Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model
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 path...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Laprairie, Robert B. [verfasserIn] Bagher, Amina M. [verfasserIn] Rourke, Jillian L. [verfasserIn] Zrein, Adel [verfasserIn] Cairns, Elizabeth A. [verfasserIn] Kelly, Melanie E.M. [verfasserIn] Sinal, Christopher J. [verfasserIn] Kulkarni, Pushkar M. [verfasserIn] Thakur, Ganesh A. [verfasserIn] Denovan-Wright, Eileen M. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2019 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Neuropharmacology - Amsterdam [u.a.] : Elsevier Science, 1970, 151, Seite 1-12 |
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| Übergeordnetes Werk: |
volume:151 ; pages:1-12 |
| DOI / URN: |
10.1016/j.neuropharm.2019.03.033 |
|---|
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| 245 | 1 | 0 | |a Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model |
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| 520 | |a 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. | ||
| 650 | 4 | |a Cannabinoid | |
| 650 | 4 | |a Type 1 cannabinoid receptor | |
| 650 | 4 | |a Huntington's disease | |
| 650 | 4 | |a Allosteric modulator | |
| 650 | 4 | |a G protein-coupled receptor | |
| 650 | 4 | |a Neurodegeneration | |
| 700 | 1 | |a Bagher, Amina M. |e verfasserin |0 (orcid)0000-0002-1850-5686 |4 aut | |
| 700 | 1 | |a Rourke, Jillian L. |e verfasserin |4 aut | |
| 700 | 1 | |a Zrein, Adel |e verfasserin |4 aut | |
| 700 | 1 | |a Cairns, Elizabeth A. |e verfasserin |4 aut | |
| 700 | 1 | |a Kelly, Melanie E.M. |e verfasserin |4 aut | |
| 700 | 1 | |a Sinal, Christopher J. |e verfasserin |4 aut | |
| 700 | 1 | |a Kulkarni, Pushkar M. |e verfasserin |4 aut | |
| 700 | 1 | |a Thakur, Ganesh A. |e verfasserin |4 aut | |
| 700 | 1 | |a Denovan-Wright, Eileen M. |e verfasserin |4 aut | |
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10.1016/j.neuropharm.2019.03.033 doi (DE-627)ELV002175460 (ELSEVIER)S0028-3908(19)30113-3 DE-627 ger DE-627 rda eng 610 DE-600 PHARM DE-84 fid 44.38 bkl 44.90 bkl Laprairie, Robert B. verfasserin (orcid)0000-0002-9994-433X aut Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Cannabinoid Type 1 cannabinoid receptor Huntington's disease Allosteric modulator G protein-coupled receptor Neurodegeneration Bagher, Amina M. verfasserin (orcid)0000-0002-1850-5686 aut Rourke, Jillian L. verfasserin aut Zrein, Adel verfasserin aut Cairns, Elizabeth A. verfasserin aut Kelly, Melanie E.M. verfasserin aut Sinal, Christopher J. verfasserin aut Kulkarni, Pushkar M. verfasserin aut Thakur, Ganesh A. verfasserin aut Denovan-Wright, Eileen M. verfasserin aut Enthalten in Neuropharmacology Amsterdam [u.a.] : Elsevier Science, 1970 151, Seite 1-12 Online-Ressource (DE-627)30666125X (DE-600)1500655-4 (DE-576)081986831 1873-7064 nnns volume:151 pages:1-12 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.38 Pharmakologie 44.90 Neurologie AR 151 1-12 |
| spelling |
10.1016/j.neuropharm.2019.03.033 doi (DE-627)ELV002175460 (ELSEVIER)S0028-3908(19)30113-3 DE-627 ger DE-627 rda eng 610 DE-600 PHARM DE-84 fid 44.38 bkl 44.90 bkl Laprairie, Robert B. verfasserin (orcid)0000-0002-9994-433X aut Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Cannabinoid Type 1 cannabinoid receptor Huntington's disease Allosteric modulator G protein-coupled receptor Neurodegeneration Bagher, Amina M. verfasserin (orcid)0000-0002-1850-5686 aut Rourke, Jillian L. verfasserin aut Zrein, Adel verfasserin aut Cairns, Elizabeth A. verfasserin aut Kelly, Melanie E.M. verfasserin aut Sinal, Christopher J. verfasserin aut Kulkarni, Pushkar M. verfasserin aut Thakur, Ganesh A. verfasserin aut Denovan-Wright, Eileen M. verfasserin aut Enthalten in Neuropharmacology Amsterdam [u.a.] : Elsevier Science, 1970 151, Seite 1-12 Online-Ressource (DE-627)30666125X (DE-600)1500655-4 (DE-576)081986831 1873-7064 nnns volume:151 pages:1-12 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.38 Pharmakologie 44.90 Neurologie AR 151 1-12 |
| allfields_unstemmed |
10.1016/j.neuropharm.2019.03.033 doi (DE-627)ELV002175460 (ELSEVIER)S0028-3908(19)30113-3 DE-627 ger DE-627 rda eng 610 DE-600 PHARM DE-84 fid 44.38 bkl 44.90 bkl Laprairie, Robert B. verfasserin (orcid)0000-0002-9994-433X aut Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Cannabinoid Type 1 cannabinoid receptor Huntington's disease Allosteric modulator G protein-coupled receptor Neurodegeneration Bagher, Amina M. verfasserin (orcid)0000-0002-1850-5686 aut Rourke, Jillian L. verfasserin aut Zrein, Adel verfasserin aut Cairns, Elizabeth A. verfasserin aut Kelly, Melanie E.M. verfasserin aut Sinal, Christopher J. verfasserin aut Kulkarni, Pushkar M. verfasserin aut Thakur, Ganesh A. verfasserin aut Denovan-Wright, Eileen M. verfasserin aut Enthalten in Neuropharmacology Amsterdam [u.a.] : Elsevier Science, 1970 151, Seite 1-12 Online-Ressource (DE-627)30666125X (DE-600)1500655-4 (DE-576)081986831 1873-7064 nnns volume:151 pages:1-12 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.38 Pharmakologie 44.90 Neurologie AR 151 1-12 |
