Endozepines and their receptors: Structure, functions and pathophysiological significance

Abstract

The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [³H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). The primary structure of DBI/ACBP has been well preserved, suggesting that endozepines exert vital functions. The DBI/ACBP gene is expressed by astroglial cells in the central nervous system, and by various cell types in peripheral organs. Endoproteolytic cleavage of DBI/ACBP generates several bioactive peptides including a triakontatetraneuropeptide that acts as a selective ligand of peripheral BZ receptors/translocator protein, and an octadecaneuropeptide that activates a G protein-coupled receptor and behaves as an allosteric modulator of the GABA_AR. Although DBI/ACBP is devoid of a signal peptide, endozepines are released by astrocytes in a regulated manner. Consistent with the diversity and wide distribution of BZ-binding sites, endozepines appear to exert a large array of biological functions and pharmacological effects. Thus, intracerebroventricular administration of DBI or derived peptides induces proconflict and anxiety-like behaviors, and reduces food intake. Reciprocally, the expression of DBI/ACBP mRNA is regulated by stress and metabolic signals. In vitro, endozepines stimulate astrocyte proliferation and protect neurons and astrocytes from apoptotic cell death. Endozepines also regulate neurosteroid biosynthesis and neuropeptide expression, and promote neurogenesis. In peripheral organs, endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of endozepines and discuss the physiopathological implications of these regulatory gliopeptides.

Introduction

The first benzodiazepine (BZ), chlordiazepoxide (Librium™), was synthesized by Sternbach and Randall who serendipitously discovered the anticonvulsant, sedative, anxiolytic and muscle relaxant properties of this compound (Sternbach, 1979; Sternbach & Reeder, 1961). The search for more potent analogs led to the design of diazepam (Valium™; Randall et al., 1961) which soon became the most highly prescribed drug in the world (Koumjian, 1981). In 2013, 13.5 million BZ prescriptions were filled in the USA (Fluyau, Revadigar, & Manobianco, 2018; Lembke, Papac, & Humphreys, 2018). The pharmacological effects of BZs are mediated through two types of receptors: central-type BZ receptors (CBRs) which are part of the γ-aminobutyric acid (GABA) type A receptor (GABA_AR)/chloride channel complex (Griffin et al., 2013; Sigel & Ernst, 2018), and peripheral-type BZ receptors (PBRs), now known as translocator protein (TSPO) (Papadopoulos et al., 2006) which are primarily located in the outer mitochondrial membrane (OMM; Papadopoulos, 1993). For consistency (Section 3.1.1), we use throughout the present review GABA_AR-BZ-binding site for naming the former CBR.

The discovery, in the mid 70’s, of enkephalins and endorphins as endogenous agonists of opiate receptors inspired the quest of “endozepines” as putative natural ligands of BZ receptors. Pioneer studies conducted by Guidotti and Costa revealed that rat brain extracts actually contain a competitive inhibitor of [³H]diazepam binding, thus termed diazepam-binding inhibitor (DBI; Guidotti et al., 1983). Intracerebroventricular (i.c.v.) administration of DBI causes anxiety-like behavior, and this effect is blocked by the GABA_AR-BZ-binding site antagonist flumazenil (Guidotti et al., 1983). Proteolytic cleavage of DBI generates several biologically active fragments including the triakontatetraneuropeptide DBI_(17–50) (TTN; Slobodyansky, Guidotti, Wambebe, Berkovich, & Costa, 1989) and the octadecaneuropeptide DBI_(33–50) (ODN; Ferrero, Santi, Conti-Tronconi, Costa, & Guidotti, 1986). In the brain, the DBI gene is primarily expressed in astrocytes, and DBI-derived peptides are particularly abundant in the olfactory bulb (OB), hypothalamus and hippocampus (Tonon, Désy, Nicolas, Vaudry, & Pelletier, 1990). TTN/ODN-related peptides are also present in several peripheral organs (Rouet-Smih, Tonon, Pelletier, & Vaudry, 1992). Consistent with the widespread distribution of DBI and its processing products, these peptides appear to exert a large array of biological effects notably on anxiety-related behaviors (de Mateos-Verchere, Leprince, Tonon, Vaudry, & Costentin, 1998), food consumption (Guillebaud et al., 2017; de Mateos-Verchere, Leprince, Tonon, Vaudry, & Costentin, 2001), neuroprotection (Ghouili et al., 2018; Masmoudi-Kouki et al., 2018) and hormonal secretions (Yoshida, Tsunoda, & Owyang, 1999). DBI-derived peptides are also implicated in various pathophysiological conditions, prompting the rational design of selective agonists and antagonists (Leprince et al., 1998, Leprince et al., 2001). The aim of the present review is to summarize the current knowledge on endozepines and their receptors, to discuss their mechanisms of action, and to give an overview of their pleiotropic biological functions.