Biomedical subjects
B Trapp
Publications and source records attributed to B Trapp.
Neuroprotective, anesthetic, and cardiovascular effects of the NMDA antagonist, CNS 5161A, in isoflurane-anesthetized lambs.
BACKGROUND: N-methyl-d-aspartate (NMDA) receptor antagonists are neuroprotective in animal models of cerebral ischemia, but adverse cardiovascular and neurobehavioral effects have precluded their clinical use. The authors present the neuroprotective, anesthetic, and cardiovascular effects of a novel NMDA antagonist, CNS 5161A. METHODS: Lambs, 4.0-6.5 kg, were anesthetized with isoflurane, intubated, and ventilated and had thermodilution catheters placed in the pulmonary artery and 20-g catheters placed in the femoral artery. The minimum alveolar concentration (MAC) of isoflurane was determined using the "bracketing technique." CNS 5161A was given as a bolus and then as an infusion at three doses. Cardiovascular measurements were determined every 15 min. Other lambs (n = 25) were subjected to cardiopulmonary bypass (CPB) with hypothermic circulatory arrest (HCA) for 120 min. Eighteen received CNS 5161A, and seven received saline vehicle. One hour after CPB, brains were perfusion-fixed and removed for in situ hybridization and immunohistochemistry analysis in half of the animals. The other half survived 48 h before their brains were examined for neuronal degeneration. RESULTS: Isoflurane at MAC significantly decreased blood pressure, heart rate, cardiac output, and systemic vascular resistance by 30-48% (n = 16; P < 0.05). CNS 5161A (n = 12) had no significant cardiovascular effects. All concentrations of CNS 5161A caused a significant reduction (21-29%) of the MAC of isoflurane (n = 12; P < 0.05). CNS 5161A, at serum concentrations greater than 25 ng/ml, completely inhibited c-fosmRNA and c-FOS protein expression in hippocampal neurons after 120 min of HCA, attenuated neuronal degeneration, and improved functional outcome by 47% (P < 0.05). CONCLUSIONS: CNS 5161A at neuroprotective concentrations before CPB-HCA significantly reduces the MAC of isoflurane without cardiovascular effects.
Myelin associated glycoprotein modulates glia-axon contact in vivo.
Myelin-associated glycoprotein (MAG) was postulated to play an important role in myelination. However, we showed previously that MAG null mutants exhibited no gross abnormality in myelination. Ultrastructural studies revealed subtle alterations in periaxonal organisation, indicating a restricted structural role for MAG in the formation and maintenance of periaxonal structures (Li et al., 1994). Here we show that myelination in MAG deficient mice is not as finely controlled as it is in wild type mice. The abnormalities manifest themselves as a decrease in the proportion of myelinated axons and a reciprocal increase in the proportion of unmyelinated axons in mutants' optic nerves. In addition, dysregulated myelination is occasionally observed in the form of multiply myelinated fibres, grouping of myelinated axons and myelin debris by a large myelin sheath, redundant myelin loops and, very rarely, massive myelin surrounding relatively small axons. Thus, in the absence of MAG, some glial cells seem unable to determine when, where and how much myelin should be laid down. These data support the notion of MAG being a glial recognition/adhesion molecule. A model is proposed regarding the roles MAG could play in the formation and maintenance of myelin structure.
Differential immediate-early gene expression in ovine brain after cardiopulmonary bypass and hypothermic circulatory arrest.
