The drug candidate, ADX71441, is a novel, potent and selective positive allosteric modulator of the GABAB receptor with a potential for treatment of anxiety, pain and spasticity

Kalinichev, Mikhail; Girard, Françoise; Haddouk, Hasnaà; Rouillier, Mélanie; Riguet, Eric; Royer-Urios, Isabelle; Mutel, Vincent; Lütjens, Robert; Poli, Sonia

doi:10.1016/j.neuropharm.2016.11.016

Cited by 26 publications

(13 citation statements)

References 58 publications

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“…A positive allosteric modulator of the GABA B receptor significantly inhibited colonic hypersensitivity to distension following systemic, but not intrathecal, administration in female rats (Kannampalli et al, 2017b ). The same compound in male mice significantly inhibited acetic acid-induced writhes following oral administration (Kalinichev et al, 2017 ). The GABA B receptor was also found to be the target for α-conotoxin Vc1.1, which inhibited colonic nociceptive afferent firing as well as the expression of phosphorylated extracellular signal-related kinase, a marker of nociceptive neuronal activation in the dorsal horn of the spinal cord (Castro et al, 2017 ).…”

Section: Neurotransmitters In Stress Pathways That Modulate Visceral mentioning

confidence: 98%

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

Meerveld

Johnson

2017

Front. Syst. Neurosci.

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Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus such as organ distension. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. Evidence suggests that long term stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders such as irritable bowel syndrome (IBS). Early life stress (ELS) is a risk-factor for the development of IBS, however the mechanisms responsible for the persistent effects of ELS on visceral perception in adulthood remain incompletely understood. In rodent models, stress in adult animals induced by restraint and water avoidance has been employed to investigate the mechanisms of stress-induce pain. ELS models such as maternal separation, limited nesting, or odor-shock conditioning, which attempt to model early childhood experiences such as neglect, poverty, or an abusive caregiver, can produce chronic, sexually dimorphic increases in visceral sensitivity in adulthood. Chronic visceral pain is a classic example of gene × environment interaction which results from maladaptive changes in neuronal circuitry leading to neuroplasticity and aberrant neuronal activity-induced signaling. One potential mechanism underlying the persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in visceral nociception, stress-induced visceral pain has been linked to alterations in DNA methylation and histone acetylation patterns within the brain, leading to increased expression of pro-nociceptive neurotransmitters. This review will discuss the potential neuronal pathways and mechanisms responsible for stress-induced exacerbation of chronic visceral pain. Additionally, we will review the importance of specific experimental models of adult stress and ELS in enhancing our understanding of the basic molecular mechanisms of pain processing.

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Section: Neurotransmitters In Stress Pathways That Modulate Visceral mentioning

confidence: 98%

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

Meerveld

Johnson

2017

Front. Syst. Neurosci.

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“…(2) Targeting GABA B receptors, which are also involved in the modulation of anxiety. Positive allosteric modulation of the GABA B receptor had an anxiolytic effect in rodent anxiety models (with compounds CGP7930 and GS39783) 77 , 78 and has been approved for clinical testing for the first time (ADX71441) 124 . (3) Enhancing GABA through blockade of GABA transaminase (e.g., with vigabatrin) or inhibition of GABA transporters (e.g., with tiagabine) 125 .…”

Section: Therapies Targeting Amygdala Inhibitory Neurons and Synapsesmentioning

confidence: 99%

Inhibition in the amygdala anxiety circuitry

2018

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Inhibitory neurotransmission plays a key role in anxiety disorders, as evidenced by the anxiolytic effect of the benzodiazepine class of γ-aminobutyric acid (GABA) receptor agonists and the recent discovery of anxiety-associated variants in the molecular components of inhibitory synapses. Accordingly, substantial interest has focused on understanding how inhibitory neurons and synapses contribute to the circuitry underlying adaptive and pathological anxiety behaviors. A key element of the anxiety circuitry is the amygdala, which integrates information from cortical and thalamic sensory inputs to generate fear and anxiety-related behavioral outputs. Information processing within the amygdala is heavily dependent on inhibitory control, although the specific mechanisms by which amygdala GABAergic neurons and synapses regulate anxiety-related behaviors are only beginning to be uncovered. Here, we summarize the current state of knowledge and highlight open questions regarding the role of inhibition in the amygdala anxiety circuitry. We discuss the inhibitory neuron subtypes that contribute to the processing of anxiety information in the basolateral and central amygdala, as well as the molecular determinants, such as GABA receptors and synapse organizer proteins, that shape inhibitory synaptic transmission within the anxiety circuitry. Finally, we conclude with an overview of current and future approaches for converting this knowledge into successful treatment strategies for anxiety disorders.

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“…Recently, encouraging news in relation to the Phase III trial of PXT3003 was reported [27]. Another promising pre-clinical therapeutic for patients carrying the CMT1A mutation is ADX71441 (a positive allosteric modulator of GABA B receptors) [28], which was approved for phase I clinical trials for other diseases [29]. In addition, the use of antisense oligonucleotides (ASOs) appears to be a good strategy for the suppression of PMP22 mRNA levels [30].…”

Section: Therapeutic Approaches For Charcot-marie-tooth Disordermentioning

confidence: 99%

A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases

Rzepnikowska

Kamińska

Kabzińska

et al. 2020

IJMS

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Charcot–Marie–Tooth (CMT) disease encompasses a group of rare disorders that are characterized by similar clinical manifestations and a high genetic heterogeneity. Such excessive diversity presents many problems. Firstly, it makes a proper genetic diagnosis much more difficult and, even when using the most advanced tools, does not guarantee that the cause of the disease will be revealed. Secondly, the molecular mechanisms underlying the observed symptoms are extremely diverse and are probably different for most of the disease subtypes. Finally, there is no possibility of finding one efficient cure for all, or even the majority of CMT diseases. Every subtype of CMT needs an individual approach backed up by its own research field. Thus, it is little surprise that our knowledge of CMT disease as a whole is selective and therapeutic approaches are limited. There is an urgent need to develop new CMT models to fill the gaps. In this review, we discuss the advantages and disadvantages of yeast as a model system in which to study CMT diseases. We show how this single-cell organism may be used to discriminate between pathogenic variants, to uncover the mechanism of pathogenesis, and to discover new therapies for CMT disease.

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The drug candidate, ADX71441, is a novel, potent and selective positive allosteric modulator of the GABAB receptor with a potential for treatment of anxiety, pain and spasticity

Cited by 26 publications

References 58 publications

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

Inhibition in the amygdala anxiety circuitry

A Yeast-Based Model for Hereditary Motor and Sensory Neuropathies: A Simple System for Complex, Heterogeneous Diseases

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