Anticonvulsant neuropeptides as drug leads for neurological diseases

Abstract

Anticonvulsant neuropeptides are best known for their ability to suppress seizures and modulate pain pathways. Galanin, neuropeptide Y, somatostatin, neurotensin, dynorphin, among others, have been validated as potential first-in-class anti-epileptic or/and analgesic compounds in animal models of epilepsy and pain, but their therapeutic potential extends to other neurological indications, including neurodegenerative and psychatric disorders. Disease-modifying properties of neuropeptides make them even more attractive templates for developing new-generation neurotherapeutics. Arguably, efforts to transform this class of neuropeptides into drugs have been limited compared to those for other bioactive peptides. Key challenges in developing neuropeptide-based anticonvulsants are: to engineer optimal receptor-subtype selectivity, to improve metabolic stability and to enhance their bioavailability, including penetration across the blood–brain barrier (BBB). Here, we summarize advances toward developing systemically active and CNS-penetrant neuropeptide analogs. Two main objectives of this review are: (1) to provide an overview of structural and pharmacological properties for selected anticonvulsant neuropeptides and their analogs and (2) to encourage broader efforts to convert these endogenous natural products into drug leads for pain, epilepsy and other neurological diseases.

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

“…The ghrelin mimetic capromorelin and the presumed GHSR antagonist A778193 (found in this study to be a GHSR inverse agonist) were generously provided by Dr. Luc Ver Donck and Dr. Dieder Moechars. The ghrelin fragments (1-5) amide, (1-7), (1-9), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and (23-28) were supplied by Phoenix Pharmaceuticals (Karlsruhe, Germany). All other chemicals were analytical reagent grade or better and were supplied by Merck (Darmstadt, Germany).…”

“…Cells were subcultured at 70 to 80 % confluency and re-suspended in 96-well plates at 60,000 cells per well. Concentrations of A778193 were added in quadruplicate to the cells and incubated for 90 minutes at 37°C in air/CO 2 (1-7), (1-9), (1-11), (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and (23)(24)(25)(26)(27)(28) were tested next to the GHSR agonist capromorelin. A sigmoidal dose response curve was fitted using GraphPad Prism software, GraphPad Software, (La Jolla, USA), yielding a pEC 50 and curve maximum.…”

“…As previously described for activation, cells were first loaded with Fluo-4-acetoxymethyl ester and then pre-incubated for 3 minutes with ghrelin, capromorelin, ghrelin (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) or ghrelin (1-5) amide to induce desensitization. Three minutes later, a second stimulation with ghrelin was performed, and it consisted of a concentration response curve for ghrelin (range, 10 -6 -10 -10 M).…”

“…After pretreatment with ghrelin at 10 -6 M, 10 -7 M, or 10 -8 M for the duration of 3 minutes, the cells were washed and re-stimulated with ghrelin (dose response 10 -6 M -10 -10 M) after 3 minutes, 20 minutes, 1 h, 2 h , 5 h, or 24 h, respectively. e In vitro desensitization concentration response curve (3 minutes) for ghrelin, the GHSR agonist capromorelin, ghrelin (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), and ghrelin(1-5) amide. Ghrelin (1)(2)(3)(4)(5) amide has a much lower capacity to desensitize the GHSR compared to ghrelin and capromorelin.…”

“…Thus, the search for new antiepileptic drugs (AEDs) is ongoing, and the emphasis is being placed in the discovery of compounds that have distinct profiles of activity than the AEDs currently on the market [13]. Increasing attention is given toward neuropeptides as potential leads in preventing seizures since they are less likely to fall under the category of "me-too" AEDs [14]. Recently ghrelin has been investigated with respect to its potential role in epilepsy.…”