BACKGROUND: This study determined the induction profiles of immediate-early genes in the ovine brain after cardiopulmonary bypass (CPB) and hypothermic circulatory arrest (HCA), and the effects of the noncompetitive N-methyl-D-aspartate antagonist, aptiganel, on immediate-early gene expression, neuronal necrosis, and functional outcome. METHODS: Cannulas were inserted into isoflurane-anesthetized neonatal lambs undergoing CPB. One group received 2.5 mg/kg intravenous aptiganel. Animals underwent 90 or 120 min of HCA at 16 degrees C, were rewarmed to 38 degrees C, and were weaned from CPB. One hour after CPB was discontinued, brain perfusion was fixed and removed for immunohistochemical analysis in one half of the animals. The other half survived 2 or 3 days before their brains were evaluated for neuronal degeneration. Data were analyzed using analysis of variance; P < 0.05 was considered significant. RESULTS: Cardiopulmonary bypass and HCA differentially induced c-Jun and Fos proteins in the hippocampal formation, with c-Jun expression increasing with the duration of HCA, whereas Fos protein expressions were greatest after 90 min of HCA. The c-Jun protein was expressed in all neurons except the dentate gyrus. The Fos proteins were expressed in all neurons, including the dentate gyrus. Neuronal necrosis was observed in CA1 (73%) and CA3 (29%) neurons but not in the dentate gyrus after 120 min of HCA. Aptiganel completely inhibited c-Jun expression (P < 0.001) but not Fos, improved functional outcome, and attenuated neuronal necrosis (P < 0.05). CONCLUSIONS: The c-Jun and c-Fos proteins are expressed differentially in hippocampal neurons after CPB and HCA. Expression of c-Jun is associated with neuronal necrosis, whereas Fos protein expression is associated with survival. Aptiganel inhibits c-Jun expression, attenuates neuronal necrosis, and improves outcome.
Interferon action and apoptosis are defective in mice devoid of 2',5'-oligoadenylate-dependent RNase L.
2',5'-Oligoadenylate-dependent RNase L functions in the interferon-inducible, RNA decay pathway known as the 2-5A system. To determine the physiological roles of the 2-5A system, mice were generated with a targeted disruption of the RNase L gene. The antiviral effect of interferon alpha was impaired in RNase L-/- mice providing the first evidence that the 2-5A system functions as an antiviral pathway in animals. In addition, remarkably enlarged thymuses in the RNase L-/- mice resulted from a suppression of apoptosis. There was a 2-fold decrease in apoptosis in vivo in the thymuses and spleens of RNase L-/- mice. Furthermore, apoptosis was substantially suppressed in RNase L-/- thymocytes and fibroblasts treated with different apoptotic agents. These results suggest that both interferon action and apoptosis can be controlled at the level of RNA stability by RNase L. Another implication is that the 2-5A system is likely to contribute to the antiviral activity of interferon by inducing apoptosis of infected cells.
Overexpression of 2',3'-cyclic nucleotide 3'-phosphodiesterase in transgenic mice alters oligodendrocyte development and produces aberrant myelination.
The function of the intracellular protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) of oligodendrocytes (ODC) is unknown. We have now generated several homozygous transgenic mouse lines in which the human CNP gene is overexpressed up to sixfold, revealing new insights into early stages of myelinogenesis. Although no behavioral phenotype is immediately apparent, abnormalities of ODC and their myelin sheaths are striking. These are manifested as redundant myelin membrane and intramyelinic vacuoles, as well as lack of myelin compaction concordant with failure of the cytoplasmic leaflets of compact myelin to fuse. Further, ODC that overexpress CNP appear to mature earlier in development, resulting in earlier maximum gene expression for myelin basic proteins and proteolipid protein. These results indicate that CNP is an early expressed regulator of cellular events that culminate in CNS myelination.
Myelination in the absence of myelin-associated glycoprotein.
The hypothesis that myelin-associated glycoprotein (MAG) initiates myelin formation is based in part on observations that MAG has an adhesive role in interactions between oligodendrocytes and neurons. Furthermore, the over- or underexpression of MAG in transfected Schwann cells in vitro leads to accelerated myelination or hypomyelination, respectively. Here we test this idea by creating a null mutation in the mag locus and deriving mice that are totally deficient in MAG expression at the RNA and protein level. In adult mutant animals the degree of myelination and its compaction are normal, whereas the organization of the periaxonal region is partially impaired. Mutant animals show a subtle intention tremor. Our findings do not support the widely held view that MAG is critical for myelin formation but rather indicate that MAG is necessary for maintenance of the cytoplasmic collar and periaxonal space of myelinated fibres.
