1,763 research outputs found
Modulation of cerebellar GABAA receptors by Benzodiazepine receptor inverse agonists
No full textSingle unit extracellular recordings were made from Purkinje cells of the in vitro cerebellar slice preparation. Application of 0.05-1.0mM γ-aminobutyric acid (GABA) produced a concentration-dependent reduction in the spontaneous firing rate of these cells. GABA responses could be bidirectionally modulated by benzodiazepine (BDZ) receptor ligands, being potentiated by the agonists RU32007 and attenuated by the inverse agonist R019-4603. These effects of the BDZs could be blocked by the BDZ antagonist flumazenil. The BDZ ligands produced simulatneous changes in the firing rate of the cells, RU32007 reducing whilst Ro19-4603 increasing the rate. These changes were attributed to modulation of tonically released GABA. Responses to 0.1mM GABA were also attenuated by the imidazopyrimidine inverse agonist RU34347. Associated with this effect was a decrease in the firing rate of the cells. Application of RU34347 for short time periods (40-60secs) produced an inhibitory response similar to that observed following GABA application. This response was partially blocked by both flumazenil and bicuculline (a GABA antagonist). A study of stimulus-evoked inhibition was also made by placing a bipolar stimulating electrode into the molecular layer of the cerebellum. Following stimulation, a period of inhibition occurred, results being recorded in the form of peri-stimulus time histograms (PSTH). Ro19-4603 (10pM-1nM) produced a dose-dependent decrease in the period of inhibition. RU34347 (10nM-10fM) produced an increase in the duration of the inhibition although the concentration-response relationship was biphasic. Between 10nM and 10pM a greater effect was observed as the concentration was decreased, the peak effect being being seen at 10pM and this could be antagonised by 1μM flumazenil. As the concentration was reduced further, a reduction in the magnitude of effect was observed, the minimum effective concentration being 100fM. It was also found that the increase in the duration of inhibition induced by 10nM RU34347 was only fully antagonised by 10μM flumazenil, a much higher concentration than would be predicted from the relative affinities of the two compounds at classical BDZ receptors.</p
Dr. Ashley Austin - Faculty Author Interview
No full textDr. Ashley Austin, Assistant Professor of Accounting, discusses a recent article in Contemporary Accounting Research, entitled “Improving Auditors’ Consideration of Evidence Contradicting Management’s Estimate Assumptions.” Dr. Austin’s research interests involve using experimental methods to understand and improve auditors’ judgments and decision making, with a focus on how to motivate auditors to exercise professional skepticism and be alert to fraud throughout the audit
Reducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitro
No full textInappropriate activation of NMDA receptors during a period of cerebral ischaemia is a crucial event in the pathway leading to neuronal degeneration. However, significant research has failed to deliver a clinically active NMDA receptor antagonist, and competitive NMDA antagonists are ineffective in many experimental models of ischaemia. The NMDA receptor itself has a number of modulatory sites which may affect receptor function under ischaemic conditions. Using rat organotypic hippocampal slice cultures we have investigated whether the redox modulatory site affects the neuroprotective efficacy of NMDA receptor antagonists against excitotoxicity and experimental ischaemia (OGD). NMDA toxicity was significantly enhanced in cultures pretreated with a reducing agent. The noncompetitive antagonist MK-801 and a glycine-site blocker were equally neuroprotective in both normal and reduced conditions, but there was a significant rightward shift in the dose–response curves of the competitive antagonists APV and CPP and the uncompetitive antagonist memantine. OGD produced neuronal damage predominantly in the CA1 region, which was prevented by MK-801 and memantine, but not by APV or CPP. Inclusion of an oxidizing agent during the period of OGD had no effect alone, but significantly enhanced the neuroprotective potency of the competitive antagonists. These data clearly demonstrate that chemical reduction of the redox modulatory site of the NMDA receptor decreases the ability of competitive antagonists to block NMDA receptor-mediated neuronal damage, and that the reducing conditions which occur during simulated ischaemia are sufficient to produce a similar effect. This may have important implications for the design of future neuroprotective agents
Organotypic cultures as tools for functional screening in the CNS
No full textScreening gets more complex with organotypic culture systems.A major challenge for the pharmaceutical industry is the development of relevant model systems in which knowledge gained from high-throughput, genomic and proteomic approaches can be integrated to study function. Animal models are still the main choice for such studies but over the past few years powerful new in vitro systems have begun to emerge as useful tools to study function. Organotypic cultures made from slices of explanted tissue represent a complex multi-cellular in vitro environment with the potential to assess biological function and are uniquely placed to act as an important link between high-throughput approaches and animal models
