Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model

Robert B. Laprairie; Amina M. Bagher; Jillian L. Rourke; Adel Zrein; Elizabeth A. Cairns; Melanie E.M. Kelly; Christopher J. Sinal; Pushkar M. Kulkarni; Ganesh A. Thakur; Eileen M. Denovan-Wright

doi:10.1016/j.neuropharm.2019.03.033

Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model

Robert B. Laprairie, Amina M. Bagher, Jillian L. Rourke, Adel Zrein, Elizabeth A. Cairns, Melanie E.M. Kelly, Christopher J. Sinal, Pushkar M. Kulkarni, Ganesh A. Thakur, Eileen M. Denovan-Wright

Medicine

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43 Citas (Scopus)

Resumen

Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by motor, cognitive, and behavioural changes. One of the earliest changes to occur in HD is a reduction in cannabinoid 1 receptor (CB₁) levels in the striatum, which is strongly correlated with HD pathogenesis. CB₁ positive allosteric modulators (PAM) enhance receptor affinity for, and efficacy of activation by, orthosteric ligands, including the endocannabinoids anandamide and 2-arachidonoylglycerol. The goal of this study was to determine whether the recently characterized CB₁ allosteric modulators GAT211 (racemic), GAT228 (R-enantiomer), and GAT229 (S-enantiomer), affected the signs and symptoms of HD. GAT211, GAT228, and GAT229 were evaluated in normal and HD cell models, and in a transgenic mouse model of HD (7-week-old male R6/2 mice, 10 mg/kg/d, 21 d, i.p.). GAT229 was a CB₁ PAM that improved cell viability in HD cells and improved motor coordination, delayed symptom onset, and normalized gene expression in R6/2 HD mice. GAT228 was an allosteric agonist that did not enhance endocannabinoid signaling or change symptom progression in R6/2 mice. GAT211 displayed intermediate effects between its enantiomers. The compounds used here are not drugs, but probe compounds used to determine the potential utility of CB₁ PAMs in HD. Changes in gene expression, and not protein, were quantified in R6/2 HD mice because HD pathogenesis is associated with dysregulation of mRNA levels. The data presented here provide the first proof of principle for the use of CB₁ PAMs to treat the signs and symptoms of HD.

Idioma original	English
Páginas (desde-hasta)	1-12
Número de páginas	12
Publicación	Neuropharmacology
Volumen	151
DOI	https://doi.org/10.1016/j.neuropharm.2019.03.033
Estado	Published - jun. 2019

Nota bibliográfica

Funding Information:
This work was supported by Bridge Funding [Dalhousie University]; the Canadian Institutes of Health Research [MOP-97768]; the National Institutes of Health [DA027113, EY024717]. Studentships from CIHR, the Huntington Society of Canada, Killam Trusts, the Nova Scotia Health Research Foundation, and King AbdulAziz and Dalhousie Universities. The authors thank Kay Murphy for her assistance with animal behaviour and housing.

Funding Information:
This work was supported by Bridge Funding [Dalhousie University]; the Canadian Institutes of Health Research [ MOP-97768 ]; the National Institutes of Health [ DA027113 , EY024717 ]. Studentships from CIHR, the Huntington Society of Canada , Killam Trusts, the Nova Scotia Health Research Foundation , and King AbdulAziz and Dalhousie Universities.

Publisher Copyright:
© 2019

ASJC Scopus Subject Areas

Pharmacology
Cellular and Molecular Neuroscience

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1016/j.neuropharm.2019.03.033

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Laprairie, R. B., Bagher, A. M., Rourke, J. L., Zrein, A., Cairns, E. A., Kelly, M. E. M., Sinal, C. J., Kulkarni, P. M., Thakur, G. A., & Denovan-Wright, E. M. (2019). Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model. Neuropharmacology, 151, 1-12. https://doi.org/10.1016/j.neuropharm.2019.03.033

Laprairie, RB, Bagher, AM, Rourke, JL, Zrein, A, Cairns, EA, Kelly, MEM , Sinal, CJ, Kulkarni, PM, Thakur, GA & Denovan-Wright, EM 2019, 'Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model', Neuropharmacology, vol. 151, pp. 1-12. https://doi.org/10.1016/j.neuropharm.2019.03.033

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title = "Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model",

abstract = "Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by motor, cognitive, and behavioural changes. One of the earliest changes to occur in HD is a reduction in cannabinoid 1 receptor (CB1) levels in the striatum, which is strongly correlated with HD pathogenesis. CB1 positive allosteric modulators (PAM) enhance receptor affinity for, and efficacy of activation by, orthosteric ligands, including the endocannabinoids anandamide and 2-arachidonoylglycerol. The goal of this study was to determine whether the recently characterized CB1 allosteric modulators GAT211 (racemic), GAT228 (R-enantiomer), and GAT229 (S-enantiomer), affected the signs and symptoms of HD. GAT211, GAT228, and GAT229 were evaluated in normal and HD cell models, and in a transgenic mouse model of HD (7-week-old male R6/2 mice, 10 mg/kg/d, 21 d, i.p.). GAT229 was a CB1 PAM that improved cell viability in HD cells and improved motor coordination, delayed symptom onset, and normalized gene expression in R6/2 HD mice. GAT228 was an allosteric agonist that did not enhance endocannabinoid signaling or change symptom progression in R6/2 mice. GAT211 displayed intermediate effects between its enantiomers. The compounds used here are not drugs, but probe compounds used to determine the potential utility of CB1 PAMs in HD. Changes in gene expression, and not protein, were quantified in R6/2 HD mice because HD pathogenesis is associated with dysregulation of mRNA levels. The data presented here provide the first proof of principle for the use of CB1 PAMs to treat the signs and symptoms of HD.",

