Biomedical subjects

Trevor W Stone

Publications and source records attributed to Trevor W Stone.

25 records · Page 2Linked to original sources

PubMed2002

Long-term potentiation and adenosine sensitivity are unchanged in the AS/AGU protein kinase Cgamma-deficient rat.

The AS/AGU rat is a spontaneously occurring mutation which exhibits locomotor abnormalities, reduced tyrosine hydroxylase levels in substantia nigra and lower extracellular levels of dopamine, making it a valuable model for some human locomotor disorders, and spontaneous chronic degeneration. The molecular defect is an absence of protein kinase Cgamma (PKCgamma), an enzyme suggested to play a role in synaptic plasticity. We have therefore examined long-term potentiation (LTP) in hippocampal slices from the mutant animals compared with the normal control strain of Albino Swiss rat. In the CA1 region, LTP was of the same magnitude in mutant and control animals, and the presynaptic inhibitory effects of adenosine were unchanged in naïve slices or following LTP. Paired-pulse inhibition and facilitation were normal. It is concluded that the absence of PKCgamma in this strain does not modify synaptic plasticity or presynaptic sensitivity to adenosine.

Adenosine↗

PubMed2002

The pharmacological manipulation of glutamate receptors and neuroprotection.

The overactivation of glutamate receptors is a major cause of Ca(2+) overload in cells, potentially leading to cell damage and death. There is an abundance of agents and mechanisms by which glutamate receptor activation can be prevented or modulated in order to control these effects. They include the well-established, competitive and non-competitive antagonists at the N-methyl-D-aspartate (NMDA) receptors and modulators of desensitisation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. More recently, it has emerged that some compounds can act selectively at different subunits of glutamate receptors, allowing a differential blockade of subtypes. It is also becoming clear that a number of endogenous compounds, including purines, can modify glutamate receptor sensitivity. The kynurenine pathway is an alternative but distinct pathway to the generation of glutamate receptor ligands. The products of tryptophan metabolism via the kynurenine pathway include both quinolinic acid, a selective agonist at NMDA receptors, and kynurenic acid, an antagonist at several glutamate receptor subtypes. The levels of these metabolites change as a result of the activation of inflammatory processes and immune-competent cells, and may have a significant impact on Ca(2+) fluxes and neuronal damage. Drugs which target some of these various sites and processes, or which change the balance between the excitotoxin quinolinic acid and the neuroprotective kynurenic acid, could also have potential as neuroprotective drugs.

Animals↗

PubMed2002

Differential effects of remacemide and desglycinyl-remacemide on epileptiform burst firing in the rat hippocampal slice.

Remacemide is a potential anticonvulsant drug with an active metabolite, desglycinyl-remacemide (DGR). Both moieties have been reported to block neuronal Na(+) channels and the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. The effects of remacemide and DGR on zero Mg(2+)/4-aminopyridine-induced epileptiform discharges were investigated in the rat hippocampal slice preparation and compared with carbamazepine (CBZ), a prototypic Na(+) channel blocker, and AR-R15896AR, a putative NMDA channel blocker. Remacemide (0-100 microM) was without significant effect, while DGR, CBZ and AR-R15896AR all decreased burst frequency in a concentration (0-100 microM) dependent manner. These findings suggest that remacemide is not sufficiently potent at the Na(+) channel or NMDA receptor to attenuate epileptiform activity in this model and that the anticonvulsant effects of the drug may be mediated by DGR.

4-Aminopyridine↗

PubMed2002

Purines and neuroprotection.

