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

Authors


Istituto di Ricerche Farmacologiche “Mario Negri,” Via Eritrea 62, 20157 Milano, Italy.

Abstract

Summary: Peptides DBI 42–50 (DRPGLLDLK) and DBI 43–50 (RPGLLDLK) are synthetic fragments of an 18 amino acid peptide called octadecaneuropeptide (QATV-GDVNTDRPGLLDLK), 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 electroen-cephalographic (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 mul-tispike 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.

Ancillary