Neuroprotection with the Cannabidiol Quinone Derivative VCE-004.8 (EHP-101) against 6-Hydroxydopamine in Cell and Murine Models of Parkinson's Disease.

Sonia Burgaz,María Gómez-Cañas,Eduardo Muñoz,Alain Rolland,Concepción García,Javier Fernández-Ruiz

doi:10.3390/molecules26113245

Abstract

The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson’s disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome proliferator-activated receptor-γ (PPAR-γ) and possibly other pathways. In the present study, we investigated VCE-004.8 (formulated as EHP-101 for oral administration), the 3-hydroxyquinone derivative of cannabidiol (CBD), with agonist activity at the cannabinoid receptor type-2 (CB2) receptor in addition to its activity at the PPAR-γ receptor. Studies were conducted in both in vivo (lesioned-mice) and in vitro (SH-SY5Y cells) models using the classic parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). Our data confirmed that the treatment with VCE-004.8 partially reduced the loss of tyrosine hydroxylase (TH)-positive neurons measured in the substantia nigra of 6-OHDA-lesioned mice, in parallel with an almost complete reversal of the astroglial (GFAP) and microglial (CD68) reactivity occurring in this structure. Such neuroprotective effects attenuated the motor deficiencies shown by 6-OHDA-lesioned mice in the cylinder rearing test, but not in the pole test. Next, we explored the mechanism involved in the beneficial effect of VCE-004.8 in vivo, by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-004.8 at a concentration of 10 µM, which was completely reversed by the addition of antagonists, T0070907 and SR144528, aimed at blocking PPAR-γ and CB2 receptors, respectively. The treatment with T0070907 alone only caused a partial reversal, whereas SR144528 alone had no effect, indicating a major contribution of PPAR-γ receptors in the cytoprotective effect of VCE-004.8 at 10 µM. In summary, our data confirmed the neuroprotective potential of VCE-004.8 in 6-OHDA-lesioned mice, and in vitro studies confirmed a greater relevance for PPAR-γ receptors rather than CB2 receptors in these effects.

Highlights

Phytocannabinoids, the active constituents of Cannabis plant, and endocannabinoids and synthetic cannabinoids have been proposed as promising neuroprotective agents, a property derived from their pleiotropism and ability to activate numerous cytoprotective targets within the endocannabinoid system, and outside this signaling system
The second part of our study consisted of a series of experiments conducted in a cell-based assay that is frequently used as an in vitro model of Parkinson’s disease (PD) [26], and that, in our case, was used as a way to confirm the in vivo data and, in particular, for exploring the potential targets (PPAR-γ and/or cannabinoid receptor type-2 (CB2) receptors) involved in the beneficial effects found with this CBD derivative
We carried out a concentration-response experiment to determine the best VCE-004.8 concentration to increase cell survival against the 6-OHDA (200 μM) insult according to similar experiments conducted in the same cell-based model with other phytocannabinoid derivatives [24]

Summary

Introduction

Phytocannabinoids, the active constituents of Cannabis plant, and endocannabinoids and synthetic cannabinoids have been proposed as promising neuroprotective agents, a property derived from their pleiotropism and ability to activate numerous cytoprotective targets within the endocannabinoid system, and outside this signaling system (reviewed in [1]) Such neuroprotective potential has been preclinically investigated in accidental brain damage (e.g., stroke, brain trauma, spinal injury) and, in particular, in chronic progressive disorders (e.g., Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and others) [2]. Strong neuroprotective properties in PD were found for those cannabinoids active against inflammation and glial reactivity, whose effects are exerted through the activation of the cannabinoid type-2 (CB2) receptor [15,16,17,18], and targeting the peroxisome proliferator-activated receptor-γ (PPAR-γ) [19,20] and the G protein-coupled receptor 55 (GPR55) [21]

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Results

Discussion

Conclusion