Insulin-regulated aminopeptidase: a novel target for antiepileptic drugs?

OBJECTIVES: Investigation of the potential of insulin-regulated aminopeptidase (IRAP) as a novel target for antiepileptic drugs. BACKGROUND: The neuropeptide somatostatin is an important regulator of hippocampal excitability and several lines of evidence implicate its involvement in temporal lobe epilepsy. Caveats on the use of somatostatin targets in the treatment of epilepsy can be considered: the somatostatin receptor subtypes underlying the antiepileptic actions of somatostatin are species dependent and somatostatin receptors are very susceptible to desensitization. We therefore propose a novel treatment strategy based on inhibition of somatostatin degradation. Such a treatment strategy would predominantly modify endogenous somatostatin levels during conditions of enhanced release such as seizures. IRAP is a somatostatin degrading enzyme with abundant expression in neurons throughout the hippocampus. We investigated the effects of intrahippocampal administration of somatostatin and IRAP inhibitors on pilocarpine induced seizures in rats using the microdialysis technique. RESULTS: Intrahippocampal administration of somatostatin protected rats against pilocarpine induced seizures. This effect was blocked by the somatostatin SST2 receptor antagonist cyanamid 154806. The peptides angiotensin IV (Ang IV) and LVV-haemorphin 7 (LVV-H7) have been characterized as potent competitive inhibitors or IRAP and protected rats against pilocarpine induced seizures upon intrahippocampal administration. This seizure suppressing effect was similarly blocked by cyanamid 154806. This strongly suggests the effects of Ang IV and LVV-H7 are indirectly mediated though somatostatin. Whereas Ang IV and LVV-H7 did not enhance basal hippocampal somatostatin levels they may decrease somatostatin degradation upon neuronal release. CONCLUSION: We propose a working hypothesis in which IRAP inhibitors protect against seizures by inhibiting the degradation of somatostatin upon neuronal release. Further experiments may provide a proof of concept for a new class of antiepileptic drugs based on inhibition of IRAP activity.

Publication year:2008

Keywords:IRAP, Angiotensin IV, LVV-Haemorphin 7, pilocarpine, seizures, epilepsy