Expression of GPR55 and either cannabinoid CB1 or CB2 heteroreceptor complexes in the caudate, putamen, and accumbens nuclei of control, parkinsonian, and dyskinetic non-human primates

Abstract

Endocannabinoids are neuromodulators acting on specific cannabinoid CB 1 and CB 2 G-protein-coupled receptors (GPCRs), representing potential therapeutic targets for neurodegenerative diseases. Cannabinoids also regulate the activity of GPR55, a recently "deorphanized" GPCR that directly interacts with CB 1 and with CB 2 receptors. Our hypothesis is that these heteromers may be taken as potential targets for Parkinson's disease (PD). This work aims at assessing the expression of heteromers made of GPR55 and CB 1 /CB 2 receptors in the striatum of control and parkinsonian macaques (with and without levodopainduced dyskinesia). For this purpose, double blind in situ proximity ligation assays, enabling the detection of GPCR heteromers in tissue samples, were performed in striatal sections of control, MPTP-treated and MPTP-treated animals rendered dyskinetic by chronic treatment with levodopa. Image analysis and statistical assessment were performed using dedicated software. We have previously demonstrated the formation of heteromers between GPR55 and CB 1 receptor (CB 1 -GPR55_ Hets), which is highly expressed in the central nervous system (CNS), but also with the CB 2 receptor (CB 2 -GPR55_Hets). Compared to the baseline expression of CB 1 -GPR55_Hets in control animals, our results showed increased expression levels in basal ganglia input nuclei of MPTP-treated animals. These observed increases in CB 1 -GPR55_Hets returned back to baseline levels upon chronic treatment with levodopa in dyskinetic animals. Obtained data regarding CB 2 -GPR55_Hets were quite similar, with somehow equivalent amounts in control and dyskinetic animals, and with increased expression levels in MPTP animals. Taken together, the detected increased expression of GPR55-endocannabinoid heteromers appoints these GPCR complexes as potential non-dopaminergic targets for PD therapy.

Preclinical Investigation in Neuroprotective Effects of the GPR55 Ligand VCE-006.1 in Experimental Models of Parkinson’s Disease and Amyotrophic Lateral Sclerosis

“…In our study, this neuroprotective effect was evident in two in vivo models of PD generated by 6-OHDA or, to a lower extent, LPS lesions in mice, and was also confirmed in an in vitro cell-based model (SH-SY5Y cells exposed to 6-OHDA). Similar benefits have been observed with other GPR55-acting compounds using additional experimental models, such as MPTP-lesioned mice and a murine model of haloperidol-induced catalepsy [51], and the same happens with more recent studies conducted by Martínez-Pinilla and coworkers [52,71]. However, whereas the neuroprotection seen in 6-OHDA-lesioned mice with VCE-006.1 in our study was accompanied by an attenuation of the reactive gliosis elicited by the neurotoxin, this did not occur in the LPS-lesioned mice, in which the inflammatory response caused by LPS has been proposed to be the primary cause of further neuropathological events (e.g., loss of TH-positive neurons, motor defects).…”

“…In addition, GPR55-deficient mice develop, among others, important impairments in motor control and coordination [53]. This possibly explains that neurodegenerative disorders such as Alzheimer's disease and related dementias have been explored for determining the neuroprotective potential of GPR55-targeting compounds only recently [69,70], whereas movement-related disorders, in particular PD, are within those neurodegenerative pathologies investigated earlier and more extensively in relation with the GPR55 ligands [51,52,71,72]. Our present study has been designed to pursue the objective of developing a GPR55-based neuroprotective therapy for PD and also by other motor-related pathologies, for example, ALS.…”

The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors

“…Also missing are the recently described interactions of the CB 2 R with glutamate N-Methyl-D-Asp (NMDA) ionotropic receptors ( Rivas-Santisteban et al, 2021 ). From a therapeutic perspective, the fact that CB 2 R may interact with other receptors that are also targeted by cannabinoids, for instance with GPR18 and GPR55, is of high interest ( Balenga et al, 2014 ; Reyes-Resina et al, 2018 ; Martínez-Pinilla et al, 2019 ; Martínez-Pinilla et al, 2020 ; Rivas-Santisteban et al, 2021 ).…”

Regulation of Expression of Cannabinoid CB2 and Serotonin 5HT1A Receptor Complexes by Cannabinoids in Animal Models of Hypoxia and in Oxygen/Glucose-Deprived Neurons

“…G-protein-coupled receptors may lead to protein–protein interactions resulting in heteromers, whose properties are different from those displayed by monomeric receptors [ 30 , 31 , 32 ]. Some of the CBD targets can form heteromers; among others, GPR55 with cannabinoid CB 1 or CB 2 receptors and the 5HT 1A receptor with the cannabinoid CB 2 receptor [ 25 , 33 , 34 , 35 , 36 ]. In addition, the pharmacological effects of CBD at cannabinoid receptors have been reported to depend on whether or not CB 1 -CB 2 receptor heteromers are formed [ 37 ].…”