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In a recent study, we described the neuroprotective properties of VCE-003.2-an aminoquinone derivative of the non-psychotropic phytocannabinoid cannabigerol (CBG)-administered intraperitoneally (i.p.) in an inflammatory model of Parkinson's disease (PD). We also demonstrated that these properties derive from its activity on the peroxisome proliferator-activated receptor-gamma, in particular at a regulatory site within this receptor type. In the present study, we wanted to further confirm this neuroprotective potential using an oral lipid formulation of VCE-003.2, developed to facilitate the clinical development of this phytocannabinoid derivative. To this end, we evaluated VCE-003.2, administered orally at two doses (10 and 20 mg/kg), to mice subjected to unilateral intrastriatal injections of lipopolysaccharide (LPS), a classic model of inflammation-driven neuronal deterioration that recapitulates characteristics of PD. The administration of VCE-003.2 to these mice showed, as expected, poor activity in the different motor tests (rotarod, computer-aided actimeter) used in experimental parkinsonism, in general due to the lack of evident changes in these behaviors by LPS lesion. However, VCE-003.2, at 20 mg/kg, was highly active in improving the changes detected in LPS-lesioned mice in the cylinder rearing test. In addition, the histopathological analysis of the basal ganglia revealed a trend towards recovery at 20 mg/kg VCE-003.2 in the loss of tyrosine hydroxylase-containing nigrostriatal neurons, as well as a complete reduction in the elevated LAMP-1 immunolabeling (reflecting autophagy impairment) caused by LPS lesion. These effects were not seen at 10 mg/kg. This was associated with a partial reduction in the intense glial reactivity provoked by LPS in the substantia nigra, in particular the astroglial reactivity labeled with glial fibrillary acidic protein. The analysis using qPCR in the striatum of proinflammatory mediators, such as tumor necrosis factor-alpha, interleukin-1beta, inducible nitric oxide synthase, and cyclooxygenase-2, showed that the marked elevations provoked by the LPS lesion tended to be, in general, attenuated by VCE-003.2 treatment, with the greatest effects normally found with the highest dose of 20 mg/kg. In summary, our data confirm the neuroprotective potential of an oral formulation of VCE-003.2 against neuronal injury in an in vivo model of PD based on neuroinflammation, and this study opens the possibility to further the development of oral VCE-003.2 in the clinic.

16/01/2018 |
Benefits of VCE-003.2, a cannabigerol quinone derivative, against inflammation-driven neuronal deterioration in experimental Parkinson's disease: possible involvement of different binding sites at the PPARgamma receptor.
Garcia C, Gomez-Canas M, Burgaz S, Palomares B, Gomez-Galvez Y, Palomo-Garo C, Campo S, Ferrer-Hernandez J, Pavicic C, Navarrete C, Luz Bellido M, Garcia-Arencibia M, Ruth Pazos M, Munoz E, Fernandez-Ruiz J

BACKGROUND: Neuroprotection with cannabinoids in Parkinson's disease (PD) has been afforded predominantly with antioxidant or anti-inflammatory cannabinoids. In the present study, we investigated the anti-inflammatory and neuroprotective properties of VCE-003.2, a quinone derivative of the non-psychotrophic phytocannabinoid cannabigerol (CBG), which may derive its activity at the peroxisome proliferator-activated receptor-gamma (PPARgamma). The compound is also an antioxidant. METHODS: We evaluated VCE-003.2 in an in vivo [mice subjected to unilateral intrastriatal injections of lipopolysaccharide (LPS)] model of PD, as well as in in vitro (LPS-exposed BV2 cells and M-213 cells treated with conditioned media generated from LPS-exposed BV2 cells) cellular models. The type of interaction of VCE-003.2 at the PPARgamma receptor was furtherly investigated in bone marrow-derived human mesenchymal stem cells (MSCs) and sustained with transcriptional assays and in silico docking studies. RESULTS: VCE-003.2 has no activity at the cannabinoid receptors, a fact that we confirmed in this study using competition studies. The administration of VCE-003.2 to LPS-lesioned mice attenuated the loss of tyrosine hydroxylase (TH)-containing nigrostriatal neurons and, in particular, the intense microgliosis provoked by LPS in the substantia nigra, measured by Iba-1/Cd68 immunostaining. The analysis by qPCR of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and inducible nitric oxide synthase (iNOS) in the striatum showed they were markedly elevated by the LPS lesion and strongly reduced by the treatment with VCE-003.2. The effects of VCE-003.2 in LPS-lesioned mice implied the activation of PPARgamma receptors, as they were attenuated when VCE-003.2 was co-administered with the PPARgamma inhibitor T0070907. We then moved to some in vitro approaches, first to confirm the anti-inflammatory profile of VCE-003.2 in cultured BV2 cells exposed to LPS. VCE-003.2 was able to attenuate the synthesis and release of TNF-alpha and IL-1beta, as well as the induction of iNOS and cyclooxygenase-2 (COX-2) elicited by LPS in these cells. However, we found such effects were not reversed by GW9662, another classic PPARgamma antagonist. Next, we investigated the neuroprotective effects of VCE-003.2 in cultured M-213 neuronal cells exposed to conditioned media generated from LPS-exposed cultured BV2 cells. VCE-003.2 reduced M-213 cell death, but again, such effects were not reversed by T0070907. Using docking analysis, we detected that VCE-003.2 binds both the canonical and the alternative binding sites in the PPARgamma ligand-binding pocket (LBP). Functional assays further showed that T0070907 almost abolished PPARgamma transcriptional activity induced by rosiglitazone (RGZ), but it did not affect the activity of VCE-003.2 in a Gal4-Luc system. However, T0070907 inhibited the effects of RGZ and VCE-003.2 on the expression of PPARgamma-dependent genes upregulated in MSCs. CONCLUSIONS: We have demonstrated that VCE-003.2 is neuroprotective against inflammation-driven neuronal damage in an in vivo model of PD and in in vitro cellular models of neuroinflammation. Such effects might involve PPARgamma receptors, although in silico and in vitro experiments strongly suggest that VCE-003.2 targets PPARgamma by acting through two binding sites at the LBP, one that is sensitive to T0070907 (canonical binding site) and other that is not affected by this PPARgamma antagonist (alternative binding site).