Further characterization of the role the ghrelin receptor plays in limbic epilepsy

Epilepsy is a common chronic disorder of the central nervous system. Approximately 30% of epilepsy patients are resistant to the present anti-epileptic drugs (AEDs), with the majority of these pharmacoresistant patients suffering from temporal lobe epilepsy (situated in the limbic system). Thus, it is of great importance to find novel drug targets that act differently from the AEDs available. Ghrelin is a 28-amino acid peptide, known as the endogenous ligand of the ghrelin receptor (GHSR1a)1. GHSR1a is expressed in several areas of the central nervous tissue, such as the pituitary, hypothalamus, thalamus, cortex and hippocampus2. Recently, ghrelin has been implicated in epilepsy and the current animal studies indicate that ghrelin has anticonvulsant properties3,4. Human studies are more contradictory, however it is evident that plasma ghrelin levels are altered in epilepsy patients5,6. Recent evidence from our laboratory suggest that inactivation of the GHSR1a attenuates limbic seizures in acute in vivo and in vitro animal models. Our aim is to further clarify the role of the GHSR1a in a corneal kindling mouse model. In this chronic experimental epilepsy model, we will compare GHSR1a+/+ and GHSR1a-/- corneally kindled mice, and see if there is a difference in seizure stage and/or number of stimulations to reach a plateau in seizure severity. In fully kindled GHSR1a+/+ mice, we will also investigate whether ghrelin administration can be protective against epileptic seizures. Since it is known that GHSR1a is expressed on neurons in the hypothalamus7 and that the receptor plays a role in glial cell activation4, we will also characterize the cellular distribution of the GHSR1a in the mouse hippocampus (double immunofluorescence labeling with markers for neurons, glia and microglia). Finally, we will investigate whether there is a possible shift in GHSR1a cell type distribution following induction of epilepsy, using fully corneal kindled mice and immunofluorescence stainings. With these experiments we want to further characterize the role of ghrelin and the GHSR1a in limbic epilepsy.

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2Zigman J.F. et al (2006) Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol. 494, 528-548.
3Obay B.D. et al (2007) Antiepileptic effects of ghrelin on pentylenetetrazole-induced seizures in rats. Peptides. 28, 1214-1219.
4Lee J. et al. (2010) Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. J Endorcrinol. 205, 263-70.
5Berilgen M.S. et al. (2006) Serum ghrelin levels are enhanced in patients with epilepsy. Seizure. 15, 106-111.
6Prodam F. et al (2010) Ghrelin levels are reduced in prepubertal epileptic children under treatment with carbamazepine or valproic acid. Epilepsia. 51, 312-315.
7Cowley M.A. et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 37, 649-661.