Endozepines and their receptors: Structure, functions and pathophysiological significance
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 (GABAAR)/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 GABAAR-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 GABAAR-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.
Section snippets
Discovery
Benzodiazepines is a class of drugs that have been developed for the treatment of anxiety and sleep disorders. Over the last 60 years, thousand BZs have been synthesized and many of them are currently on the market. Binding studies using [3H]diazepam as a radioligand have revealed the occurrence of two classes of BZ receptors/binding sites in the central nervous system (CNS) and in peripheral tissues: GABAAR-BZ-binding site exhibits high affinity for clonazepam and flumazenil (Griffin et al.,
Structure
GABA is the predominant inhibitory neurotransmitter in the mature brain, in which a dynamic balance of excitatory and inhibitory signaling is a rudder of all functions. GABA binds the orthosteric site of the two types of receptors, GABAAR and GABABR. GABAAR are ionotropic, whereas GABABR are GPCR (Bowery et al., 2002; Olsen & Sieghart, 2008, for reviews). Pioneer research on the effect of BZs on GABAAR function has led to the discovery of endogenous molecules, endozepines, which are able to
Anxiety-like and stress behaviors
Several endozepines, including DBI and ODN, compete with the binding of the anxiolytic drug diazepam (Costa & Guidotti, 1991). In addition, the DBI/ACBP gene is actively expressed in brain regions implicated in the control of anxiety-like behavior and stress response, notably in the hypothalamus and amygdala (Guidotti, 1991; Section 2.5). In agreement with these observations, i.c.v. injection of DBI induces pro-conflict responses and suppresses the anticonflict action of diazepam (Corda,
Acute brain diseases
DBI and ODN bind to GABAAR-BZ-binding site (Section 3.1.3) and application of micromolar concentrations of ODN on neurons decrease the GABA mediated inhibitory current (Alfonso et al., 2012; Bormann et al., 1985; Dumitru et al., 2017). Endozepines appear like new glio-mediators of neuronal activity and should be considered for their potential to correct a pathological excess of inhibition. Recently, it has been demonstrated by several groups that, after a stroke, the surviving neurons located
Conclusion and perspectives
Since the discovery of DBI/ACBP as an endogenous ligand of “BZ receptors” (Guidotti et al., 1983; Mocchetti et al., 1986; Shoyab et al., 1986), a number of studies have been conducted to elucidate the cellular distribution, the biological activities and pharmacological effects, the mechanism of action and the pathophysiological significance of endozepines. The organization of the DBI/ACBP cDNA and the primary structure of the polypeptide have been strongly preserved in the vertebrate phylum,
Declaration of Competing Interest
The authors declare that this review article was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
This work was supported by the Agence Nationale de la Recherche (grant EZICROM; ANR-16-CE14-0011 to JL, VPr and JDT), the Institut National de la Santé et de la Recherche Médicale (Inserm), the Normandy University (Rouen), the LARC-Neuroscience Network, the Institute for Research and Innovation in Biomedicine (IRIB), the Region Normandy, the Canadian Institutes of Health Research, the John Stauffer Dean’s Chair in Pharmaceutical Sciences (University of Southern California), the Partenariat
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