Abstract

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.

Highlights

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

  • Neuroactive peptides involved in the control of metabolism are putative candidates as mediators of ketogenic diet (KD) effects in pharmacoresistant epilepsy [119, 184]

  • Fasting is mimicked by KDs through inducing ketone bodies and by lowering glucose plasma levels, effects that depend on the activation of some endocrine axis and on the suppression of others

Read more

Summary

PTZ infusion test ECS Maximal PTZ test Subcutaneous PTZ test

6-Hz test (corneal) Succinic semialdehyde dehydrogenase/γ-aminobutyric acid deficiency. The arcuate nucleus of the hypothalamus contains two distinct neuronal populations that produce orexigenic and anorexigenic peptides, which seem to play antagonistic roles in energy balance control and that are regulated by leptin and insulin [152,153,154]. The mechanisms for controlling food intake during fasting or a KD involve a complex interplay between the peripheral systems controlling gastrointestinal peptide secretion and the central nervous system These neuronal systems include neuropeptides and peripheral neuroactive peptides such as CRF, opioids, NPY, CCK, orexin, galanin, and leptin, as well as monoamines (serotonin, dopamine, and noradrenaline). The classic KD could deeply alter peptide hormone levels and their function by virtue of the prevalent lipid content of the diet This effect could be further influenced by the presence of ketone bodies or, in some cases, by weight loss. Upregulation of ghrelin levels during the course of starvation is expected, since ghrelin production is stimulated by a negative energy balance as a compensatory response

Animal model of epilepsy Change Reference
KA model
CONCLUSION
Findings
Results
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call