A restricted population of CB1 cannabinoid receptors with neuroprotective activity

被引:122
作者
Chiarlone, Anna [1 ,2 ]
Bellocchio, Luigi [1 ,2 ]
Blazquez, Cristina [1 ,2 ]
Resel, Eva [1 ,2 ]
Soria-Gomez, Edgar [3 ,4 ]
Cannich, Astrid [3 ,4 ]
Ferrero, Jose J. [5 ]
Sagredo, Onintza [1 ,6 ]
Benito, Cristina [7 ]
Romero, Julian [7 ]
Sanchez-Prieto, Jose [5 ]
Lutz, Beat [8 ]
Fernandez-Ruiz, Javier [1 ,6 ]
Galve-Roperh, Ismael [1 ,2 ]
Guzman, Manuel [1 ,2 ]
机构
[1] Inst Ramon & Cajal Invest Sanitaria, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28040, Spain
[2] Univ Complutense, Inst Univ Invest Neuroquim, Dept Biochem & Mol Biol 1, E-28040 Madrid, Spain
[3] INSERM, NeuroCtr Magendie U862, F-33077 Bordeaux, France
[4] Univ Bordeaux, NeuroCtr Magendie U862, F-33077 Bordeaux, France
[5] Univ Complutense, Dept Biochem & Mol Biol 4, E-28040 Madrid, Spain
[6] Univ Complutense, Inst Univ Invest Neuroquim, Dept Biochem & Mol Biol 3, E-28040 Madrid, Spain
[7] Hosp Univ Fdn Alcorcon, Res Unit, Madrid 28922, Spain
[8] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55099 Mainz, Germany
关键词
neuroprotection; neuromodulation; excitotoxicity; PROTEIN-COUPLED RECEPTORS; HUNTINGTONS-DISEASE MICE; ENDOCANNABINOID SYSTEM; TRANSGENIC MICE; BASAL GANGLIA; NEURONS; HIPPOCAMPUS; EXPRESSION; PHENOTYPE; KEY;
D O I
10.1073/pnas.1400988111
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The CB1 cannabinoid receptor, the main molecular target of endo-cannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. Of note, CB1 receptors are expressed at the synapses of two opposing (i.e., GABAergic/inhibitory and glutamatergic/excitatory) neuronal populations, so the activation of one and/or another receptor population may conceivably evoke different effects. Despite the widely reported neuroprotective activity of the CB1 receptor in animal models, the precise pathophysiological relevance of those two CB1 receptor pools in neurodegenerative processes is unknown. Here, we first induced excitotoxic damage in the mouse brain by (i) administering quinolinic acid to conditional mutant animals lacking CB1 receptors selectively in GABAergic or glutamatergic neurons, and (ii) manipulating corticostriatal glutamatergic projections remotely with a designer receptor exclusively activated by designer drug pharmacogenetic approach. We next examined the alterations that occur in the R6/2 mouse, a well-established model of Huntington disease, upon (i) fully knocking out CB1 receptors, and (ii) deleting CB1 receptors selectively in corticostriatal glutamatergic or striatal GABAergic neurons. The data unequivocally identify the restricted population of CB1 receptors located on glutamatergic terminals as an indispensable player in the neuroprotective activity of (endo) cannabinoids, therefore suggesting that this precise receptor pool constitutes a promising target for neuroprotective therapeutic strategies.
引用
收藏
页码:8257 / 8262
页数:6
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