Biomedical subjects
Publications and source records attributed to Philip A S Lowden.
A novel anthracene-tagged oligonucleotide can discriminate between a fully-matched DNA target sequence and one with a single mismatching base-pair through a remarkable difference in fluorescence emission intensity upon duplex formation.
Huntington's disease (HD) is an inherited progressive neurological disorder for which there is no effective therapy. It is caused by a CAG/polyglutamine repeat expansion that leads to abnormal protein aggregation and deposition in the brain. Several compounds have been shown to disrupt the aggregation process in vitro, including a number of benzothiazoles. To further explore the therapeutic potential of the benzothiazole aggregation inhibitors, we assessed PGL-135 and riluzole in hippocampal slice cultures derived from the R6/2 mouse, confirming their ability to inhibit aggregation with an EC50 of 40 microM in this system. Preliminary pharmacological work showed that PGL-135 was metabolically unstable, and therefore, we conducted a preclinical trial in the R6/2 mouse with riluzole. At the maximum tolerated dose, we achieved steady-state riluzole levels of 100 microM in brain. However, this was insufficient to inhibit aggregation in vivo and we found no improvement in the disease phenotype.
Isotopically labelled intermediates in a proposed biosynthesis of the naphthoate fragment of azinomycin B have been made and successfully incorporated by the azinomycin producing organism.
Explore the source record for details and available documents.
13C-labelled acetate efficiently labels the antitumour natural product azinomycin B, revealing a polyketide origin for the naphthoate fragment, that threonine is the probable precursor of the enol fragment, and that alpha-ketoglutarate is a probable precursor of the aziridine fragment.
Integrated catalysts as redox sensitisers towards cancer.
Huntington's disease (HD) is an inherited, progressive neurological disorder that is caused by a CAG/polyglutamine repeat expansion and for which there is no effective therapy. Recent evidence indicates that transcriptional dysregulation may contribute to the molecular pathogenesis of this disease. Supporting this view, administration of histone deacetylase (HDAC) inhibitors has been shown to rescue lethality and photoreceptor neurodegeneration in a Drosophila model of polyglutamine disease. To further explore the therapeutic potential of HDAC inhibitors, we have conducted preclinical trials with suberoylanilide hydroxamic acid (SAHA), a potent HDAC inhibitor, in the R6/2 HD mouse model. We show that SAHA crosses the blood-brain barrier and increases histone acetylation in the brain. We found that SAHA could be administered orally in drinking water when complexed with cyclodextrins. SAHA dramatically improved the motor impairment in R6/2 mice, clearly validating the pursuit of this class of compounds as HD therapeutics.
Huntington's Disease (HD) is an inherited neurological disorder causing movement impairment, personality changes, dementia, and premature death, for which there is currently no effective therapy. The modified tetracycline antibiotic, minocycline, has been reported to ameliorate the disease phenotype in the R6/2 mouse model of HD. Because the tetracyclines have also been reported to inhibit aggregation in other amyloid disorders, we have investigated their ability to inhibit huntingtin aggregation and further explored their efficacy in preclinical mouse trials. We show that tetracyclines are potent inhibitors of huntingtin aggregation in a hippocampal slice culture model of HD at an effective concentration of 30 microM. However, despite achieving tissue levels approaching this concentration by oral treatment of R6/2 mice with minocycline, we observed no clear difference in their behavioral abnormalities, or in aggregate load postmortem. In the light of these new data, we would advise that caution be exercised in proceeding into human clinical trials of minocycline.