S23 Sst2 And Sst3 Receptors Are Implicated In The

s2.3 sst2 and sst3 receptors are implicated in the anticonvulsant actions of cortistatin-14 but is the ghsr-1a receptor also involved? n

S2.3
Sst2 and sst3 receptors are implicated in the anticonvulsant actions
of cortistatin-14 but is the GHSR-1a receptor also involved?
Najat Aourz, Jeanelle Portelli, Yvette Michotte and Ilse Smolders
Center for Neurosciences,Department of Pharmaceutical Chemistry and
Drug Analysis,Vrije Universiteit Brussel,Brussels,Belgium
Objectives: Unlike somatostatin(SST)-14,anticonvulsant actions of
cortistatin(CST)-14 have not been extensively studied.Both peptides
are structurally related and have high affinities for the five SST
receptor subtypes(sst1-sst5).Despite these homologies,CST-14 seems to
act also on other receptors.It has been suggested that the Growth
Hormone secretagogue receptor(GHS-R1a) may fulfill such a role.We here
aim to unveil which receptors are involved in the anticonvulsant
effects of CST-14.
Methods: We use in vivo microdialysis and telemetry-based
electrocorticography (ECoG)in rats and mice.
In rats, CST-14(0.1µM-1µM-10µM) was administered in the presence and
absence of selective sst2 and sst3 receptor antagonists via
intrahippocampal (IH) administration. Seizures were evoked by IH
pilocarpine perfusion(10mM,40min) and seizure severity was assessed
using a behavioural scoring system and ECoG.
In mice,CST-14(0.1µM-1µM-10µM) was administered IH to confirm the
anticonvulsant actions observed in rats.The involvement of GHS-R1a was
tested by administering anticonvulsant doses of CST-14 in both GHS-R1a
KO and WT mice (ongoing experiments). Seizures were evoked by IH
pilocarpine perfusion (25mM,40min).Seizure severity was assessed by
ECoG in KO and WT animals.
Results: ECoG recordings in rats treated with 0.1µM CST-14 showed
clear epileptic discharges following pilocarpine perfusion.In none of
the rats epileptic discharges were recorded during treatment with 1µM
and 10 µM CST-14. Hence,IH administration of 1µM and 10µM CST-14 was
anticonvulsant against pilocarpine-induced seizures.Furthermore,we
showed that the CST-14 (1µM)-mediated anticonvulsant actions were
reversed in the presence of 0.1µM Cyanamid,a selective sst2 antagonist
or 0.1µM SST3-ODN8,a selective sst3 antagonist.IH perfusion of these
antagonists alone did not affect the pilocarpine-induced seizure
severity per se.
Conclusion: Our results show that CST-14 prevents seizures in a focal
pilocarpine rat model and that selective sst2 or sst3 receptor
antagonism abolishes these anticonvulsant actions.
Experiments investigating the role of GHS-R1a in the anticonvulsant
actions of CST-14 are still ongoing.