Neuropeptides in epilepsy
Introduction
Epilepsy is one of the commonest chronic brain diseases, affecting over 50 million people worldwide. It is characterised by recurrent, unprovoked seizures. The number of drugs marketed to treat epilepsy has been rapidly growing with most antiepileptic drugs targeting either sodium channels or GABA receptors. Unfortunately, despite the burgeoning of new antiepileptic drugs, one third of patients with epilepsy continues to have seizures and their epilepsies are resistant to all current available treatments (Duncan et al., 2006). In addition, the classic antiepileptic drugs which typically target ion channels or ionotropic receptors have substantial side effects which are causally linked to their mechanism of action. Neuromodulators have been explored as potential alternatives to classic antiepileptic drugs (Casillas-Espinosa et al., 2012). Unlike classical neurotransmitters, neuromodulators act through indirect modulation of neurotransmitter release or ion channel/receptor function. Their physiological function is believed to be fine-tuning of neurotransmission, thereby controlling the balance between excitation and inhibition in the CNS (Baraban and Tallent, 2004). Some of the neuromodulators, such as neuropeptide Y, share similarities in molecular structure with hormones regulating feeding (Kageyama et al., 2012). It is therefore unsurprising that whereas classical neurotransmitters operate on a millisecond scale, neuropeptides usually act over periods that are orders of magnitude longer. Neuropeptides are stored in large dense vesicles in interneurons and are released upon high frequency firing. Neuropeptides exert both pre- and postsynaptic actions on excitatory and inhibitory transmission (Baraban and Tallent, 2004). A long list of neuropeptides has been explored for the treatment of epilepsy. Of those the most promising candidates with multiple reports corroborating their direct antiepileptic and antiepileptogenic action include neuropeptide Y (NPY), galanin, dynorphin, somatostatin and ghrelin. In contrast, substance P and the tachykinens seem to have a pro-epileptic effect. These are all small peptides with several aminoacids which lack a complex protein structure (Table 1). Most of the neuropeptides act at G-protein coupled receptors thereby modulating release of neurotransmitters or modifying effects of postsynaptic receptor activation. Receptor distribution of the peptidic neuromodulators within the brain varies; however, unsurprisingly, given their importance in also regulating feeding behavior, most of the peptidic neuromodulators show high expression within the hypothalamus and hippocampal structures (Allen et al., 1983, Mitsukawa et al., 2008). Limbic, archecortical, structures have a strong impact on feeding regulation (Mogenson et al., 1980). The distribution of their target receptors renders the neuromodulators an attractive target for the treatment of epilepsy. Hippocampal sclerosis and limbic structure dysfunction is one of the most common pathologies underlying pharmacoresistant epilepsy and therefore constitutes the largest cohort in surgical series (de Tisi et al., 2011). In addition, epilepsy in patients with hippocampal sclerosis is more likely to be pharmacoresistant than epilepsy due to other lesions within the brain (Stephen et al., 2001).
Neuromodulation to treat epilepsy harbours great translational potential as neuropeptide structure, such as the structure of NPY, is highly conserved among species (Larhammar, 1996). Moreover, as endogenous substances, neuropeptides are less likely substrates of multi drug transporters. Multi drug transporters are abundantly expressed at the blood brain barrier and can prevent drugs from reaching sufficient concentrations within the brain parenchyma, thereby contributing to pharmacoresistant epilepsy (Lazarowski et al., 2007).
One pharmacokinetic difficulty that needs to be overcome is the poor bioavailability of neuropeptides, which are prone to cleavage by peptidases and show poor blood brain barrier penetration. This can be overcome by non-peptide analogues such as galnon, a synthetic galanin receptor agonist (Saar et al., 2002). An alternative to this approach is local neuromodulator delivery. This can be achieved via polymers or with viral vector based technologies which are increasingly recognized as a technique that has translational potential in treating pharmacoresistant epilepsy (Szybala et al., 2009, Wykes et al., 2012).
