Lack of tolerance to anxiolysis and withdrawal symptoms in mice repeatedly treated with AC-5216, a selective TSPO ligand

Kita, Atsuko; Kinoshita, Tomoko; Kohayakawa, Hitoshi; Furukawa, Kiyoshi; Akaike, Akinori

doi:10.1016/j.pnpbp.2009.05.018

Cited by 34 publications

(21 citation statements)

References 31 publications

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“…Consequently, TSPO ligands may offer symptomatic therapeutic opportunities for a range of neurological disorders, including Alzheimer's disease. For example, the new generation TSPO ligand, XBD-173, reduced anxiety-related behaviour in both rats and humans (117, 132). Mechanistically, the anxiolytic effect of XBD-173 was linked to enhanced GABA neurotransmission as a result of increased production of the neuroactive steroid 3α,5α-THP, which is an allosteric GABA A receptor modulator (117).…”

Section: Translocator Protein As a Therapeutic Target For Alzheimer'smentioning

confidence: 99%

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

Porcu

Barron²,

Frye

et al. 2016

J Neuroendocrinology

142

120

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Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the γ-amino-butyric type A (GABAA) receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases. Neuroactive steroids regulate many physiological functions such as stress response, puberty, ovarian cycle, pregnancy and reward. Their levels are altered in several neuropsychiatric and neurologic diseases and both preclinical and clinical studies emphasise a therapeutic potential of neuroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. However, direct administration of neuroactive steroids has several challenges, including pharmacokinetics, low bioavailability, addiction potential, safety and tolerability that limit its therapeutic use. Therefore, modulation of neurosteroidogenesis to restore the altered endogenous neuroactive steroid tone may represent a better therapeutic approach. This review summarizes recent approaches that target the neuroactive steroid biosynthetic pathway at different levels in order to promote neurosteroidogenesis. These include modulation of neurosteroidogenesis through ligands of the translocator protein 18 kDa (TSPO), and the pregnane xenobiotic receptor (PXR), as well as targeting of specific neurosteroidogenic enzymes like 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) or P450 side chain cleavage (P450scc). Enhanced neurosteroidogenesis through these targets may be beneficial for neurodegenerative diseases such as Alzheimer's disease and age-related dementia, but also for neuropsychiatric diseases, including alcohol use disorders.

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Section: Translocator Protein As a Therapeutic Target For Alzheimer'smentioning

confidence: 99%

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

Porcu

Barron²,

Frye

et al. 2016

J Neuroendocrinology

142

120

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“…Although it did slightly prolong the ethanol-induced sleep time at 1000 mg/kg, Emapunil produced no distinct changes in the rats' electroencephalograms. In a more recent study, the same authors [137] demonstrated that Emapunil, when repeatedly administrated, did not induce tolerance to its anxiolytic-like effects or withdrawal symptoms. Recently, Rupprecht and collaborators [138] have shown that ao aa = data from reference [139]; ab = data from [140]; ac = data from [141]; ad = data from [142]; ae = data from [143]; af = data from [145]; ag = data from [146]; ah = data from [147]; ai = data from [148]; al = data from reference [149]; am = data from [151]; an = data from [144]; ao = data from [152].…”

Section: Pk11195mentioning

confidence: 94%

“…-Exerted anxiolytic effects in elevated plus maze test (30 mg/kg, intraperitoneal injection) o r = data from reference [129]; g = data from [130]; s = data from [131]; t = data from [118]; f = data from [117]; u = data from [150]; p = data from [128]; v = data from [134]; z = data from [122]; x = data from reference [132]; w = data from [136]; j = data from [135]; m = data from [126]; q = data from [138]; y = data from [137]; o = data from [127].…”

Section: Pk11195mentioning

confidence: 99%

Translocator Protein as a Promising Target for Novel Anxiolytics

Costa

Pozzo²,

Martini³

2012

CTMC

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Neurosteroids are able to rapidly control the excitability of the central nervous system, acting as regulators of type A receptors for GABA. Over the last two decades, many authors have confirmed that neurosteroid level alterations occur in psychiatric disorders, including anxiety disorders. More recently, investigators have manipulated neurosteroidogenesis in an effort to correct neuronal excitation and inhibition imbalances, which may lie at the root of neuropsychiatric conditions. In line with this strategy, emerging data have demonstrated that a promising target for therapy of anxiety disorders is the Translocator Protein (TSPO). TSPO is a five transmembrane domain protein (18 kDa) that is expressed predominantly in steroid-synthesizing tissues. At the subcellular level, TSPO is localized at contact sites between the outer and inner mitochondrial membranes and mediates the rate-limiting step of neurosteroidogenesis. Brain concentrations of neurosteroids can be affected by selective TSPO activation. Indeed, TSPO drug ligands are able to stimulate the primary neurosteroid formations that enhance GABAA receptor activity, pregnenolone and allopregnenalone, both in in vitro steroidogenic cells and in vivo animal models. A spectrum of TSPO ligands has been shown to exert anxiolytic actions when administered in rodents. Some TSPO drug ligands could potentially reach clinical development. For example, recent evidence has shown that the selective TSPO ligand, XBD173 (AC-5216, Emapunil), exerts anxiolytic effects not only in animal models, but also in human volunteers. Herein, we review the current literature regarding the central nervous system biology of TSPO, a promising molecular target, in combination with its available ligands.

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“…XBD173, a new selective and high affinity TSPO ligand, presents anxiolytic and antidepressant effects in different experimental models, without causing the side effects normally associated with conventional benzodiazepines, such as myorelaxant effects, tolerance and withdrawal symptoms [63,64]. Also, XBD173 exerted anti-panic effects in rodents and humans, in the absence of sedation, tolerance development and withdrawal symptoms [65].…”

Section: Tspo Ligands and Psychiatric Disordersmentioning

confidence: 99%

“…Different anxiety and depression animal models XBD173 Anxiolytic and antidepressant-like effects [63,64].…”

Section: Experimental Models Tspo Ligands Effectmentioning

confidence: 99%

Therapeutic actions of translocator protein (18 kDa) ligands in experimental models of psychiatric disorders and neurodegenerative diseases

Arbo

Benetti

Garcia-Segura

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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Lack of tolerance to anxiolysis and withdrawal symptoms in mice repeatedly treated with AC-5216, a selective TSPO ligand

Cited by 34 publications

References 31 publications

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

Translocator Protein as a Promising Target for Novel Anxiolytics

Therapeutic actions of translocator protein (18 kDa) ligands in experimental models of psychiatric disorders and neurodegenerative diseases

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