Interleukin-1beta does not affect the energy metabolism of rat organotypic hippocampal-slice cultures
No full textThe aim of this study was to examine the effect of the archetypal pro-inflammatory cytokine, interleukin-1beta (IL-1?), on high-energy phosphate levels within an ex vivo rat organotypic hippocampal-slice culture (OHSC) preparation using phosphorus ((31)P) magnetic resonance spectroscopy (MRS). Intrastriatal microinjection of IL-1? induces a chronic reduction in the apparent diffusion coefficient (ADC) of tissue water, which may be indicative of metabolic failure as established by in vivo models of acute cerebral ischaemia. The OHSC preparation enables examination of the effects of IL-1? on brain parenchyma per se, independent of the potentially confounding effects encountered in vivo such as perfusion changes, blood-brain barrier (BBB) breakdown and leukocyte recruitment. (31)P MRS is a technique that can detect multiple high-energy phosphate metabolites within a sample non-invasively. Here, for the first time, we characterise the energy metabolism of OHSCs using (31)P MRS and demonstrate that IL-1? does not compromise high-energy phosphate metabolism. Thus, the chronic reduction in ADC observed in vivo is unlikely to be a consequence of metabolic failure
Data Set of Psychiatry Journal Author Guidelines for Case Reports
No full textData set for psychiatry journal author guidelines for case report
Ashley Judd and Candelaria Silva discuss, Bittersweet Humanitarianism at Ford Hall Forum, video recording, 4/8/2011
No full textAshley Judd, award-winning actress, humanitarian, and author of All That Is Bitter and Sweet joins moderator Candelaria Silva, author and Roxbury Film Festival founder, to discuss Judd\u27s experiences in feminist social justice work to discover the relationship between healing oneself and healing others.https://dc.suffolk.edu/fhf-av/1107/thumbnail.jp
Interleukin-1? exacerbates hypoxia-induced neuronal damage, but attenuates toxicity produced by simulated ischaemia and excitotoxicity in rat organotypic hippocampal slice cultures
No full textUsing organotypic hippocampal slice cultures we have investigated the actions of Interleukin-1 (IL-1) in a number of injury paradigms. Low concentrations of IL-1 potentiated hypoxia-induced neurodegeneration whilst high concentrations had no effect. In contrast, higher concentrations of IL-1 were strongly neuroprotective in models of combined oxygen/glucose deprivation and N-methyl-D-aspartate toxicity, but no potentiation was observed at low IL-1 concentrations. Both protective and toxic effects of IL-1 were fully antagonized by IL-1 receptor antagonist. These data demonstrate that the effects of IL-1 on neuronal injury are complex, and may be directly related to the injury paradigm studied
Time window and pharmacological characterisation of kainate-mediated preconditioning in organotypic rat hippocampal slice cultures
No full textTolerance to normally neurotoxic insults can be induced by prior a preconditioning exposure to a sublethal insult. Kainate toxicity can be attenuated by prior exposure to very low concentrations of kainate both in vivo and in vitro. Using organotypic hippocampal slice cultures from rats we have shown that 5 ?M kainate induces a selective lesion in the CA3 region and this can be significantly attenuated by 1 ?M kainate administered 1–5 days earlier. The time window for this effect was affected by the length of time in culture, and preconditioning was blocked by NBQX but not the selective AMPA receptor antagonist GYKI53655. These data demonstrate a role for kainate receptors in preconditioning for the first time and show that organotypic cultures can be used as a model to investigate long-term preconditioning mechanisms
Intraischaemic hypothermia reduces free radical production and protects against ischaemic insults in cultured hippocampal slices
No full textHypothermia has been demonstrated to be an effective neuroprotective strategy in a number of models of ischaemic and excitotoxic neurodegeneration in vitro and in vivo. Reduced glutamate release and free radical production have been postulated as potential mechanisms underlying this effect but no definitive mechanism has yet been reported. In the current study, we have used oxygen–glucose deprivation in organotypic hippocampal slice cultures as an in vitro model of cerebral ischaemia. When assessed by propidium iodide fluorescence, reducing the temperature during oxygen–glucose deprivation to 31–33C was significantly neuroprotective but this effect was lost if the initiation of hypothermia was delayed until the post-insult recovery period. The neuroprotective effects of hypothermia were associated with a significant decrease in both nitric oxide production, as assessed by 3-amino-4-aminomethyl-2¢,7¢-difluorofluorescein fluorescence, and superoxide formation. Further, hypothermia significantly attenuated NMDA-induced nitric oxide formation in the absence of hypoxia/hypoglycaemia. We conclude that the neuroprotective effects of hypothermia are mediated through a reduction in nitric oxide and superoxide formation and that this effect is likely to be downstream of NMDA receptor activation
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