Endozepines and their receptors: Structure, functions and pathophysiological significance

Tonon, Marie‐Christine; Vaudry, Hubert; Chuquet, Julien; Guillebaud, Florent; Fan, Jinjiang; Masmoudi-Kouki, Olfa; Vaudry, David; Lanfray, Damien; Morin, Fabrice; Prévot, Vincent; Papadopoulos, Vassilios; Troadec, Jean‐Denis; Leprince, Jérôme

doi:10.1016/j.pharmthera.2019.06.008

Cited by 46 publications

(70 citation statements)

References 658 publications

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“…The absence of TATA and CCAAT boxes, the presence of several element initiators of transcription, and the high content of nucleotide acids C and G in a promoter are often considered as the hallmarks of a domestic gene. Nevertheless, the expression level of DBI gene is regulated in different cell types ( 25 ). In addition, the P1 and P2 regions of the DBI gene have several consensus sequences for transcription factors including a glucocorticoid-response element (GRE), a CAAT-binding transcription factor/nuclear factor 1 (CTF/NF1), a hepatocyte nuclear factor (HNF), a sterol regulatory element-like sequence (SRE), and a PPAR sequence.…”

Section: Organization and Regulation Of The Octadecaneuropeptide Genementioning

confidence: 99%

“…In all vertebrate species studied, endozepines are present both in the CNS and in many peripheral organs and tissues ( 25 , 36 ). Although DBI and its derivatives are found in the gonads (126 pM), duodenum (100 pM), kidneys (73 pM), heart (30 pM), liver (22 pM), skeletal muscle (18 pM), adrenals (15 pM), lungs (13 pM), and spleen (11 pM) ( 25 ), the highest concentrations are found in rat brain (10–50 μM). Peptides of the ODN family are widely distributed in the brain, with the highest levels measured in the olfactory bulb, hypothalamus, hippocampus, cerebellum, striatum, cerebral cortex, and circumventricular organs ( Table 1 ).…”

Section: Distribution Of Octadecaneuropeptide Family Peptides In the mentioning

confidence: 99%

“…A limited number of immunocytochemical studies using antibodies against DBI show a localization of endozepines in neurons ( 37 , 38 ). However, the majority of the data in the literature indicate that endozepines are primarily expressed in glial cells ( 25 ). For example, ODN- and/or DBI-like immunoreactivities are detected in astrocytes in many brain areas including the cerebral cortex, hippocampus, amygdala, and olfactory bulb ( 39 , 40 ), in the ependymocytes bordering the cerebral ventricles ( 39 , 41 ), in the tanycytes of the median eminence ( 39 , 42 ), in Bergmann cells from the cerebellum ( 40 ), and in Gomori-positive astrocytes from the arcuate nucleus ( 43 ).…”

Section: Distribution Of Octadecaneuropeptide Family Peptides In the mentioning

confidence: 99%

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Cytoprotective and Neurotrophic Effects of Octadecaneuropeptide (ODN) in in vitro and in vivo Models of Neurodegenerative Diseases

et al. 2020

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Octadecaneuropeptide (ODN) and its precursor diazepam-binding inhibitor (DBI) are peptides belonging to the family of endozepines. Endozepines are exclusively produced by astroglial cells in the central nervous system of mammals, and their release is regulated by stress signals and neuroactive compounds. There is now compelling evidence that the gliopeptide ODN protects cultured neurons and astrocytes from apoptotic cell death induced by various neurotoxic agents. In vivo , ODN causes a very strong neuroprotective action against neuronal degeneration in a mouse model of Parkinson's disease. The neuroprotective activity of ODN is based on its capacity to reduce inflammation, apoptosis, and oxidative stress. The protective effects of ODN are mediated through its metabotropic receptor. This receptor activates a transduction cascade of second messengers to stimulate protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathways, which in turn inhibits the expression of proapoptotic factor Bax and the mitochondrial apoptotic pathway. In N2a cells, ODN also promotes survival and stimulates neurite outgrowth. During the ODN-induced neuronal differentiation process, numerous mitochondria and peroxisomes are identified in the neurites and an increase in the amount of cholesterol and fatty acids is observed. The antiapoptotic and neurotrophic properties of ODN, including its antioxidant, antiapoptotic, and pro-differentiating effects, suggest that this gliopeptide and some of its selective and stable derivatives may have therapeutic value for the treatment of some neurodegenerative diseases.

