases in uterine VP and ECFV that precede endometrial decidualization and that PGE2 is sufficient to accomplish these vascular changes. Whereas PGs appear necessary for the increases in total uterine BF that maintain constant tissue BF during early decidualization, PGE2 alone does not appear to serve this function.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Uterine vascular permeability after uterine stimulation to rats differentially sensitized for the decidual cell reaction.

Uterine vascular permeability (VP) was assessed after unilateral intrauterine injection of sesame oil to rats given either optimal sensitization for the decidual cell reaction or one of several forms of suboptimal sensitization. The study was intended to determine the relationship between changes in uterine VP and imminent endometrial decidualization. Uterine VP was estimated by the rate at which the uterine volume of distribution of i.v. injected 125I-labeled albumin approached the uterine extracellular fluid volume (ECFV). When ideal sensitization was provided, uterine VP was significantly greater in stimulated than nonstimulated horns at 4, 8, 16, and 32 h after stimulation (p < 0.05). Maximum VP in stimulated horns occurred at 8 h, with the time for the 125I-labeled albumin volume to reach half the uterine ECFV (t1/2) estimated to be 30 min. Different types of sensitization resulted in different levels of uterine VP in stimulated and nonstimulated horns, with maximal VP occurring in stimulated horns of rats that had previously received optimal sensitization for decidualization. We conclude that endometrial decidualization is preceded by significant increases in uterine VP and that optimal sensitization promotes an optimal VP response.

Animals↗