Epileptogenic Activity of Two Peptides Derived from Diazepam Binding Inhibitor After Intrahippocampal Injection in Rats

Abstract

Peptides DBI 42-50 (DRPGLLDLK) and DBI 43-50 (RPGLLDLK) are synthetic fragments of an 18 amino acid peptide called octadecaneuropeptide (QATVGDVNTDRPGLLDLK), a brain derivative of diazepam-binding inhibitor (DBI). The two peptides were unilaterally injected into the dorsal hippocampus (granule cells of dentate gyrus) of freely moving adult rats. The electroencephalographic (EEG) pattern was continuously recorded from bilateral hippocampal and cortical electrodes, and the animals' behavior was observed throughout the experiment. A dose of 100 nmol peptide 42-50 was required to reliably cause EEG alterations (seizures and spiking). EEG changes, defined as seizures, were characterized by discrete repetitive periods of high-frequency and/or multispike complexes and/or high-voltage synchronized spike or wave activity. EEG seizures were often associated with a frozen appearance of the animal and "wet dog shakes." Tonic-clonic convulsions were not observed. EEG seizures induced by peptide 42-50 were prevented by 90 mg/kg PK 11195, a selective antagonist of a novel GABAA receptor-linked subtype of a benzodiazepine (BDZ) receptor, but were unaffected by flumazenil, an agonist of the "central" type of BDZ receptor and by D(-)2-amino-7-phosphonoheptanoic acid, a selective antagonist of the N-methyl-D-aspartate subtype of excitatory amino acid receptors. Light microscopy showed no neuropathological changes in the injected hippocampus. The data show that these DBI-derived peptide fragments induce a typical pattern of limbic seizures in rats. DBI and/or its natural processing products may play a role in the pathophysiology of epilepsy.