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Section: Organization and Regulation Of The Octadecaneuropeptide Genementioning

confidence: 99%

Section: Distribution Of Octadecaneuropeptide Family Peptides In the mentioning

confidence: 99%

Section: Distribution Of Octadecaneuropeptide Family Peptides In the mentioning

confidence: 99%

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Cytoprotective and Neurotrophic Effects of Octadecaneuropeptide (ODN) in in vitro and in vivo Models of Neurodegenerative Diseases

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“…Recordings obtained 3-7 days after stroke showed an increase in GABA A R-mediated tonic inhibition (Control: 53.13 ± 20.04 pA vs. Stroke: 130.90 ± 39.01 pA; P < 0.001; Figure 6B). As ODN is released exclusively by astrocytes, extrasynaptic GABA A receptors are a likely candidate to mediate its effect on neuronal excitability (Tonon et al, 2019). Therefore, we next examined if bath application of ODN could correct peri-infarct tonic inhibition.…”

Section: Effects Of Odn On Tonic Inhibitory Currentsmentioning

confidence: 99%

“…Endozepines, known as the endogenous ligands of benzodiazepine-binding sites, comprise the diazepam binding inhibitor (DBI, also known as acetyl Co-A binding protein, ACBP) and its processing products, including the octadecaneuropeptide (ODN), a small peptide of 18 amino-acids (DBI 33-50 ) (Tonon et al, 2019). In the brain, DBI is one of the major proteins expressed and released by astrocytes but not by neurons (Loomis et al, 2010;Tonon et al, 2019). DBI and ODN bind to the benzodiazepine site of the GABA A R where they act as allosteric neuromodulators (Bormann, 1991;Barmack et al, 2004;Quian et al, 2008;Möhler, 2014;Dumitru et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The gliopeptide ODN, a ligand for the benzodiazepine site of GABA_A receptors, boosts functional recovery after stroke

Lamtahri

Hazime

Gowing

et al. 2020

Preprint

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Following stroke, the survival of neurons and their ability to re-establish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABA A receptors (GABA A R). Conversely, in the late phase, negative allosteric modulation of GABA A R can correct the sub-optimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABA A R synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which make it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in both young and aged mice. Furthermore, we bring evidence that during the sub-acute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity.

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GABA _A Receptor Modulators

Ernst¹,

Silva²,

Vogel³

2020

Encyclopedia of Life Sciences

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Allosteric modulators are molecules that act at sites different from orthosteric sites and influence the effects of orthosteric ligands on the target protein. For the family of GABA A receptors, allosteric modulation is a key concept exploited by widely used pharmaceuticals, for example tranquilisers of the benzodiazepine type or sedative anaesthetics such as etomidate. Recent developments reflect efforts to identify the binding sites involved in such allosteric modulation and the selective targeting of individual receptor subtypes. The precise number and structures of native GABA A receptor subtypes are still not known. A widely used useful distinction refers to synaptic and extrasynaptic pools of receptors, and some progress has been made in targeting these pools separately. A recent surge identified endogenous modulators, among them endocannabinoids and dopamine. As knowledge about modulators as well as their binding sites increases, development of more selective agents will be facilitated. Key Concepts Clinically used drugs targeting GABA A receptors are mostly allosteric modulators – benzodiazepines and sedative narcotics are prominent examples. Allosteric modulators change agonist function in various ways by interactions with allosteric modulatory sites. Diverse effects have been categorised; acronyms such as PAM type I and similar are used – but the terminology is not standardised. Functional selectivity has been introduced as a term to differentiate selective action from selective binding. For many chemotypes the exact binding sites on GABA A receptors are not yet known; structural knowledge is still needed. While receptors consisting of alpha, beta and gamma subunits are very well characterised, much less is known about receptors that contain only alpha and beta subunits and receptors that contain delta, pi, theta, epsilon or rho subunits.

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Endozepines and their receptors: Structure, functions and pathophysiological significance

Cited by 46 publications

References 658 publications

Cytoprotective and Neurotrophic Effects of Octadecaneuropeptide (ODN) in in vitro and in vivo Models of Neurodegenerative Diseases

Cytoprotective and Neurotrophic Effects of Octadecaneuropeptide (ODN) in in vitro and in vivo Models of Neurodegenerative Diseases

The gliopeptide ODN, a ligand for the benzodiazepine site of GABA_A receptors, boosts functional recovery after stroke

GABA _A Receptor Modulators

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Endozepines and their receptors: Structure, functions and pathophysiological significance

Cited by 46 publications

References 658 publications

Cytoprotective and Neurotrophic Effects of Octadecaneuropeptide (ODN) in in vitro and in vivo Models of Neurodegenerative Diseases

Cytoprotective and Neurotrophic Effects of Octadecaneuropeptide (ODN) in in vitro and in vivo Models of Neurodegenerative Diseases

The gliopeptide ODN, a ligand for the benzodiazepine site of GABAA receptors, boosts functional recovery after stroke

GABA A Receptor Modulators

Contact Info

Product

Resources

About

The gliopeptide ODN, a ligand for the benzodiazepine site of GABA_A receptors, boosts functional recovery after stroke

GABA _A Receptor Modulators