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 M1, Matute C2,3,4, Maldonado R5, Mato S6,7,8, Ozaita A9.
1Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and Health Sciences, Program of Genetics and Neurosciences, University Pompeu Fabra, Barcelona 08003, Spain. maria.gomis@upf.edu.
2Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa 48940, Spain. carlos.matute@ehu.eus.
3Achucarro Basque Center for Neuroscience, Zamudio 48170, Spain. carlos.matute@ehu.eus.
4Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid 28031, Spain. carlos.matute@ehu.eus.
5Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and Health Sciences, Program of Genetics and Neurosciences, University Pompeu Fabra, Barcelona 08003, Spain. rafael.maldonado@upf.edu.
6Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa 48940, Spain. susana.mato@ehu.eus.
7Achucarro Basque Center for Neuroscience, Zamudio 48170, Spain. susana.mato@ehu.eus.
8Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid 28031, Spain. susana.mato@ehu.eus.
9Laboratory of Neuropharmacology-NeuroPhar, Department of Experimental and Health Sciences, Program of Genetics and Neurosciences, University Pompeu Fabra, Barcelona 08003, Spain. andres.ozaita@upf.edu.
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 Rimonabant was commercialized at high doses for its anti-obesity properties, and withdrawn from the market on the bases of mood-related adverse effects.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. |
