Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key Alterations in Fragile X Syndrome Mouse Model.
Genes. 2016-08-31; 7(9): 56
DOI: 10.3390/genes7090056
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1. Genes (Basel). 2016 Aug 31;7(9). pii: E56. doi: 10.3390/genes7090056.
Possible Therapeutic Doses of Cannabinoid Type 1 Receptor Antagonist Reverses Key
Alterations in Fragile X Syndrome Mouse Model.
Gomis-González M(1), Busquets-Garcia A(2), Matute C(3)(4)(5), Maldonado R(6),
Mato S(7)(8)(9), Ozaita A(10).
Author information:
(1)Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and
Health Sciences, Program of Genetics and Neurosciences, University Pompeu Fabra,
Barcelona 08003, Spain. .
(2)Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and
Health Sciences, Program of Genetics and Neurosciences, University Pompeu Fabra,
Barcelona 08003, Spain. .
(3)Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa
48940, Spain. .
(4)Achucarro Basque Center for Neuroscience, Zamudio 48170, Spain.
.
(5)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
(CIBERNED), Madrid 28031, Spain. .
(6)Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and
Health Sciences, Program of Genetics and Neurosciences, University Pompeu Fabra,
Barcelona 08003, Spain. .
(7)Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa
48940, Spain. .
(8)Achucarro Basque Center for Neuroscience, Zamudio 48170, Spain.
.
(9)Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas
(CIBERNED), Madrid 28031, Spain. .
(10)Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and
Health Sciences, Program of Genetics and Neurosciences, University Pompeu Fabra,
Barcelona 08003, Spain. .
Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual
disability. The cognitive deficits in the mouse model for this disorder, the
Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mouse, have been restored by
different pharmacological approaches, among those the blockade of cannabinoid
type 1 (CB1) receptor. In this regard, our previous study showed that the CB1
receptor antagonist/inverse agonist rimonabant normalized a number of core
features in the Fmr1 knockout mouse. Rimonabant was commercialized at high doses
for its anti-obesity properties, and withdrawn from the market on the bases of
mood-related adverse effects. In this study we show, by using
electrophysiological approaches, that low dosages of rimonabant (0.1 mg/kg)
manage to normalize metabotropic glutamate receptor dependent long-term
depression (mGluR-LTD). In addition, low doses of rimonabant (from 0.01 mg/kg)
equally normalized the cognitive deficit in the mouse model of FXS. These doses
of rimonabant were from 30 to 300 times lower than those required to reduce body
weight in rodents and to presumably produce adverse effects in humans.
Furthermore, NESS0327, a CB1 receptor neutral antagonist, was also effective in
preventing the novel object-recognition memory deficit in Fmr1 KO mice. These
data further support targeting CB1 receptors as a relevant therapy for FXS.
DOI: 10.3390/genes7090056
PMCID: PMC5042387
PMID: 27589806
Conflict of interest statement: A.B.-G., R.M. and A.O. declare intellectual
property of the patent PCT/EP2013/055728. The remaining authors declare no
conflict of interest.