Novel Indications for Benzodiazepine Antagonist Flumazenil in GABA Mediated Pathological Conditions of the Central Nervous System

Abstract

This review paper discusses the central role of gamma-aminobutyric acid (GABA) in diverse physiological systems and functions and the therapeutic potential of the benzodiazepine antagonist flumazenil (Ro 15- 1788) for a wide range of disorders of the central nervous system (CNS). Our group and others have studied the potential of flumazenil as a treatment for benzodiazepine dependence. A small but growing body of research has indicated that flumazenil may also have clinical application in CNS disorders such as Parkinson's disease, idiopathic hypersomnia and amyotrophic lateral sclerosis. Despite this body of research the therapeutic potential of flumazenil remains poorly understood and largely unrealized. The purpose of this paper is not to provide an exhaustive review of all possible therapeutic applications for flumazenil but rather to stimulate research interest, and discussion of the exciting therapeutic potential of this drug for a range of chronic debilitating conditions.

Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6 GABAA receptors

“…Although DK‐I‐56‐1 is a highly selective positive modulator of α6‐containing GABA A receptors, we cannot exclude alternative sites of action of this compound, which is a clear limitation of the present study; namely, its action might also be in part mediated by interactions with some of the high‐affinity benzodiazepine binding site subtypes of GABA A receptors (Hulse et al, ), at which DK‐I‐56‐1 acts as a high‐affinity, electrophysiologically silent ligand (functional benzodiazepine antagonist; Knutson et al, ; Varagic et al, ). Furthermore, although it has been demonstrated that DK‐I‐56‐1 displayed negligible displacement in a panel of radioligand binding assays for 46 receptors, transporters and channels, except for the benzodiazepine site of GABA A receptors and very weak binding at 5‐HT 7 and μ‐opioid receptors (Knutson et al, ), we also cannot exclude a possible functional modulation by this ligand of these and other targets.…”

America Addresses Two Epidemics – Cannabis and Coronavirus and their Interactions: An Ecological Geospatial Study

“…Cannabinoids are known to interact with the immune system at multiple points including CB1 and CB2 receptors, six vanilloid channels, peroxisome proliferator-activated receptors (PPAR's), serotonin, adenosine, histamine, glycine, sphingosine, dopamine and opioid receptors, three class A orphan G-protein coupled receptors (GPCR's), toll-like receptors, Tcells, B-cells, macrophages and regulatory cells, effects on sodium channels and several types of potassium and calcium channels, modulation of GABA signalling and inhibition of cyclooxygenase and lipoxygenase enzymes, bind directly to mitochondria and cannabinoid receptors also form heterodimers with opioid, adenosine, dopamine, GABA and other GPCR's and have myriad and major epigenetic effects [13][14][15][16][17][18][19][20][33][34][35][36][37][38] .…”

International Union of Basic and Clinical Pharmacology. CVI: GABAA Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans

“…5, indicating that flumazenil, like other imidazobenzodiazepines, is also a positive allosteric modulator at a4b3g2 and a6b3g2 receptors (Ramerstorfer et al, 2010). The relatively weak positive or negative allosteric modulation of this compound at these other receptors as well as changes in GABA A receptor expression and activity during benzodiazepine treatment or disease states can at least partially (see also section V.H) explain a variety of surprising observations when flumazenil was used in humans as an antagonist of benzodiazepine actions (Nutt, 1983;Hulse et al, 2015).…”

“…Flumazenil seems to be able to inhibit the actions of these endogenous modulators (Möhler, 2014), and similar effects can also be expected from other benzodiazepine site null modulators. Thus antagonists at the benzodiazepine site are not necessarily silent but might interfere with the actions of endogenous modulators in the brain, and this could contribute to their spectrum of action in vivo (Hulse et al, 2015). Because the receptor subtype selectivity of endogenous modulators of the benzodiazepine site of GABA A receptors currently is not known, the receptor subtype(s) mediating the behavioral action of a benzodiazepine site antagonist via blockade of endogenous modulators cannot be delineated.…”