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Project
In search for anticonvulsive and antiepileptogenic neuropeptides as a strategy for innovative future antiepileptic drug development (FWOAL562)
Although the anticonvulsant properties of NPY and SRIF were first described in the late 1990's, many questions regarding their mechanisms of action and the role of specific neuropeptide receptor subtypes remain unanswered. In this context, we were the first to show that in addition to the known NPY Y2 receptor-mediated inhibition of hippocampal excitability, sigma-1 receptor-mediated increases in hippocampal dopamine and the resulting increase in activation of hippocampal dopamine D2 receptors also contribute to the anticonvulsant effect of NPY in the focal pilocarpine rat model for limbic seizures (Meurs et al., 2007a). In other innovative work, our group investigated the role of SRIF sst1, sst2, sst3 en sst4 receptor-selective ligands in the pilocarpine rat model, focussing on the anticonvulsant effects of SRIF-14, but also of the structurally related cortistatine-14, which has not been studied in epilepsy before (Aourz et al., in preparation). We also showed a clear functional coupling of sst receptors in rat hippocampus. Our work with angiotensin fragments revealed that the anticonvulsant effect of angiotensin IV (AngIV) in the pilocarpine model is mediated by the sst2 receptor (Stragier et al., 2006). This may be due to the fact that AngIV is an inhibitor of insulin-regulated aminopeptidase (IRAP), an enzyme that is responsible for the degradation of SRIF. We compared seizure sensitivity in wild-type and IRAP knock-out mice, and found that IRAP knock-out mice are more sensitive to pilocarpine-induced seizures than wildtype mice (De Bundel, Loyens et al., in preparation), thereby confirming the aforementioned hypothesis.
To date, the primary aim of our research has been to elucidate the mechanisms of action of neuropeptides with known anticonvulsant effects. This is a strategy we certainly intend to pursue in the future, since many highly relevant questions in this field remain unanswered. In this way, the continuity and feasibility of this project is also guaranteed. In the current project, however, we wish to go further by identifying new neuropeptides involved in the pathophysiology of seizures and epileptogenesis. In addition, we want to contribute to the development of clinically applicable therapeutic strategies that target these peptides in epilepsy.
The first step in our research plan will be to screen a number of neuropeptides that have not yet been studied extensively in epilepsy for anticonvulsant effects. Neuropeptides for which anticonvulsant effects are observed during screening will be studied in greater detail. We will determine the effect of seizure activity (e.g. seizures induced by intrahippocampal administration of pilocarpine via a microdialysis probe) or an initial epileptogenic insult (e.g. kainate-induced status epilepticus) on the expression of these peptides in various brain regions involved in epilepsy. Where possible, transgenic animal models will be used to clarify the role of selected neuropeptides and neuropeptide receptors in the pathophysiology of epilepsy. This will be done by screening transgenic animals for spontaneous seizures using long-term video-EEG monitoring, and by determining seizure thresholds in validated intravenous infusion models using pentylenetetrazol, pilocarpine and kainate (Schallier et al., 2009) or in the 6 Hz mouse model for pharmacoresistant limbic seizures. next we will ivestigate the mechanism(s) of action of peptides with anticonvulsant activity with both in vivo and ex vivo neuropharmacological and electrophysiological tools. Finally, we aim to contribute to the development of clinically relevant and applicable therapeutic strategies that target neuropeptide systems in epilepsy
To date, the primary aim of our research has been to elucidate the mechanisms of action of neuropeptides with known anticonvulsant effects. This is a strategy we certainly intend to pursue in the future, since many highly relevant questions in this field remain unanswered. In this way, the continuity and feasibility of this project is also guaranteed. In the current project, however, we wish to go further by identifying new neuropeptides involved in the pathophysiology of seizures and epileptogenesis. In addition, we want to contribute to the development of clinically applicable therapeutic strategies that target these peptides in epilepsy.
The first step in our research plan will be to screen a number of neuropeptides that have not yet been studied extensively in epilepsy for anticonvulsant effects. Neuropeptides for which anticonvulsant effects are observed during screening will be studied in greater detail. We will determine the effect of seizure activity (e.g. seizures induced by intrahippocampal administration of pilocarpine via a microdialysis probe) or an initial epileptogenic insult (e.g. kainate-induced status epilepticus) on the expression of these peptides in various brain regions involved in epilepsy. Where possible, transgenic animal models will be used to clarify the role of selected neuropeptides and neuropeptide receptors in the pathophysiology of epilepsy. This will be done by screening transgenic animals for spontaneous seizures using long-term video-EEG monitoring, and by determining seizure thresholds in validated intravenous infusion models using pentylenetetrazol, pilocarpine and kainate (Schallier et al., 2009) or in the 6 Hz mouse model for pharmacoresistant limbic seizures. next we will ivestigate the mechanism(s) of action of peptides with anticonvulsant activity with both in vivo and ex vivo neuropharmacological and electrophysiological tools. Finally, we aim to contribute to the development of clinically relevant and applicable therapeutic strategies that target neuropeptide systems in epilepsy
Date:1 Jan 2010 → 31 Dec 2013
Keywords:Aminoacids, Parkinsons Disease, Neuro-Transmitters, Neuropharmacology, clinical pharmacy, Stroke, Receptors, Rat Models, Neurochemistry, Pharmacokinetics, Microdialysis, neuroscience, Drug Research, Bioanalysis, Epilepsy, seamless care, Monoamines, Neurosciences, Liquid Chromatography, pharmaceutical care, Electrochemical Detection
Disciplines:(Bio)chemical engineering, Basic sciences, Health sciences, Pharmaceutical sciences