Neuropeptides and beyond


Neuropeptides appear to be of importance when the central nervous system is challenged, such as during high-frequency firing and/or pathological conditions. Neuropeptides are then released mainly extrasynaptically where their peptide receptors can modulate overall excitability without interfering too much with the fast synaptic neurotransmission. Potential advantages of treatments that target neuropeptide systems in comparison to classical neurotransmitter systems and ion channels revolve consequently around the subject of efficacy as well as the reduced likelihood of side effects, thus making them attractive candidates for the development of new clinical applications for various disorders including epilepsy and epileptogenesis. Indeed, since high frequency firing is the pathological hallmark of epileptic seizures, the search for neuropeptides linked to epilepsy is of utmost interest.


Current neuropeptide projects:

Neuropeptide Y and related neuropeptide receptors

PIs: Ilse Smolders, Jeanelle Portelli
Technical/administrative support: Ria Berckmans, Gino De Smet, Carina De Rijck, Rose-Marie Geens, Gerda De Boeck
Scientific collaboration with Alfred Meurs (UGent), Frederic Simonin (Université de Strassbourg, France), Jean-Jacques Bourgignon (Université de Strassbourg, France), Frederic Bihel (Université de Strassbourg, France)

Neuropeptide Y (NPY or YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY) is a well-established first-in-class antiepileptic neuropeptide in animal models of seizures and epileptogenesis (reviewed by Meurs et al., 2007) with inhibitory actions on excitability via mainly NPY Y2 and Y5 receptors. Our team has contributed to the field by showing that NPY increases extracellular hippocampal dopamine and glutamate levels in vivo, the dopamine increase being sigma1 receptor-mediated and contributing to NPY’s anticonvulsant action (Meurs et al., 2007), and the glutamate increase being Y1 receptor-mediated without interfering with NPY's anticonvulsant effects (Meurs, Portelli et al., 2012). The role of NPY Y1 receptors in anticonvulsant mechanisms was reassessed using different Y1 receptor ligands, namely two highly selective Y1 receptor ligands (the agonist D-His23-NPY and the antagonist BVD10) and the mixed Y1/FF receptor antagonist BIBP3226. We established that the highly selective Y1 receptor ligands did not affect limbic seizure severity when compared to the control group, whereas BIBP3226 administration significantly attenuated the seizures possibly due to its action on NPFF (FLFQPQRFamide) receptors.  This has led us to further investigate the role of NPFF receptors in seizure-modulating effects. NPFF1 and NPFF2 receptors belong to the G protein-coupled receptor (GPCR) family and possess a 30-35% structure homology with NPY receptors.

Ghrelin

PIs: Jeanelle Portelli, Ilse Smolders, Ann Massie
PhD student: Jessica Coppens
Technical/administrative support: Ria Berckmans, Gino De Smet, Carina De Rijck, Rose-Marie Geens, Gerda De Boeck
Scientific collaboration with Paul Boon (UGent), Alfred Meurs (UGent), Kristl Vonck (UGent), Robrecht Raedt (UGent), Jean-Alain Fehrentz (Université de Montpellier, France)

Ghrelin (GSSFLSPEHQRVQQRKESKKPPAKLQPR, n-octanoylated on Ser-3) is a pleiotropic neuropeptide that has only very recently been introduced into the field of epilepsy (reviewed by Portelli et al., 2012).  Animal studies performed to date indicate that ghrelin has anticonvulsant properties; however, there is a great paucity with regard to what mechanism of action is utilized by ghrelin to inhibit seizures. We recently showed that the anticonvulsant effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR). To our surprise, however, we found that the GHSR knockout mice had a higher seizure threshold than their wild-type littermates when treated with the chemoconvulsant pilocarpine. Using both in vivo and in vitro models, we further discovered that inverse agonism and desensitization/internalization of the GHSR attenuate limbic seizures in rats and epileptiform activity in hippocampal slices. This constitutes a novel mechanism of anticonvulsant action, whereby an endogenous agonist reduces the activity of a constitutively active receptor (Portelli et al., 2012). We are now studying the effects of ghrelin and its receptor on inflammation and neuroprotection in chronic epilepsy models.


Somatostatin and cortistatin

PI: Ilse Smolders
PhD student: Najat Aourz
Technical/administrative support: Ria Berckmans, Gino De Smet, Carina De Rijck, Rose-Marie Geens, Gerda De Boeck
Scientific collaboration with Kyriaki Thermos (University of Heraklion)

Somatostatin-14 (SRIF or AGCKNFFWKTFTSC) is a potent anticonvulsant in rodent models of limbic seizures with the hippocampus as major site of action. Moreover loss of SRIF function in the dentate gyrus contributes to epileptogenesis and seizure susceptibility. We contributed to the field by showing that - in rats - the hippocampal sst1 receptor acts as an inhibitory autoreceptor but is not involved in the SRIF-mediated anticonvulsant effects (De Bundel et al., 2010). We also provided the first in vivo evidence for potent anticonvulsive properties exerted by intrahippocampal administration of highly selective sst3 and sst4 receptor agonists (respectively L-796,778 and L-803,087). Nevertheless, selective sst2 receptor antagonism prevented these sst3- or sst4 receptor-mediated anticonvulsant effects, suggesting a functional cooperation with rat hippocampal sst2 receptors (Aourz et al., 2011). Rodent cortistatin shares 11 of its 14 amino acids with SRIF and mediates several of its effects via activation of the 5 types of sst receptors. Cortistatin (PCKNFFWKTFSSCK) has also affinity for the ghrelin receptor (GHSR) and the possible existence of a cortistatin-specific receptor has been suggested as well (possibly orphan receptor MRGX2). We are currently investigating which receptor subtypes are involved in the anticonvulsant effects mediated by cortistatin in a rodent limbic seizure model.