author = "Laprairie, {Robert B.} and Bagher, {Amina M.} and Rourke, {Jillian L.} and Adel Zrein and Cairns, {Elizabeth A.} and Kelly, {Melanie E.M.} and Sinal, {Christopher J.} and Kulkarni, {Pushkar M.} and Thakur, {Ganesh A.} and Denovan-Wright, {Eileen M.}",

note = "Funding Information: This work was supported by Bridge Funding [Dalhousie University]; the Canadian Institutes of Health Research [MOP-97768]; the National Institutes of Health [DA027113, EY024717]. Studentships from CIHR, the Huntington Society of Canada, Killam Trusts, the Nova Scotia Health Research Foundation, and King AbdulAziz and Dalhousie Universities. The authors thank Kay Murphy for her assistance with animal behaviour and housing. Funding Information: This work was supported by Bridge Funding [Dalhousie University]; the Canadian Institutes of Health Research [ MOP-97768 ]; the National Institutes of Health [ DA027113 , EY024717 ]. Studentships from CIHR, the Huntington Society of Canada , Killam Trusts, the Nova Scotia Health Research Foundation , and King AbdulAziz and Dalhousie Universities. Publisher Copyright: {\textcopyright} 2019",

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AU - Laprairie, Robert B.

AU - Bagher, Amina M.

AU - Rourke, Jillian L.

AU - Zrein, Adel

AU - Cairns, Elizabeth A.

AU - Kelly, Melanie E.M.

AU - Sinal, Christopher J.

AU - Kulkarni, Pushkar M.

AU - Thakur, Ganesh A.

AU - Denovan-Wright, Eileen M.

N1 - Funding Information: This work was supported by Bridge Funding [Dalhousie University]; the Canadian Institutes of Health Research [MOP-97768]; the National Institutes of Health [DA027113, EY024717]. Studentships from CIHR, the Huntington Society of Canada, Killam Trusts, the Nova Scotia Health Research Foundation, and King AbdulAziz and Dalhousie Universities. The authors thank Kay Murphy for her assistance with animal behaviour and housing. Funding Information: This work was supported by Bridge Funding [Dalhousie University]; the Canadian Institutes of Health Research [ MOP-97768 ]; the National Institutes of Health [ DA027113 , EY024717 ]. Studentships from CIHR, the Huntington Society of Canada , Killam Trusts, the Nova Scotia Health Research Foundation , and King AbdulAziz and Dalhousie Universities. Publisher Copyright: © 2019

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N2 - Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by motor, cognitive, and behavioural changes. One of the earliest changes to occur in HD is a reduction in cannabinoid 1 receptor (CB1) levels in the striatum, which is strongly correlated with HD pathogenesis. CB1 positive allosteric modulators (PAM) enhance receptor affinity for, and efficacy of activation by, orthosteric ligands, including the endocannabinoids anandamide and 2-arachidonoylglycerol. The goal of this study was to determine whether the recently characterized CB1 allosteric modulators GAT211 (racemic), GAT228 (R-enantiomer), and GAT229 (S-enantiomer), affected the signs and symptoms of HD. GAT211, GAT228, and GAT229 were evaluated in normal and HD cell models, and in a transgenic mouse model of HD (7-week-old male R6/2 mice, 10 mg/kg/d, 21 d, i.p.). GAT229 was a CB1 PAM that improved cell viability in HD cells and improved motor coordination, delayed symptom onset, and normalized gene expression in R6/2 HD mice. GAT228 was an allosteric agonist that did not enhance endocannabinoid signaling or change symptom progression in R6/2 mice. GAT211 displayed intermediate effects between its enantiomers. The compounds used here are not drugs, but probe compounds used to determine the potential utility of CB1 PAMs in HD. Changes in gene expression, and not protein, were quantified in R6/2 HD mice because HD pathogenesis is associated with dysregulation of mRNA levels. The data presented here provide the first proof of principle for the use of CB1 PAMs to treat the signs and symptoms of HD.

AB - Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by motor, cognitive, and behavioural changes. One of the earliest changes to occur in HD is a reduction in cannabinoid 1 receptor (CB1) levels in the striatum, which is strongly correlated with HD pathogenesis. CB1 positive allosteric modulators (PAM) enhance receptor affinity for, and efficacy of activation by, orthosteric ligands, including the endocannabinoids anandamide and 2-arachidonoylglycerol. The goal of this study was to determine whether the recently characterized CB1 allosteric modulators GAT211 (racemic), GAT228 (R-enantiomer), and GAT229 (S-enantiomer), affected the signs and symptoms of HD. GAT211, GAT228, and GAT229 were evaluated in normal and HD cell models, and in a transgenic mouse model of HD (7-week-old male R6/2 mice, 10 mg/kg/d, 21 d, i.p.). GAT229 was a CB1 PAM that improved cell viability in HD cells and improved motor coordination, delayed symptom onset, and normalized gene expression in R6/2 HD mice. GAT228 was an allosteric agonist that did not enhance endocannabinoid signaling or change symptom progression in R6/2 mice. GAT211 displayed intermediate effects between its enantiomers. The compounds used here are not drugs, but probe compounds used to determine the potential utility of CB1 PAMs in HD. Changes in gene expression, and not protein, were quantified in R6/2 HD mice because HD pathogenesis is associated with dysregulation of mRNA levels. The data presented here provide the first proof of principle for the use of CB1 PAMs to treat the signs and symptoms of HD.

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Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

PubMed: MeSH publication types

Acceder al documento

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