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Donald Robertson

Publications and source records attributed to Donald Robertson.

8 recordsLinked to original sources
PubMed2006

Potent, selective pyrimidinetrione-based inhibitors of MMP-13.

Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and >100-fold selectivity against other MMPs have been identified. Despite high molecular weights, clogPs, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50.

Animals↗
PubMed2005

Cellular localization of voltage-gated calcium channels and synaptic vesicle-associated proteins in the guinea pig cochlea.

The cellular localization of voltage-gated calcium channels (VGCCs) and synaptic vesicle-associated proteins, SV2, synapsin I, and vesicle-associated membrane protein (VAMP) (synaptobrevin), was investigated in the guinea pig cochlea using immunocytochemistry and confocal laser scanning microscopy. Reactivity, in guinea pig, of antibodies to the alpha1 subunits of L-type, alpha1C [Cav1.2] and alpha 1D [Cav1.3]; P/Q-type, alpha1A [Cav2.1]; and R-type, a1E [Cav2.3] high voltage-activated calcium channels, was determined by Western blotting and immunolabeling of cerebellum. In the cochlea the sensory inner hair cells of the organ of Corti displayed strong intracellular staining, predominantly localized to their basolateral poles, with an antibody directed against the alpha1C subunit. Some alpha1C labeling was also observed in the inner pillar cells, in cell bodies of afferent neurons in the spiral ganglion, and in the inferior region of the spiral ligament. The supporting pillar cells were strongly immunoreactive throughout for alpha1D, but no alpha1D labeling of the inner hair cells was seen. The alpha1A subunit showed a cytoplasmic distribution in all three rows of outer hair cells. alpha1E labeling localized to the outer hair cells, predominantly in the subcuticular plate region, and also to nerve fiber bundles beneath these hair cells. Strong immunoreactivity was consistently seen with antibodies directed against SV2 and synapsin I in neuronal structures surrounding the basolateral surfaces of both the inner and outer hair cells but was absent from the sensory cells themselves. VAMP labeling was found throughout the cytoplasm of the inner hair cells and in neuronal structures beneath the hair cells. These results reveal a differential distribution of VGCC-types in the sensory and nonsensory elements of the guinea pig cochlea, with the inner hair cells expressing alpha1C L-type channels and VAMP but not synapsin I or SV2.

Animals↗
PubMed2003

Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project.

The role that metabonomics has in the evaluation of xenobiotic toxicity studies is presented here together with a brief summary of published studies. To provide a comprehensive assessment of this approach, the Consortium for Metabonomic Toxicology (COMET) has been formed between six pharmaceutical companies and Imperial College of Science, Technology and Medicine (IC), London, UK. The objective of this group is to define methodologies and to apply metabonomic data generated using (1)H NMR spectroscopy of urine and blood serum for preclinical toxicological screening of candidate drugs. This is being achieved by generating databases of results for a wide range of model toxins which serve as the raw material for computer-based expert systems for toxicity prediction. The project progress on the generation of comprehensive metabonomic databases and multivariate statistical models for prediction of toxicity, initially for liver and kidney toxicity in the rat and mouse, is reported. Additionally, both the analytical and biological variation which might arise through the use of metabonomics has been evaluated. An evaluation of intersite NMR analytical reproducibility has revealed a high degree of robustness. Second, a detailed comparison has been made of the ability of the six companies to provide consistent urine and serum samples using a study of the toxicity of hydrazine at two doses in the male rat, this study showing a high degree of consistency between samples from the various companies in terms of spectral patterns and biochemical composition. Differences between samples from the various companies were small compared to the biochemical effects of the toxin. A metabonomic model has been constructed for urine from control rats, enabling identification of outlier samples and the metabolic reasons for the deviation. Building on this success, and with the completion of studies on approximately 80 model toxins, first expert systems for prediction of liver and kidney toxicity have been generated.

Animals↗
PubMed2003

Primary afferent and cochlear nucleus contributions to extracellular potentials during tone-bursts.

Gross electrical responses to tone bursts were measured in the guinea pig with electrodes located in scala tympani (ST) and scala vestibuli (SV) of the cochlea, on the central portion of the VIIIth nerve fibres in the internal auditory meatus, and on the surface of the cochlear nuclear complex (CN). Intracochlear perfusion of pharmacological blockers of neural and postsynaptic activity as well as aspiration of parts or all of the CN were used to dissect the origin of the many components of the gross responses. It was shown that single-ended recordings from either ST or SV or those derived from the sum of the ST and SV responses not only contain mixed responses from the auditory nerve fibres and cochlear hair cells, but are contaminated or modified by neural activity central to the internal auditory meatus, probably in various parts of the CN. Differential recordings between ST and SV were relatively uncontaminated by such activity. Recordings from central locations were largely uncontaminated by potentials from cochlear hair cells. These results suggest that a revised and extended system of nomenclature for the different components of the gross cochlear potentials is necessary, and interpretation of such potentials needs to take into account multiple central as well as peripheral generators.

Acoustic Stimulation↗
PubMed2002

Role of L-type Ca2+ channels in transmitter release from mammalian inner hair cells. II. Single-neuron activity.

Previously reported changes in the gross sound-evoked cochlear potentials after intracochlear perfusion of nimodipine suggest that dihydropyridine-sensitive Ca2+ channels (L-type) control the sound-evoked release of transmitter from the inner hair cells of the mammalian cochlea. In the present study, we combined recording of the action potentials of single primary auditory afferent neurons with intracochlear perfusion to further investigate the role of voltage-gated Ca2+ channels at this synapse. Spontaneous action potential firing rates were depressed by the L-type channel blocker nimodipine, but were elevated by S(-) BAY K8644, an L-type channel agonist. Sound-evoked responses of single primary afferents were depressed by nimodipine in a manner that was consistent with a block at the inner hair cell-afferent dendrite synapse. Perfusions with solutions containing the N-type channel blocker conotoxin GVIA did not differ in their effects from control artificial perilymph perfusions. The results extend the conclusions of the earlier study by showing that L-type Ca2+ channels are primarily responsible for controlling both spontaneous and sound-evoked transmitter release from inner hair cells. In addition it was found that afferent neurons with widely different spontaneous firing rates were all sensitive to nimodipine and to BAY K8644, suggesting that the multiple synaptic outputs of each inner hair cell are under the control of only one major type of Ca2+ channel.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2002

A balanced approach.

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Persons with Disabilities↗
PubMedDate not supplied

A role for purinergic receptors at the inner hair cell-afferent synapse?

Previously published evidence is reviewed for a functional role of ATP and its receptors at the chemical synapse between the mammalian inner hair cell and the primary afferent dendrites of the VIIIth nerve. New findings are also presented, both from gross cochlear potentials and single neurone recordings during intracochlear perfusion of ATP-receptor antagonists and agonists. Both the previous and present results are consistent with the notion that endogenous ATP may act to regulate the excitability of the primary afferent dendrite, possibly acting on P2X2 receptors.

Adenosine Triphosphate↗