%0 Journal Article
%A García García, María Concepción
%A Gómez Cañas, María
%A Burgaz García-Oteyza, Sonia
%A Gómez Gálvez, Yolanda
%A Palomo Garo, Cristina
%A Campo, Sara
%A Ferrer Hernández, Joel
%A García Arencibia, Moisés
%A Pazos, Ruth M.
%A Fernández Ruiz, José Javier
%T 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 PPARγ receptor
%D 2018
%@ 1742-2094
%U https://hdl.handle.net/20.500.14352/93328
%X Background: Neuroprotection with cannabinoids in Parkinson’s disease (PD) has been afforded predominantlywith antioxidant or anti-inflammatory cannabinoids. In the present study, we investigated the anti-inflammatoryand neuroprotective properties of VCE-003.2, a quinone derivative of the non-psychotrophic phytocannabinoidcannabigerol (CBG), which may derive its activity at the peroxisome proliferator-activated receptor-γ (PPARγ). Thecompound 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 conditionedmedia generated from LPS-exposed BV2 cells) cellular models. The type of interaction of VCE-003.2 at thePPARγ 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 usingcompetition studies. The administration of VCE-003.2 to LPS-lesioned mice attenuated the loss of tyrosinehydroxylase (TH)-containing nigrostriatal neurons and, in particular, the intense microgliosis provoked by LPSin the substantia nigra, measured by Iba-1/Cd68 immunostaining. The analysis by qPCR of proinflammatorymediators such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and inducible nitric oxide synthase(iNOS) in the striatum showed they were markedly elevated by the LPS lesion and strongly reduced by thetreatment with VCE-003.2. The effects of VCE-003.2 in LPS-lesioned mice implied the activation of PPARγreceptors, as they were attenuated when VCE-003.2 was co-administered with the PPARγ inhibitor T0070907.We then moved to some in vitro approaches, first to confirm the anti-inflammatory profile of VCE-003.2 incultured BV2 cells exposed to LPS. VCE-003.2 was able to attenuate the synthesis and release of TNF-α and IL 1β, 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 PPARγ antagonist. Next, we investigatedthe neuroprotective effects of VCE-003.2 in cultured M-213 neuronal cells exposed to conditioned media generatedfrom LPS-exposed cultured BV2 cells. VCE-003.2 reduced M-213 cell death, but again, such effects were not reversed byT0070907. Using docking analysis, we detected that VCE-003.2 binds both the canonical and the alternative bindingsites in the PPARγ ligand-binding pocket (LBP). Functional assays further showed that T0070907 almost abolishedPPARγ transcriptional activity induced by rosiglitazone (RGZ), but it did not affect the activity of VCE-003.2 in a Gal4-Lucsystem. However, T0070907 inhibited the effects of RGZ and VCE-003.2 on the expression of PPARγ-dependent genesupregulated in MSCs.Conclusions: We have demonstrated that VCE-003.2 is neuroprotective against inflammation-driven neuronal damagein an in vivo model of PD and in in vitro cellular models of neuroinflammation. Such effects might involve PPARγreceptors, although in silico and in vitro experiments strongly suggest that VCE-003.2 targets PPARγ by acting throughtwo binding sites at the LBP, one that is sensitive to T0070907 (canonical binding site) and other that is not affected bythis PPARγ antagonist (alternative binding site).
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