Chronic cannabinoid receptor stimulation selectively prevents motor impairments in a mouse model of Huntington’s disease.
Neuropharmacology. 2015-02-01; 89: 368-374
DOI: 10.1016/j.neuropharm.2014.07.021
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Pietropaolo S(1), Bellocchio L(2), Ruiz-Calvo A(2), Cabanas M(3), Du Z(3), Guzmán M(2), Garret M(3), Cho YH(3).
Author information:
(1)Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS UMR
5287, Bat B2 – Avenue des Facultés, 33405 Talence Cedex, France; Université de
Bordeaux, Bat B2 – Avenue des Facultés, 33405 Talence Cedex, France. Electronic
address: .
(2)Department of Biochemistry and Molecular Biology I, School of Biology,
Complutense University and CIBERNED, 2 Calle José Antonio Novais, 28040 Madrid,
Spain.
(3)Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, CNRS UMR
5287, Bat B2 – Avenue des Facultés, 33405 Talence Cedex, France; Université de
Bordeaux, Bat B2 – Avenue des Facultés, 33405 Talence Cedex, France.
Huntington’s disease (HD) is a devastating neurodegenerative disease
characterized by a progressive decline in motor abilities, as well as in
cognitive and social behaviors. Most of these behavioral deficits are
recapitulated in the R6/1 transgenic mouse, which can therefore be used as an
experimental model to identify the neurobiological substrates of HD pathology
and to design novel therapeutic approaches. The endocannabinoid system (ECS) is
a relevant candidate to participate in the etiopathology of HD as it is a key
modulator of brain function, especially in areas primarily affected by HD
dysfunction such as the striatum. Thus, some studies have demonstrated an
association between HD progression and alterations in the expression of several
ECS elements, thereby suggesting that improving ECS function may constitute a
useful strategy to eliminate or at least delay the appearance of HD symptoms.
Here this hypothesis was specifically tested by evaluating whether the
administration of a well-characterized cannabinoid receptor agonist (WIN
55,212), either acutely or chronically, improves the HD-like symptoms in R6/1
mice. While acute treatment did not change the behavioral phenotype of
transgenic animals, chronic administration was able to prevent the appearance of
motor deficits, to increase the number of striatal huntingtin inclusions and to
prevent the loss of striatal medium-sized spiny neurons, without affecting the
social or cognitive alterations. These findings suggest that prolonged
administration of cannabinoid receptor agonists could be an appropriate strategy
for selectively improving motor symptoms and stimulating neuroprotective
processes in HD patients.
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