HLA class II molecules (HLA-DR, -DP, -DQ) on cells in the human CNS studied in situ and in vitro.
Human leucocyte antigen (HLA) class II molecules expressed by antigen-presenting cells (APC) are major restriction elements in the interaction between APC and T cells of the CD4+ subtype. To explore the immune accessory function of cells in the central nervous system (CNS), we studied the expression of HLA-DR, -DP, and -DQ molecules on CNS cells in situ and in vitro. Reactive microglia and perivascular cells in multiple sclerosis lesions expressed all three HLA class II molecules, whereas microglia in the normal CNS expressed HLA-DR only. All three HLA class II molecules were up-regulated on cultured microglia after stimulation with interferon-gamma (IFN-gamma). Microglial stimulation of allogeneic CD4+ T cells in a mixed lymphocyte reaction (MLR) was effectively blocked using anti-HLA-DR monoclonal antibodies (mAb) but not using anti-HLA-DQ mAb. HLA class II-positive astrocytes and endothelial cells were not identified in normal or diseased CNS. Cultured astrocytes stimulated with IFN-gamma could, however, be induced to express HLA class II antigens of all subtypes, although great variability was observed between different donors. Our results indicate that although both microglia and astrocytes are capable of expressing all HLA class II subtypes in vitro, subtype expression differs between normal and pathological states in situ. Such selective expression may be associated with functional properties.
An isoform of ankyrin is localized at nodes of Ranvier in myelinated axons of central and peripheral nerves.
Two variants of ankyrin have been distinguished in rat brain tissue using antibodies: a broadly distributed isoform (ankyrinB) that represents the major form of ankyrin in brain and another isoform with a restricted distribution (ankyrinR) that shares epitopes with erythrocyte ankyrin. The ankyrinR isoform was localized by immunofluorescence in cryosections of rat spinal cord gray matter and myelinated central and peripheral nerves to: (a) perikarya and initial axonal segments of neuron cells, (b) nodes of Ranvier of myelinated nerve with no detectable labeling in other areas of the myelinated axons, and (c) the axolemma of unmyelinated axons. Immunogold EM on ultrathin cryosections of myelinated nerve showed that ankyrinR was localized on the cytoplasmic face of the axolemma and was restricted to the nodal and, in some cases, paranodal area. The major isoform of ankyrin in brain (ankyrinB) displayed a broad distribution on glial and neuronal cells of the gray matter and a mainly glial distribution in central myelinated axons with no significant labeling on the axolemma. These results show that (a) ankyrin isoforms display a differential distribution on glial and neuronal cells of the nervous tissue; (b) an isoform of ankyrin codistributes with the voltage-dependent sodium channel in both myelinated and unmyelinated nerve fibers. Ankyrin interacts in vitro with the voltage-dependent sodium channel (Srinivasan, Y., L. Elmer, J. Davis, V. Bennett, and K. Angelides. 1988. Nature (Lond.). 333:177-180). A specific interaction of an isoform of ankyrin with the sodium channel thus may play an important role in the morphogenesis and/or maintenance of the node of Ranvier.
Neuropathological changes in early HIV-1 dementia.
Early pathological abnormalities in human immunodeficiency virus (HIV-1)-related dementia have not been well documented. We report a homosexual man with fatigue and intermittent diarrhea in whom early HIV-1-related dementia was demonstrated during neurological screening in the Multicenter AIDS Cohort Study. Within 4 months he died of massive epistaxis, and the brain revealed astrocytosis of white matter and mild pallor of myelin staining in the absence of inflammation, multinucleated giant cells, and brain atrophy.
Lyme-borreliosis and possible association with HLA-antigens.
