RT Journal Article
T1 Preclinical Investigation in Neuroprotective Effects of the GPR55 Ligand VCE-006.1 in Experimental Models of Parkinson's Disease and Amyotrophic Lateral Sclerosis
A1 Burgaz, Sonia
A1 Garcia, Concepcion
A1 Gonzalo-Consuegra, Claudia
A1 Gomez-Almeria, Marta
A1 Ruiz-Pino, Francisco
A1 Unciti, Juan Diego
A1 Gomez-Canas, Maria
A1 Alcalde, Juan
A1 Morales, Paula
A1 Jagerovic, Nadine
A1 Rodriguez-Cueto, Carmen
A1 de Lago, Eva
A1 Munoz, Eduardo
A1 Fernandez-Ruiz, Javier
K1 cannabinoids
K1 GPR55 receptors
K1 VCE-006
K1 1
K1 chromenopyrazole
K1 Parkinson's disease
K1 6-hydroxydopamine
K1 lipopolysaccharide
K1 amyotrophic lateral sclerosis
K1 mSOD1 mice
K1 TDP-43 transgenic mice
K1 Cannabinoid cb2 receptor
K1 Spinal-cord
K1 Mouse model
K1 Neurons
K1 Mice
K1 Activation
K1 Target
K1 Phytocannabinoids
K1 Identification
K1 Combination
AB Cannabinoids act as pleiotropic compounds exerting, among others, a broad-spectrum of neuroprotective effects. These effects have been investigated in the last years in different preclinical models of neurodegeneration, with the cannabinoid type-1 (CB1) and type-2 (CB2) receptors concentrating an important part of this research. However, the issue has also been extended to additional targets that are also active for cannabinoids, such as the orphan G-protein receptor 55 (GPR55). In the present study, we investigated the neuroprotective potential of VCE-006.1, a chromenopyrazole derivative with biased orthosteric and positive allosteric modulator activity at GPR55, in murine models of two neurodegenerative diseases. First, we proved that VCE-006.1 alone could induce ERK1/2 activation and calcium mobilization, as well as increase cAMP response but only in the presence of lysophosphatidyl inositol. Next, we investigated this compound administered chronically in two neurotoxin-based models of Parkinson's disease (PD), as well as in some cell-based models. VCE-006.1 was active in reversing the motor defects caused by 6-hydroxydopamine (6-OHDA) in the pole and the cylinder rearing tests, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity detected in the substantia nigra. Similar cytoprotective effects were found in vitro in SH-SY5Y cells exposed to 6-OHDA. We also investigated VCE-006.1 in LPS-lesioned mice with similar beneficial effects, except against glial reactivity and associated inflammatory events, which remained unaltered, a fact confirmed in BV2 cells treated with LPS and VCE-006.1. We also analyzed GPR55 in these in vivo models with no changes in its gene expression, although GPR55 was down-regulated in BV2 cells treated with LPS, which may explain the lack of efficacy of VCE-006.1 in such an assay. Furthermore, we investigated VCE-006.1 in two genetic models of amyotrophic lateral sclerosis (ALS), mutant SOD1, or TDP-43 transgenic mice. Neither the neurological decline nor the deteriorated rotarod performance were prevented with this compound, and the same happened with the elevated microglial and astroglial reactivities, albeit modest spinal motor neuron preservation was achieved in both models. We also analyzed GPR55 in these in vivo models and found no changes in both TDP-43 transgenic and mSOD1 mice. Therefore, our findings support the view that targeting the GPR55 may afford neuroprotection in experimental PD, but not in ALS, thus stressing the specificities for the development of cannabinoid-based therapies in the different neurodegenerative disorders.
PB Mdpi
YR 2021
FD 2021-12-01
LK https://hdl.handle.net/10668/25635
UL https://hdl.handle.net/10668/25635
LA en
DS RISalud
RD Apr 6, 2025