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

Abstract

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.

Intrapallidal injection of cannabidiol or a selective GPR55 antagonist decreases motor asymmetry and improves fine motor skills in hemiparkinsonian rats

“…They observed a beneficial neuroprotective effect on dopaminergic neurons injured by 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and an anti-inflammatory and anti-cataleptic effect as a result of GPR55 activation in parkinsonian mice models. Burgaz et al (2021) found similar results in two PD models, which revealed the neuroprotective effect of VCE-006.1, which is a chromenopyrazole derivative with biased orthosteric and positive allosteric modulator effects on GPR55. They found that the drug reversed motor dysfunction, the loss of tyrosine hydroxylase-containing neurons, and the elevated glial reactivity detected in the SNpc of parkinsonian mice.…”

Cannabidiol for neurodegenerative disorders: A comprehensive review

“…Recovery of dopamine depletion is observed when rats were treated with AM404 but not with UCM707, indicating antioxidant properties of phytocannabinoid molecules/analogue behind the neuroprotective role against PD which is further confirmed by upregulation of superoxide dismutase, a key endogenous enzyme against oxidative stress. It is worth mentioning that a recent study by the same group using a similar 6-HDA-induced cellular and murine model of PD demonstrates that the quinone derivative of CBD exhibits its neuroprotective behavior via PPAR-γ receptors ( Burgaz et al, 2021 ). Furthermore, recently, Giuliano et al have demonstrated that a higher dose of CBD (10 mg/KgBW) can reduce nigrostriatal degeneration and improve motor function in rats bearing 6-HDA-induced PD ( Giuliano et al, 2021 ).…”

Cannabinoids as Glial Cell Modulators in Ischemic Stroke: Implications for Neuroprotection

“…In particular, PPARα can be activated in vitro by the eCB-like compound PEA, leading to an increase in CB 2 R expression and 2-AG production ( Guida et al, 2017 ), and the migration capacity of these cells ( Franklin et al, 2003 ; Guida et al, 2017 ). The orphan receptor GPR55 is also expressed in microglia and is attracting special attention in different neuroinflammatory pathologies ( Marichal-Cancino, 2017 ; Saliba et al, 2018 ; Burgaz et al, 2021 ). This receptor appears to follow a similar expression pattern to CB 2 R when microglia are stimulated with LPS.…”