Targeting the Ghrelin Receptor as a Novel Therapeutic Option for Epilepsy

Abstract

Epilepsy is a neurological disease affecting more than 50 million individuals worldwide. Notwithstanding the availability of a broad array of antiseizure drugs (ASDs), 30% of patients suffer from pharmacoresistant epilepsy. This highlights the urgent need for novel therapeutic options, preferably with an emphasis on new targets, since “me too” drugs have been shown to be of no avail. One of the appealing novel targets for ASDs is the ghrelin receptor (ghrelin-R). In epilepsy patients, alterations in the plasma levels of its endogenous ligand, ghrelin, have been described, and various ghrelin-R ligands are anticonvulsant in preclinical seizure and epilepsy models. Up until now, the exact mechanism-of-action of ghrelin-R-mediated anticonvulsant effects has remained poorly understood and is further complicated by multiple downstream signaling pathways and the heteromerization properties of the receptor. This review compiles current knowledge, and discusses the potential mechanisms-of-action of the anticonvulsant effects mediated by the ghrelin-R.

Prospective Evaluation of Ghrelin and Des-Acyl Ghrelin Plasma Levels in Children with Newly Diagnosed Epilepsy: Evidence for Reduced Ghrelin-to-Des-Acyl Ghrelin Ratio in Generalized Epilepsies

“…In the literature, other studies investigated ghrelin levels during the seizure-free interictal periods in relation to the disease progression, but the analyzed isoform was undefined in all studies [21][22][23][24][25], making the results' interpretation difficult [5]. In general, most of the above-cited studies support our data, as they did not find significant differences between the treatment and pre-treatment periods [21][22][23]25].…”

“…To our knowledge, this is the first time that the ghrelin-to-DAG ratio has been found to be specifically affected in children with generalized epilepsy. Indeed, similar results were reported only in adult patients with a history of generalized seizures [28][29][30] by some, but not all, investigators [31,32] and, especially, no data were available before the drug treatment [5].…”

“…These discrepancies could be due to confounding factors such as an insufficient handling of samples to effectively block the conversion of ghrelin to DAG, as well as the use of a specific ASM to suppress the seizures [5]. Unlike many of the above-mentioned studies [21][22][23][24][25], our cohort was characterized by a large variety of ASMs to rule out the influence of a particular activity of the administered ASM.…”

“…Indeed, the advancement of knowledge on these issues could help in predicting who will develop refractoriness to antiseizure medications (ASMs) and may allow for a more efficient identification of candidates for novel drug therapies for epilepsy. In this regard, peptides have recently been under consideration as potential new targets [5].…”

“…Ghrelin, a gastric-mucosa-secreted neuropeptide hormone, is an endogenous ligand of the growth hormone secretagogues receptor 1a (GHS-R1a) [6]. In addition to its well-established function in the stimulation of growth hormone (GH) secretion and food intake [7][8][9][10], growing evidence suggests a key role of ghrelin in different physiological and pathological conditions, including epilepsy [5,11,12]. In particular, both ghrelin and des-acyl ghrelin (DAG), as well as ghrelin analogous, have been shown to possess anticonvulsant properties.…”