IRAP deletion enhances pentylenetetrazol seizure thresholds but does not lead to accumulation of somatostatin-14

Angiotensin (Ang) IV has been shown to be antiepileptogenic in a pentylenetetrazol (PTZ) kindling model. It is suggested that Ang IV inhibits insulin-regulated aminopeptidase (IRAP) and prolongs the half-life of neuropeptides. Stragier et al. suggested that somatostatin (sst)-14 is involved, since a sst-2 receptor antagonist prevented the Ang IV-mediated inhibition of seizures in a rat pilocarpine model.
To study the role of IRAP in seizure generation, IRAP wild-type (WT) and knock-out (KO) mice were subjected to an intravenous tail infusion of PTZ. We compared the aminopeptidase activity and the degradation of sst-14 in cortical homogenates of WT and KO.
Compared to male WT mice, male KO showed higher PTZ thresholds for myoclonic twitch, clonus with and without loss of reflexes. In brain cortex membranes of WT, 70% of the aminopeptidase activity was IRAP and 30% aminopeptidase-N (AP-N), while AP-N was the only active aminopeptidase in KO. Radio immuno assay data indicate a similar degradation of sst-14 in WT and KO.
This study shows that IRAP is involved in seizure generation, since male IRAP KO are less susceptible to PTZ-induced seizures. The mechanism by which IRAP deletion enhances seizure thresholds remains elusive since we showed it is not due to cumulation of sst-14.