Neurotensin/Neuromedins

PIs: Ilse Smolders, Ann Van Eeckhaut
PhD students: Katrien Maes, Yannick Van Wanseele, An De Prins
Technical/administrative support: Ria Berckmans, Gino De Smet, Carina De Rijck, Rose-Marie Geens, Gerda De Boeck
Scientific collaboration with Steven Ballet (VUB), Dirk Tourwé (VUB), Vicky Caveliers (VUB), Bart De Spiegeleer (UGent)

The tridecapeptide neurotensin (NT or pELYENKPRRPYIL) mediates its central and peripheral effects through interaction with three identified receptor subtypes, referred to as NTS1, NTS2 and NTS3 (Sortilin 1). NTS1 and NTS2 belong to the GPCR family, whereas Sortilin 1 is a single transmembrane domain receptor. Cerebral administration of NT can strongly modulate dopaminergic neurotransmission, leads to hypothermia and protects against ischemic stroke, and exhibits naloxone-independent analgesic responses. Glycosylated neurotensin analogues were shown to have also anticonvulsant effects in the 6Hz model of farmacoresistent seizures (Lee et al., ChemMedChem, 2009). Neuromedin N (KIPYIL) is closely related to NT in terms of sequence and activity at NT1S1 and NTS2 receptors. We are currently studying whether whether neuromedin N also plays a role in limbic seizure susceptibility. Finally we are interested in another neuromedin family, containing neuromedin U and neuromedin S. Neuromedin U (FRVDEEFQSPFASQSRGYFLFRPRN) is a highly conserved neuropeptide present in many species. It can activate the HPA axis and is therefore linked to the stress response; it can affect feeding behaviour, blood pressure regulation, pronociception and proinflammatory mechanisms, amongst others. We are currently developing selective NMUR1 and NMUR2 ligands for further in vivo proof-of-principle testing.

Other related projects:

Insulin-regulated aminopeptidase, an enzyme with various neuropeptide substrates

PIs: Ilse Smolders, Ann Massie
PhD student: Jessica Coppens
Technical/administrative support: Ria Berckmans, Gino De Smet, Carina De Rijck, Rose-Marie Geens, Gerda De Boeck
Scientific collaboration with Siew Chai (Monash University, Australia), Patrick Vander Heyden (VUB), Dimitri De Bundel (Université de Marseille), Zsolt Csaba (INSERM Paris, France), Pascal Dournaud (INSERM Paris, France)

We have long been intrigued by the biological effects of the hexapeptide angiotensin IV (Ang IV or VYIHPF) and contributed to the field by showing that Ang IV improved spatial memory in a plus maze task (De Bundel et al., 2009) and exerted anticonvulsant effects against pilocarpine-induced seizures (Stragier et al., 2006; for review De Bundel et al., 2009). Nevertheless, to date the exact mechanism of action of Ang IV in these effects remains elusive and is part of our current investigations. An interesting breakthrough was the fact that our Australian colleagues demonstrated that the Ang IV binding site was an enzyme, insulin-regulated aminopeptidase (IRAP) (Albiston et al., 2001), and that Ang IV acts as an IRAP inhibitor but not an IRAP substrate. We could subsequently show that genetic deletion of IRAP can alter the threshold for pentylenetetrazole-induced seizures (Loyens et al., 2011) and that IRAP is required to observe the antidepressant-like effects of one of the IRAP substrates, namely oxytocin (Loyens et al., 2013). Other possible in vivo substrates of IRAP that could explain some of the biological effects of IRAP inhibition by Ang IV are SRIF and vasopressin. We are especially focussing at the moment on the link between IRAP and SRIF-mediated actions. 

Connexin-mimetic peptides

PI: Ilse Smolders
PhD student: Laura Walrave
Technical/administrative support: Ria Berckmans, Gino De Smet, Carina De Rijck, Rose-Marie Geens, Gerda De Boeck
Scientific collaboration with Mathieu Vinken (VUB), Luc Leybaert (UGent)

Connexins (Cxs) are the constituents of gap junctions (GJs) and hemichannels (HCs), which mediate intercellular and extracellular communication, respectively. Accruing evidence underscores a key role for Cx43 signalling in hippocampal physiology. The specific involvement of Cx43HCs in in vivo hippocampal functioning however remains elusive. In this project, we will use a tool set of Cx43 mimetic peptides that can finally distinguish Cx43GJs and Cx43HCs, and that will unveil for the first time the possible roles of Cx43HCs in in vivo hippocampal physiology and dysfunctioning.

 

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