The activation of adenosine A1, A2 andA3 receptors can protect neurones against damage generated by mechanical or hypoxic/ischaemic insults as well as excitotoxins. A1 receptors are probably effective by suppressing transmitter release and producing neuronal hyperpolarisation. They are less likely to be of therapeutic importance due to the plethora of side effects resulting from A1 agonism, although the existence of receptor subtypes and recent synthetic chemistry efforts to increase ligand selectivity, may yet yield clinically viable compounds. Activation of A2A receptors can protect neurons, although there is much uncertainty as to whether agonists are acting centrally or via a peripheral mechanism such as altering blood flow or immune cell function. Selective antagonists at the A2A receptor, such as 4-(2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-yl-amino]ethyl)phenol (ZM 241385) and 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH 58261), can also protect against neuronal death produced by ischaemia or excitotoxicity. In addition, A2A receptor antagonists can reduce damage produced by combinations of subthreshold doses of the endogenous excitotoxin quinolinic acid and free radicals. Since the A2A receptors do not seem to be activated by normal endogenous levels of adenosine, their blockade should not generate significant side effects, so that A2A receptor antagonists appear to be promising candidates as new drugs for the prevention of neuronal damage. Adenosine A3 receptors have received less attention to date, but agonists are clearly able to afford protection against damage when administered chronically. Given the disappointing lack of success of NMDA receptor antagonists in human stroke patients, despite their early promise in animal models, it is possible that A2A receptor antagonists could have a far greater clinical utility.

Adenosine↗

PubMed2002

Endogenous kynurenines as targets for drug discovery and development.

The kynurenine pathway is the main pathway for tryptophan metabolism. It generates compounds that can modulate activity at glutamate receptors and possibly nicotinic receptors, in addition to some as-yet-unidentified sites. The pathway is in a unique position to regulate other aspects of the metabolism of tryptophan to neuroactive compounds, and also seems to be a key factor in the communication between the nervous and immune systems. It also has potentially important roles in the regulation of cell proliferation and tissue function in the periphery. As a result, the pathway presents a multitude of potential sites for drug discovery in neuroscience, oncology and visceral pathology.

Animals↗

PubMedDate not supplied

Purine, kynurenine, neopterin and lipid peroxidation levels in inflammatory bowel disease.

The kynurenine metabolites of tryptophan may be involved in the regulation of neuronal activity and thus gut motility and secretion. We have now performed a pilot study to measure serum concentrations of purines and kynurenines in patients with mild inflammatory bowel disease, as well as in sex- and age-matched control subjects. For some analyses, the patients were subdivided into subgroups of those with Crohn's disease and those with ulcerative colitis. The analyses indicated an increased activity in one branch of the kynurenine pathway. While there was no demonstrable difference in neopterin levels in either of the patient groups compared with controls, indicating that the disorders were in an inactive quiescent phase, both groups showed significantly higher levels of lipid peroxidation products. This suggests the presence of increased oxidative stress even during relative disease inactivity. The increased level of kynurenic acid may represent either a compensatory response to elevated activation of enteric neurones or a primary abnormality which induces a compensatory increase in gut activity. In either case, the data may indicate a role for kynurenine modulation of glutamate receptors in the symptoms of inflammatory bowel disease.

Adolescent↗

PubMedDate not supplied

Barium, glibenclamide and CGS21680 prevent adenosine A1 receptor changes of ES coupling and spike threshold.

Activation of adenosine A1 receptors raised spike thresholds and induced a dissociation of excitatory postsynaptic potential (EPSP) spike coupling in hippocampal pyramidal neurones. This effect could be prevented by activation of A2A adenosine receptors. The A1 receptor agonist N6-cyclopentyladenosine caused a dissociation of the EPSP spike coupling recorded extracellularly and increased the threshold for spike generation measured intracellularly. These effects were prevented by the A2A receptor agonist CGS21680. A series of agents interfering with adenylate cyclase activity, protein kinase A or C, or nitric oxide synthase had no effect on these responses to N6-cyclopentyladenosine. Superfusion with barium or glibenclamide prevented both the dissociation of EPSP spike coupling and the increase of spike threshold. It is concluded that a barium- and glibenclamide-sensitive potassium current may be involved in the postsynaptic effects of A1 receptors on spike threshold, and it is suggested that a similar suppression of a potassium current by A2A receptors could underlie the inhibition of A1 receptor responses.

Action Potentials↗