Purpose: 

Neuropeptide Y's anticonvulsant activity is generally believed to be mediated by Y₂ and/or Y₅ receptors. Conversely, Y₁ receptors are thought to have a permissive effect on seizures. Two Y₁ antagonists, BIBP3226 and BIBO3304, have been shown to inhibit seizures in animal models. Brain-entering Y₁ antagonists with good oral bioavailability may therefore be useful treatments of epilepsy. Our aim was to better characterise the role of Y₁ receptors in epilepsy using novel, highly selective Y₁ receptor ligands.

Method: 

Freely moving Wistar rats underwent a 3 hour intrahippocampal microperfusion of the Y₁ antagonists BIBP3226 (10mM) or BVD10 (40mM) or a 2 hour microperfusion of the Y₁ agonist D-His26-NPY (0-20-50-200mM) via a stereotactically implanted microdialysis probe. Pilocarpine (10 mM) was subsequently co-administered in the hippocampus for 40 min, and behavioural changes indicative of seizure activity were scored.

Result: 

BIBP3226 (10mM) was potently anticonvulsant. An equivalent concentration of BVD10

(40mM) had no effect on pilocarpine-induced seizures. D-His26-NPY had no effect on pilocarpine-induced seizures at low concentrations (20-50mM), and attenuated seizures at high concentrations (200mM).

Conclusion: 

Y₁ receptor antagonists may not be useful in the treatment of epilepsy. Previously reported anticonvulsant effects of BIBP3226 were confirmed, but the more selective Y₁ antagonist BVD10 did not suppress seizures, suggesting that BIBP3226 acts through non-Y₁ receptors. Moreover, the permissive effect of hippocampal Y₁ receptor activation on seizures could not be confirmed. The anticonvulsant effect of high doses of the Y₁ agonist D-His26-NPY is probably due to a loss of selectivity.