The frequencies of HLA A, B, C and DR antigens were evaluated in 220 persons from West Germany with inapparent and manifest Borrelia burgdorferi infections. Thirty-seven forest workers showing elevated antibody titres against Borrelia burgdorferi had asymptomatic infection, and are described as stage 0. One hundred and eighty-three patients presented with the clinical stages 1-3 of the infection. Control persons (n = 655) were typed in the same time period and by identical staff. HLA CW3 was present in 36.3% of patients as compared to 23.2% of the controls (RR = 1.88, pcorr = 0.03) and was significantly associated with manifest infection. In addition, the antigen A2 was found slightly but not significantly more frequent in the patients (55.2% vs 44%; pcorr = 0.41). The phenotype combination HLA A2 and Cw3, however, was significantly elevated in patients (24.6% vs 10.8%; pcorr = 0.0005). In contrast to these class 1 antigens, HLA DR3 showed a tendency of negative association with manifest infection. But this finding was not yet found to be significant (15.3% vs 25.3%; RR = 0.53, pcorr = 0.26). The frequency of HLA DR2 showed a constant decrease from stage 0 to stage 3 (inapparent infection to late complications). Using the rank correlation coefficient of Spearman, this association was found to be significant (-1.00, p less than or equal to 0.05). All other tested HLA antigens and antigen combinations showed no significant differences. The data suggest that HLA CW3 may be associated with Borrelia burgdorferi infection, whereas HLA DR2 and DR3 may be associated with less incidence of severe courses and less complications in this disorder.
Congenital absence of peripheral myelin: abnormal Schwann cell development causes lethal arthrogryposis multiplex congenita.
We describe a 37-week gestational age infant who presented with lethal arthrogryposis multiplex congenita due to complete absence of peripheral nervous system (PNS) myelin. Schwann cells accomplished successful developmental proliferation, migration, axonal ensheathment, basal lamina production, and subsequent cessation of proliferation, but failed in spiral lengthening and longitudinal growth. Internuclear distance was very short, resulting in marked Schwann cell hypercellularity. No supernumerary Schwann cells (onion bulbs) were found. No PNS myelin proteins (P0, P1, MAG) were detected by immunocytochemical methods, and the Schwann cells adopted many morphologic features characteristic of unmyelinated nerves. The defect appears to be an arrest in Schwann cell differentiation at the stages of mesaxon elongation and longitudinal growth.
Modulation by fenoldopam (SKF 82526) and bromocriptine of the electrically evoked release of vasopressin from the rat neurohypophysis. Effects of dopamine depletion.
Single neurointermediate lobes were fixed by their stalks to a platinum wire electrode and incubated in Krebs-bicarbonate solution. Vasopressin release into the medium was determined by a radioimmunoassay. Vasopressin secretion was increased by electrical stimulation (15 Hz, 10 s trains with 10 s intervals for 10 min). Fenoldopam (SKF 82526) had a dual effect on vasopressin release, 30 nM decreasing (by 30%) and 3 microM increasing (by 32%) the evoked vasopressin secretion. The facilitatory effect of fenoldopam was antagonized in a concentration-dependent manner by flupenthixol but not by sulpiride. Sulpiride (1 microM) prevented the inhibitory effect of fenoldopam (30 microM). After pretreatment of the rats with the dopamine depleting agent, Ro4-1284 (2 mg/kg i.p. 1 h before the experiments), the evoked vasopressin release was decreased by 21% and the inhibitory effect of fenoldopam disappeared, but the facilitatory effect of fenoldopam was already seen at 30 nM. Similarly, bromocriptine (1-10 microM) decreased the evoked vasopressin release from untreated neurointermediate lobes by 30-40% but increased the vasopressin release by 30% after pretreatment with Ro4-1284. The present findings further support the concept that vasopressin from the neurohypophysis is modulated by dopaminergic mechanisms. Facilitatory effects are mediated via D 1 and inhibition via D 2 receptors. The presence of endogenous dopamine seems to be necessary for the inhibitory effects to occur.
Dopaminergic modulation of evoked vasopressin release from the isolated neurohypophysis of the rat. Possible involvement of endogenous opioids.
Explore the source record for details and available documents.