Biomedical subjects

B Tavitian

Publications and source records attributed to B Tavitian.

26 records · Page 2Linked to original sources

PubMed1993

Positron emission tomography study of [11C]methyl-tetrahydroaminoacridine (methyl-tacrine) in baboon brain.

THA (1,2,3,4-tetrahydro-9-amino-acridine, tacrine), a potential therapeutic agent for patients suffering from Alzheimer's disease, has multiple pharmacological sites of action in the brain. In order to study the cerebral binding sites of THA in vivo, we labeled a close derivative of THA with carbon 11 for positron emission tomography (PET) analysis. We report the biodistribution of this compound, 1,2,3,4-tetrahydro-9-[11C]methylaminoacridine ([11C]MTHA), in the rodent and describe the first PET experiments in non-human primates. The distribution of [11C]MTHA in baboon brain, although rather diffuse in the gray matter, showed a higher concentration in the cortex and basal ganglia than in the cerebellum and binding could be displaced (50%) by cold THA. These results suggest that [11C]MTHA is a promising PET ligand for the study of the cerebral binding of THA.

Acetylcholinesterase↗

PubMed1993

In vivo visualization of acetylcholinesterase with positron emission tomography.

The cerebral distribution of [11C]physostigmine, an acetylcholinesterase inhibitor, was studied with autoradiography in rats and positron emission tomography in primates. In rat brain [11C]physostigmine radioactivity was exactly superimposable to acetylcholinesterase activity, being highest in the basal ganglia, moderate in the cortex and hippocampus, and low in the cerebellum. In primate brain, the early blood-flow dependent distribution of [11C]physostigmine was followed by a rapid redistribution to acetylcholinesterase-rich regions such as the striatum. The cerebral uptake of [11C]physostigmine was significantly reduced by competition with an excess of unlabeled physostigmine. These results suggest that [11C]physostigmine is a promising new ligand for in vivo imaging of acetylcholinesterase activity with PET.

Acetylcholinesterase↗

PubMed1992

Localization of the ras-like rab3A protein in the adult rat brain.

Rab3A is a small GTP-binding synaptic vesicle protein, shown to dissociate from synaptic vesicle membranes upon depolarization-induced exocytosis. Using an antiserum raised against rab3A, we found that the antigen was localized to the neuropil of specific brain regions, but was not present in major fiber tracts or most cell bodies. For example, the neuropil of several thalamic nuclei (i.e., dorsal lateral geniculate nucleus, lateral posterior nucleus, ventroposterior nucleus), cerebral cortex, upper layers of the superior colliculus and matrix zones of the neostriatum, were strongly immunoreactive, while the anterior commissure, corpus callosum, optic tract and internal capsule were devoid of staining. The hippocampus, regions of cerebral cortex and the cerebellum exhibited striking laminar distributions of rab3A immunoreactivity. In the hippocampus, dark staining was observed in the stratum oriens, stratum radiatum and molecular layer of the dentate gyrus, while the pyramidal, stratum lacunosum moleculare and dentate granule layers were not stained. In cerebellum the molecular layer and to a lesser extent, the underlying granule cell layer showed enhanced immunoreactivity. Seven days after excitotoxic lesions of the cerebral cortex, rab3A immunoreactivity was diminished in the mirror locus in the contralateral cortical hemisphere and in certain thalamic nuclei ipsilateral to the injection site. These results show that rab3A is localized to a number of specific regions. Its absence from other areas suggests that this synaptic vesicle protein is not universal to all neuronal terminals and pathways. In addition, our lesion studies indicate that for some brain regions, much of the antigen originates in cortical neurons and is distributed within specific axonal projections.

Animals↗

PubMed1991

Axonal transport reversal of acetylcholinesterase molecular forms in transected nerve.

Reversal of anterograde rapid axonal transport of four molecular forms of acetylcholinesterase (AChE) was studied in chick sciatic nerve during the 24-h period following a nerve transection. Reversal of AChE activity started approximately 1 h after nerve transection, and all the forms of the enzyme, except the monomeric ones, showed reversal of transport. The quantity of enzyme activity reversed 24 h after transection was twofold greater than that normally conveyed by retrograde transport. We observed no leakage of the enzyme at the site of the nerve transection and no reversal of AChE activity transport in the distal segment of the severed nerve, a result indicating that the material carried by retrograde axonal transport cannot be reversed by axotomy. Thus, a nerve transection induces both quantitative and qualitative changes in the retrograde axonal transport, which could serve as a signal of distal injury to the cell body. The velocity of reverse transport, measured within 6 h after transection, was found to be 213 mm/day, a value close to that of retrograde transport (200 mm/day). This suggests that the reversal taking place in severed sciatic nerve is similar to the anterograde-to-retrograde conversion process normally occurring at the nerve endings.