Numerous neuropetides have been proposed to have direct and indirect effects on epilepsy and seizures. One, ACTH, has a long history of use in childhood epilepsies, in particular West syndrome, although its mode of action in epilepsy is unclear. We have concentrated on the direct antiepileptogenic and anticonvulsive effect of NPY, galanin, somatostatin, dynorphin and ghrelin, and the pro-epileptic effects of substance P. We will review their mechanism of action and receptor function with regards to their effects on epilepsy. Finally, we will highlight the translational research that has been done in the past few years aimed at treating seizures with neuropeptide delivery focussing on reports of viral vector mediated delivery of neuropeptides.
Section snippets
Npy
NPY is probably the most studied neuropeptide in epilepsy. NPY is structurally related to two gut peptides, peptideYY and pancreatic polypeptide (Tatemoto, 1982, Tatemoto et al., 1982) and similarly plays a pivotal role in regulating food intake (Chee and Colmers, 2008, Kageyama et al., 2012). Since its discovery, the range of functions identified for NPY has expanded considerably. NPY’s effects on the brain include regulation of anxiety, pain, depression, drug addiction and regulation of
Galanin
Galanin is a small peptide containing 29 amino acids, which was first isolated in porcrine intestine (Tatemoto et al., 1983). The first compelling observations pointing to a role of galanin in epilepsy were made in animal models of status epilepticus. Mazarati and colleagues found that rats subjected to continuous seizure activity such as is seen in sustained status epilepticus (SSSE) exhibit profound and prolonged galanin depletion within the hippocampus for at least a week after SSSE (
Ghrelin
Ghrelin, a growth-hormone secretagogue (GHS), was isolated from rodent stomach in (Kojima et al., 1999). Growth-hormone secretagogues (GHSs) are molecules which stimulate the release of growth hormone (GH) from the pituitary. Ghrelin stimulates the release of GH from the pituitary, which is one of its main functions. In the recent years, the spectrum of ghrelins function has been expanded to include sleep regulation, cardiovascular regulation and anticonvulsant properties (Portelli et al., 2012
Somatostatin
Somatostatin is a small neuropeptide, also called growth hormone-inhibiting hormone (GHIH), which is expressed in the hypothalamus in the periventricular nucleus along with its main functions which is regulation of the endocrine system, mainly inhibition of growth hormone release. Apart from the hypothalamus, somatostatin is abundantly expressed in the brain in the amygdala, hippocampus, striatum, cerebral cortex, olfactory regions, and the brainstem (Viollet et al., 2008). To date five
Dynorphin
Dynorphin, a tridecapeptide which acts at opioid receptors, was first characterized in 1979 (Goldstein et al., 1979, Schwarzer, 2009). Dynorphin is a ligand of the opioid receptors (delta, mu and kappa) with the kappa receptor mediating many of dynorphin’s effects (Chavkin et al., 1982). However, dynorpin and prodynorphin-derived peptides also modulate NMDA receptor signaling in a receptor independent manner thus reducing NMDA receptor activity (Kanemitsu et al., 2003, Kuzmin et al., 2006, Oz
Substance P
Substance P is an 11 aminoacid long peptide which is a member of the tachykinin family (Table 1). This peptide was intensively investigated with regards to pain and nociception (Vaught, 1988). However, subsequently a role for substance P in CNS disorders such as psychiatric disorders has been elucidated (Kramer et al., 1998). Substance P acts at the neurokinin 1 (NK1) receptor, which is a G-protein coupled receptor. Binding of substance P at the NK1 receptor evokes a depolarization of the cell
Conclusion
NPY, galanin, ghrelin, somatostatin and dynorphin are promising candidates for future treatment trials targeting pharmacoresistant seizures in patients. Their pharmacodynamic properties make them attractive targets for future research into treatment of human epilepsies. However, the pharmacokinetic profile of these neuropeptidic modulators requires local delivery techniques. Recent studies used adenoassociated viral (AAV) delivery techniques, which have emerged as promising techniques for local
Acknowledgments
This work was undertaken at University of College London (UCL) and was partly funded by the Department of Health National Institute for Health Research Biomedical Research Centres funding scheme and Epilepsy Research UK.
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