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10.1016/j.neuropharm.2019.03.033 doi (DE-627)ELV002175460 (ELSEVIER)S0028-3908(19)30113-3 DE-627 ger DE-627 rda eng 610 DE-600 PHARM DE-84 fid 44.38 bkl 44.90 bkl Laprairie, Robert B. verfasserin (orcid)0000-0002-9994-433X aut Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Cannabinoid Type 1 cannabinoid receptor Huntington's disease Allosteric modulator G protein-coupled receptor Neurodegeneration Bagher, Amina M. verfasserin (orcid)0000-0002-1850-5686 aut Rourke, Jillian L. verfasserin aut Zrein, Adel verfasserin aut Cairns, Elizabeth A. verfasserin aut Kelly, Melanie E.M. verfasserin aut Sinal, Christopher J. verfasserin aut Kulkarni, Pushkar M. verfasserin aut Thakur, Ganesh A. verfasserin aut Denovan-Wright, Eileen M. verfasserin aut Enthalten in Neuropharmacology Amsterdam [u.a.] : Elsevier Science, 1970 151, Seite 1-12 Online-Ressource (DE-627)30666125X (DE-600)1500655-4 (DE-576)081986831 1873-7064 nnns volume:151 pages:1-12 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.38 Pharmakologie 44.90 Neurologie AR 151 1-12 |
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10.1016/j.neuropharm.2019.03.033 doi (DE-627)ELV002175460 (ELSEVIER)S0028-3908(19)30113-3 DE-627 ger DE-627 rda eng 610 DE-600 PHARM DE-84 fid 44.38 bkl 44.90 bkl Laprairie, Robert B. verfasserin (orcid)0000-0002-9994-433X aut Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model 2019 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Cannabinoid Type 1 cannabinoid receptor Huntington's disease Allosteric modulator G protein-coupled receptor Neurodegeneration Bagher, Amina M. verfasserin (orcid)0000-0002-1850-5686 aut Rourke, Jillian L. verfasserin aut Zrein, Adel verfasserin aut Cairns, Elizabeth A. verfasserin aut Kelly, Melanie E.M. verfasserin aut Sinal, Christopher J. verfasserin aut Kulkarni, Pushkar M. verfasserin aut Thakur, Ganesh A. verfasserin aut Denovan-Wright, Eileen M. verfasserin aut Enthalten in Neuropharmacology Amsterdam [u.a.] : Elsevier Science, 1970 151, Seite 1-12 Online-Ressource (DE-627)30666125X (DE-600)1500655-4 (DE-576)081986831 1873-7064 nnns volume:151 pages:1-12 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 44.38 Pharmakologie 44.90 Neurologie AR 151 1-12 |
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English |
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Enthalten in Neuropharmacology 151, Seite 1-12 volume:151 pages:1-12 |
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Enthalten in Neuropharmacology 151, Seite 1-12 volume:151 pages:1-12 |
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Cannabinoid Type 1 cannabinoid receptor Huntington's disease Allosteric modulator G protein-coupled receptor Neurodegeneration |
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Laprairie, Robert B. @@aut@@ Bagher, Amina M. @@aut@@ Rourke, Jillian L. @@aut@@ Zrein, Adel @@aut@@ Cairns, Elizabeth A. @@aut@@ Kelly, Melanie E.M. @@aut@@ Sinal, Christopher J. @@aut@@ Kulkarni, Pushkar M. @@aut@@ Thakur, Ganesh A. @@aut@@ Denovan-Wright, Eileen M. @@aut@@ |
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2019-01-01T00:00:00Z |
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Laprairie, Robert B. |
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Laprairie, Robert B. ddc 610 fid PHARM bkl 44.38 bkl 44.90 misc Cannabinoid misc Type 1 cannabinoid receptor misc Huntington's disease misc Allosteric modulator misc G protein-coupled receptor misc Neurodegeneration Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model |
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610 DE-600 PHARM DE-84 fid 44.38 bkl 44.90 bkl Positive allosteric modulation of the type 1 cannabinoid receptor reduces the signs and symptoms of Huntington's disease in the R6/2 mouse model Cannabinoid Type 1 cannabinoid receptor Huntington's disease Allosteric modulator G protein-coupled receptor Neurodegeneration |
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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 |
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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 |
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Laprairie, Robert B. Bagher, Amina M. Rourke, Jillian L. Zrein, Adel Cairns, Elizabeth A. Kelly, Melanie E.M. Sinal, Christopher J. Kulkarni, Pushkar M. Thakur, Ganesh A. Denovan-Wright, Eileen M. |
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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 |
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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 |
| 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. |
| abstractGer |
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. |
| abstract_unstemmed |
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 |
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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.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Cannabinoid</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Type 1 cannabinoid receptor</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Huntington's disease</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Allosteric modulator</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">G protein-coupled receptor</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Neurodegeneration</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Bagher, Amina M.</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-1850-5686</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" 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7.399393 |