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T Woolf

Publications and source records attributed to T Woolf.

10 recordsLinked to original sources
PubMed1995

Induction of dopaminergic neuron phenotype in the midbrain by Sonic hedgehog protein.

Loss of substantia nigra dopaminergic neurons, which develop from the ventral region of the midbrain, is associated with Parkinson's disease. During embryogenesis, induction of these and other ventral neurons is influenced by interactions with the induction of mesoderm of the notochord and the floor plate, which lies at the ventral midline of the developing CNS. Sonic hedgehog encodes a secreted peptide, which is expressed in notochord and floor plate cells and can induce appropriate ventral cell types in the basal forebrain and spinal cord. Here we demonstrate that Sonic hedgehog is sufficient to induce dopaminergic and other neuronal phenotypes in chick mesencephalic explants in vitro. We find that Sonic hedgehog is a general ventralizing signal in the CNS, the specific response being determined by the receiving cells. These results suggest that Sonic hedgehog may have utility in the induction of clinically important cell types.

Animals↗
PubMed1990

Activins are expressed early in Xenopus embryogenesis and can induce axial mesoderm and anterior structures.

We show that mammalian and Xenopus activins induce dorsal axial mesoderm and anterior structures in explants of Xenopus blastula cells that would otherwise form epidermis. The induced explants of animal cap cells can form notochord, muscle, neural tissue, and eyes all arranged in a rudimentary axial pattern. Activin A shares inductive properties and antigenic determinants with PIF, an inducing factor recently isolated from mouse macrophage culture supernatants. Genes encoding Xenopus activin beta A and beta B chains were cloned. Activin beta B transcripts are first detected in Xenopus blastula, whereas activin beta A transcripts do not appear until the late gastrula stage. Recombinant Xenopus activin beta B protein induces mesodermal and neural tissues similar to those induced by mammalian activin A and PIF. Furthermore, ectopic expression of Xenopus activin beta B produces a second body axis in embryos injected with synthetic mRNA. Our results suggest that early induction and axial patterning are accomplished by endogenous activin B, not activin A, in Xenopus.

Activins↗
PubMed1990

Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats.

In vivo metabolic studies have revealed that haloperidol is converted to the corresponding pyridinium metabolite which has been characterized in both urine and brain tissues isolated from haloperidol treated rats. Unlike the corresponding conversion of the structurally related Parkinsonian inducing agent MPTP to the ultimate neurotoxic pyridinium metabolite MPP+, the oxidative biotransformation of haloperidol is not catalyzed by MAO-B. Microdialysis studies in the rat indicate that intrastriatal administration of this pyridinium metabolite is about 10% as effective as MPP+ in causing the irreversible depletion of striatal nerve terminal dopamine. The results point to the possibility that some of the neurological disorders observed in experimental animals and man during the course of chronic haloperidol treatment may be mediated by this pyridinium metabolite.

Animals↗
PubMed1988

Mapping genomic organization by field inversion and two-dimensional gel electrophoresis: application to the murine T-cell receptor gamma gene family.

A new two-dimensional gel electrophoresis technique has been developed for the mapping of multigene families. Resolution in the first dimension is based on the generation of large size DNA fragments by infrequently-cutting restriction enzymes, and separation of these fragments by field inversion gel (FIG) electrophoresis. A second restriction enzyme digestion is then carried out with the separated DNA fragments in the agarose gel. Standard gel electrophoresis in the second dimension allows one to estimate the number of hybridizing genes contained in each large DNA fragment. We have also developed a novel method to increase the separation, resolution and hybridization signal in the second dimension by condensing the bands from the first dimension into spots. As an example, we have applied these techniques to determine the organization of the murine T-cell receptor gamma locus. The murine gamma gene family was found to be contained on two DNA fragments encompassing 195 kilobases of DNA. The two-dimensional gel electrophoresis method is particularly useful in the analysis of the organization of multigenic families where single copy probes are not readily available, and should extend the potential usefulness of field inversion gel electrophoresis in gene mapping.

Animals↗
PubMedDate not supplied

Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite.

Evidence that partially oxidized piperidine derivatives such as the Parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are biotransformed in a reaction catalyzed by monoamine oxidase B (MAO-B) to neurotoxic pyridinium metabolites led to studies resulting in the identification of the haloperidol-derived pyridinium metabolite in the urine of drug-treated rats. The present in vitro studies examine the metabolic pathway governing this overall four-electron oxidation. Although haloperidol and its 1,2,3,6-tetrahydropyridine dehydration product were not substrates for purified bovine liver MAO-B, both compounds were biotransformed to the pyridinium product by rat liver microsomal preparations. The dependence on NADPH and the inhibition by SKF-525A argue that one or more liver cytochrome P-450 isozymes may catalyze this transformation. Attempts to detect possible metabolic intermediates were not successful. Chemical model studies, however, suggest that the expected intermediary amino enol and dihydropyridinium species may be too unstable to isolate. The possible significance of this pathway with respect to haloperidol-induced central nervous system dysfunction is considered.

Animals↗
PubMedDate not supplied

Identification of a pyridinium metabolite in human urine following a single oral dose of 1-[2-[bis[4-(trifluoromethyl)phenyl]methoxy]ethyl]- 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid monohydrochloride, a gamma-aminobutyric acid uptake inhibitor.

Single-dose administration of 50 mg of 1-[2-[bis[4- (trifluoromethyl)phenyl]methoxy]ethyl]-1,2,5,6-tetrahydro-3- pyridinecarboxylic acid monohydrochloride resulted in temporary neurological and psychological symptoms in two subjects. Because of the nature of adverse effects, urine from a subject who received CI-966 orally was extracted to investigate the metabolism of CI-966 in man. An unknown urinary component was identified as a pyridinium metabolite of CI-966 based on HPLC-MS and 1H and 19F NMR. Structural confirmation was achieved by chromatographic and spectroscopic comparisons to a reference standard. In several in vitro screens and preclinical studies, the pyridinium metabolite appears to possess minimal pharmacological activity.

Administration, Oral↗