Acetylcholinesterase↗

PubMed1988

Axonal transport of the molecular forms of acetylcholinesterase in rats at the onset of diabetes induced by streptozotocin.

During the development of streptozotocin-induced diabetic neuropathy in the rat, the axonal transport of 4 acetylcholinesterase molecular forms was studied by measuring their accumulation on both sides of transected sciatic nerves. Our results indicate that both the anterograde and retrograde axonal transport of all these forms remain normal between 2 and 5 weeks after the induction of diabetes by streptozotocin injection.

Acetylcholinesterase↗

PubMed1986

Slow and fast axonal transport of acetylcholinesterase molecular forms in polyarthritic rats.

Acetylcholinesterase (AChE) activity and its distribution among different molecular forms were studied in the sciatic nerve of normal and polyarthritic rats. Axonal transport of each form was investigated on the basis of its accumulation on both sides of a transection. Although an increase in total AChE activity could be detected in the sciatic nerves of polyarthritic animals, both anterograde and retrograde axonal transport of all the molecular forms investigated were similar in normal and polyarthritic rats. This suggests that neither slow nor fast axonal transport is impaired in polyarthritic rats. Hence, the neurophysiological modifications observed at the spinal, thalamic and cortical levels of the CNS are presumably not a consequence of peripheral axonal disability.

Acetylcholinesterase↗

PubMedDate not supplied

Aptamers against extracellular targets for in vivo applications.

Oligonucleotides are multifunctional molecules which can interfere with gene expression by different mechanism such as antisense, RNA interference, ribozymes, etc. For most in vivo diagnostic and therapeutic applications, oligonucleotides need to be delivered to the intracellular compartment of a specific organ, a difficult task which limits considerably their use. However, aptamer oligonucleotides which target extracellular markers obviate this problem. Aptamers are short oligonucleotides (<100 bases) selected from large combinatorial pools of sequences for their capacity to bind to many types of different targets, ranging from small molecules (amino acids, antibiotics...) to proteins or nucleic acid structures. Aptamers present the same high specificity and affinity for their targets as antibodies. In addition to efficient binding, aptamers have been shown in many cases to display an inhibitory activity on their targets. Moreover, they seem to lack immunogenicity and can be chemically modified in order to improve their stability against nucleases or extend their blood circulation time, two properties which are particularly useful for in vivo applications. Recently, aptamers have been selected against whole living cells, opening a new avenue which presents three major advantages 1) direct selection without prior purification of the targets; 2) conservation of membrane proteins in their native conformation similar to the in vivo conditions and 3) identification of (new) targets for a specific phenotype. Many aptamers are now being developed against biomedical relevant extracellular targets: membrane receptor proteins, hormones, neuropeptides, coagulation factors... Among them, one aptamer that inhibits the human VEGF165 has recently been approved by FDA for the treatment of age-related macular degeneration. Here we discuss the recent developments of aptamers against extracellular targets for in vivo therapy and as tools for diagnosis using molecular imaging.

Autoimmune Diseases↗

PubMedDate not supplied

General method to label antisense oligonucleotides with radioactive halogens for pharmacological and imaging studies.

Evaluation of oligonucleotides for biomedical applications requires different in vivo and in vitro approaches (pharmacokinetics, biodistribution, macro- and microimaging, metabolism,.), that are performed with different radioisotopes according to the temporal and spatial resolution needed. A method to introduce radioactive isotopes of halogens (fluorine, bromine, and iodine) in a small and stable molecule has been developed. Radiosynthons can then be conjugated with any given oligonucleotide in one step to create the appropriate radiotracer. This general radiolabeling procedure for oligonucleotides is efficient to synthesize (18)F-, (76)Br-, and (125)I-oligonucleotides for biological needs. Applications of the method to biodistribution, metabolism, in vivo and ex vivo imaging of (125)I- and (18)F-labeled oligonucleotides are reported.

Animals↗