This article is part of the Research Topic Diet and Brain Disorders.


Front. Neurol., 29 April 2014 | doi: 10.3389/fneur.2014.00063

Neuroactive peptides as putative mediators of antiepileptic ketogenic diets

imageCarmela Giordano1, imageMaddalena Marchiò1,2,3, imageElena Timofeeva4 and imageGiuseppe Biagini1,3*
  • 1Laboratory of Experimental Epileptology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
  • 2Neuropediatric Unit, Department of Medical and Surgical Sciences for Children and Adults, Policlinico Hospital, University of Modena and Reggio Emilia, Modena, Italy
  • 3Department of Neurosciences, NOCSAE Hospital, Modena, Italy
  • 4Département Psychiatrie et Neurosciences, Faculté de Médecine, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Québec, QC, Canada

Various ketogenic diet (KD) therapies, including classic KD, medium chain triglyceride administration, low glycemic index treatment, and a modified Atkins diet, have been suggested as useful in patients affected by pharmacoresistant epilepsy. A common goal of these approaches is to achieve an adequate decrease in the plasma glucose level combined with ketogenesis, in order to mimic the metabolic state of fasting. Although several metabolic hypotheses have been advanced to explain the anticonvulsant effect of KDs, including changes in the plasma levels of ketone bodies, polyunsaturated fatty acids, and brain pH, direct modulation of neurotransmitter release, especially purinergic (i.e., adenosine) and γ-aminobutyric acidergic neurotransmission, was also postulated. Neuropeptides and peptide hormones are potent modulators of synaptic activity, and their levels are regulated by metabolic states. This is the case for neuroactive peptides such as neuropeptide Y, galanin, cholecystokinin, and peptide hormones such as leptin, adiponectin, and growth hormone-releasing peptides (GHRPs). In particular, the GHRP ghrelin and its related peptide des-acyl ghrelin are well-known controllers of energy homeostasis, food intake, and lipid metabolism. Notably, ghrelin has also been shown to regulate the neuronal excitability and epileptic activation of neuronal networks. Several lines of evidence suggest that GHRPs are upregulated in response to starvation and, particularly, in patients affected by anorexia and cachexia, all conditions in which also ketone bodies are upregulated. Moreover, starvation and anorexia nervosa are accompanied by changes in other peptide hormones such as adiponectin, which has received less attention. Adipocytokines such as adiponectin have also been involved in modulating epileptic activity. Thus, neuroactive peptides whose plasma levels and activity change in the presence of ketogenesis might be potential candidates for elucidating the neurohormonal mechanisms involved in the beneficial effects of KDs. In this review, we summarize the current evidence for altered regulation of the synthesis of neuropeptides and peripheral hormones in response to KDs, and we try to define a possible role for specific neuroactive peptides in mediating the antiepileptic properties of diet-induced ketogenesis.

Keywords: adiponectin, fasting, ghrelin, ketogenic diet, neuropeptide Y, epilepsy

Citation: Giordano C, Marchiò M, Timofeeva E and Biagini G (2014) Neuroactive peptides as putative mediators of antiepileptic ketogenic diets. Front. Neurol. 5:63. doi: 10.3389/fneur.2014.00063

Received: 19 March 2014; Paper pending published: 09 April 2014;
Accepted: 14 April 2014; Published online: 29 April 2014.

Edited by:

Cara Jean Westmark, University of Wisconsin, USA

Reviewed by:

Richard Eugene Frye, Children’s Hospital Boston, USA; Harvard University, USA
David Ruskin, Trinity College, USA

Copyright: © 2014 Giordano, Marchiò, Timofeeva and Biagini. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Giuseppe Biagini, Laboratorio di Epilettologia Sperimentale, Sezione di Fisiologia e Neuroscienze, Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze, Università di Modena e Reggio Emilia, Via Campi 287, Modena 41125, Italy e-mail:

Back to top