TY - JOUR
T1 - GPR55
T2 - A therapeutic target for Parkinson's disease?
AU - Celorrio, Marta
AU - Rojo-Bustamante, Estefanía
AU - Fernández-Suárez, Diana
AU - Sáez, Elena
AU - Estella-Hermoso de Mendoza, Ander
AU - Müller, Christa E.
AU - Ramírez, María J.
AU - Oyarzábal, Julen
AU - Franco, Rafael
AU - Aymerich, María S.
N1 - Funding Information:
This work was supported by the projects PI14/02070 and SAF2012-39875-C02-01 from the Spanish Government (Plan estatal I+D+I 2013–2016 and ISCIII-FEDER) and by the Fundación Gangoiti. Estefanía Rojo was supported by a predoctoral fellowship from Colfuturo. We thank Diana Horn for the synthesis, and Dr. Viktor Rempel for the in vitro testing of PSB-1216. Diana Horn and Christa Müller were supported by the Deutsche Forschungsgemeinschaft (GRK1873). The authors have no conflict of interest.
Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017/10
Y1 - 2017/10
N2 - The GPR55 receptor is expressed abundantly in the brain, especially in the striatum, suggesting it might fulfill a role in motor function. Indeed, motor behavior is impaired in mice lacking GPR55, which also display dampened inflammatory responses. Abnormal-cannabidiol (Abn-CBD), a synthetic cannabidiol (CBD) isomer, is a GPR55 agonist that may serve as a therapeutic agent in the treatment of inflammatory diseases. In this study, we explored whether modulating GPR55 could also represent a therapeutic approach for the treatment of Parkinson's disease (PD). The distribution of GPR55 mRNA was first analyzed by in situ hybridization, localizing GPR55 transcripts to neurons in brain nuclei related to movement control, striatum, globus pallidus, subthalamic nucleus, substantia nigra and cortex. Striatal expression of GPR55 was downregulated in parkinsonian conditions. When Abn-CBD and CBD (5 mg/kg) were chronically administered to mice treated over 5 weeks with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp), Abn-CBD but not CBD prevented MPTPp induced motor impairment. Although Abn-CBD protected dopaminergic cell bodies, it failed to prevent degeneration of the terminals or preserve dopamine levels in the striatum. Both compounds induced morphological changes in microglia that were compatible with an anti-inflammatory phenotype that did not correlate with a neuroprotective activity. The symptomatic relief of Abn-CBD was further studied in the haloperidol-induced catalepsy mouse model. Abn-CBD had an anti-cataleptic effect that was reversed by CBD and PSB1216, a newly synthesized GPR55 antagonist, and indeed, two other GPR55 agonists also displayed anti-cataleptic effects (CID1792197 and CID2440433). These results demonstrate for the first time that activation of GPR55 might be beneficial in combating PD.
AB - The GPR55 receptor is expressed abundantly in the brain, especially in the striatum, suggesting it might fulfill a role in motor function. Indeed, motor behavior is impaired in mice lacking GPR55, which also display dampened inflammatory responses. Abnormal-cannabidiol (Abn-CBD), a synthetic cannabidiol (CBD) isomer, is a GPR55 agonist that may serve as a therapeutic agent in the treatment of inflammatory diseases. In this study, we explored whether modulating GPR55 could also represent a therapeutic approach for the treatment of Parkinson's disease (PD). The distribution of GPR55 mRNA was first analyzed by in situ hybridization, localizing GPR55 transcripts to neurons in brain nuclei related to movement control, striatum, globus pallidus, subthalamic nucleus, substantia nigra and cortex. Striatal expression of GPR55 was downregulated in parkinsonian conditions. When Abn-CBD and CBD (5 mg/kg) were chronically administered to mice treated over 5 weeks with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp), Abn-CBD but not CBD prevented MPTPp induced motor impairment. Although Abn-CBD protected dopaminergic cell bodies, it failed to prevent degeneration of the terminals or preserve dopamine levels in the striatum. Both compounds induced morphological changes in microglia that were compatible with an anti-inflammatory phenotype that did not correlate with a neuroprotective activity. The symptomatic relief of Abn-CBD was further studied in the haloperidol-induced catalepsy mouse model. Abn-CBD had an anti-cataleptic effect that was reversed by CBD and PSB1216, a newly synthesized GPR55 antagonist, and indeed, two other GPR55 agonists also displayed anti-cataleptic effects (CID1792197 and CID2440433). These results demonstrate for the first time that activation of GPR55 might be beneficial in combating PD.
KW - Cannabinoids
KW - GPR55
KW - Neuroprotection
KW - Parkinson's disease
UR - http://www.scopus.com/inward/record.url?scp=85027488482&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2017.08.017
DO - 10.1016/j.neuropharm.2017.08.017
M3 - Article
C2 - 28807673
AN - SCOPUS:85027488482
SN - 0028-3908
VL - 125
SP - 319
EP - 332
JO - Neuropharmacology
JF - Neuropharmacology
ER -