Rationale: 

Ghrelin is a 28 amino acid-containing bioactive peptide that plays a significant role in various functions, such as in the modulation of appetite, energy and glucose homeostasis. Studies are also implicating this peptide in the pathogenesis of many diseases, namely growth hormone deficiency, obesity and myopathy. Ghrelin is a peptide that is predominantly produced in the stomach, however it is also produced in the brain. This hormone is known to be a natural ligand of the growth hormone secretagogue (GHS) receptor type 1a (GHS-R1a) of which the mRNA is abundantly expressed in various brain structures such as the hypothalamus and hippocampus. The role of ghrelin in the mechanisms of epileptic seizures is not well explored to date. There are currently two studies showing that ghrelin has an inhibitory effect on seizures (Obay et al., 2007; Aslan et al., 2009), while another study illustrates that ghrelin protects against hippocampal neuron cell death following pilocarpine-induced status epilepticus (Jingjing et al., 2009). No studies have been performed to date to study the role of ghrelin receptor agonists in limbic seizures and to unravel whether the GHS-R1a receptor is the primary receptor involved in the possible anticonvulsant effects. To this end, two selective GHS-R1a antagonists were used.

Methods:

Freely moving Wistar rats underwent a 2 hour intrahippocampal microperfusion of the selective ghrelin receptor agonist capromorelin (0.5-1-10-20mM), the ghrelin receptor antagonist D-Lys³-GHRP-6 (40mM) or the ghrelin receptor antagonist A-778139 (10-25-50mM) via a stereotactically implanted microdialysis probe. Ten mM pilocarpine was subsequently co-administered intrahippocampally for 40 min. Behavioural changes that were indicative of seizure activity were scored following the initiation of pilocarpine administration.

Results: 

Capromorelin dose-dependently suppressed pilocarpine-induced limbic seizures. Surprisingly, both ghrelin receptor antagonists D-Lys³-GHRP-6 and A-778139 also showed anticonvulsant properties.

Conclusions: 

Our results suggest that activation of an unknown ghrelin receptor, other than GHS-R1a, results in the attenuation of locally provoked limbic seizures since both the agonist and GHS-R1a antagonists reproduce the same anticonvulsant effect.