Person: Burgaz García-Oteyza, Sonia
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First Name
Sonia
Last Name
Burgaz García-Oteyza
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Bioquímica y Biología Molecular
Area
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Item 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(Journal of Neuroinflammation, 2018) García García, María Concepción; Gómez Cañas, María; Burgaz García-Oteyza, Sonia; Gómez Gálvez, Yolanda; Palomo Garo, Cristina; Campo, Sara; Ferrer Hernández, Joel; García Arencibia, Moisés; Pazos, Ruth M.; Fernández Ruiz, José JavierBackground: 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-γ (PPARγ). 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 PPARγ 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-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 the treatment with VCE-003.2. The effects of VCE-003.2 in LPS-lesioned mice implied the activation of PPARγ receptors, 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 in cultured 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 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 PPARγ ligand-binding pocket (LBP). Functional assays further showed that T0070907 almost abolished PPARγ 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 PPARγ-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 PPARγ receptors, although in silico and in vitro experiments strongly suggest that VCE-003.2 targets PPARγ 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 PPARγ antagonist (alternative binding site).- Project number: 310
Item Diseño de la asignatura de Bioquímica del Grado de Fisioterapia: elaboración de materiales para el aprendizaje a través de la clase invertida(2021) Sagredo Ezquioga, Onintza; Lago Femia, Eva de; García García, María Concepción; Fernández Ruiz, José Javier; Navas Hernández, María de los Ángeles; Hernández Fisac, Inés; Gómez Cañas, María; Rodríguez Cueto, Carmen; Alonso Gómez, Cristina; Díez Gutiérrez, Paula; García Toscano, Laura; Burgaz García-Oteyza, Sonia; Santos-García Sanz, Irene Item BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis(International Journal of Molecular Sciences, 2021) Gómez Almería, Marta; Burgaz García-Oteyza, Sonia; Costas Insua, Carlos; Rodríguez Cueto, Carmen; Santos García, Irene; Rodríguez Crespo, Ignacio; García García, María De La Concepción; Guzmán Pastor, Manuel; Fernández Ruiz, JavierIn the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.Item BiP Heterozigosity Aggravates Pathological Deterioration in Experimental Amyotrophic Lateral Sclerosis(International Journal of Molecular Sciences, 2021) Gómez Almería, Marta; Burgaz García-Oteyza, Sonia; Costas Insua, Carlos; Rodríguez Cueto, Carmen; Santos García, Irene; Rodríguez Crespo, Ignacio; García García, María De La Concepción; Guzmán Pastor, Manuel; Lago Femia, Eva de; Fernández Ruiz, JavierIn the present study, we investigated the involvement of the chaperone protein BiP (also known as GRP78 or Hspa5), a master regulator of intracellular proteostasis, in two mouse models of neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). To this end, we used mice bearing partial genetic deletion of the BiP gene (BiP+/− mice), which, for the ALS model, were crossed with mutant SOD1 (mSOD1) transgenic mice to generate mSOD1/BiP+/− double mutant mice. Our data revealed a more intense neurological decline in the double mutants, reflected in a greater deterioration of the neurological score and rotarod performance, with also a reduced animal survival, compared to mSOD1 transgenic mice. Such worsening was associated with higher microglial (labelled with Iba-1 immunostaining) and, to a lesser extent, astroglial (labelled with GFAP immunostaining) immunoreactivities found in the double mutants, but not with a higher loss of spinal motor neurons (labelled with Nissl staining) in the spinal cord. The morphological analysis of Iba-1 and GFAP-positive cells revealed a higher presence of activated cells, characterized by elevated cell body size and shorter processes, in double mutants compared to mSOD1 mice with normal BiP expression. In the case of the PD model, BiP+/− mice were unilaterally lesioned with the parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). In this case, however, we did not detect a greater susceptibility to damage in mutant mice, as the motor defects caused by 6-OHDA in the pole test and the cylinder rearing test, as well as the losses in tyrosine hydroxylase-containing neurons and the elevated glial reactivity (labelled with CD68 and GFAP immunostaining) detected in the substantia nigra were of similar magnitude in BiP+/− mice compared with wildtype animals. Therefore, our findings support the view that a dysregulation of the protein BiP may contribute to ALS pathogenesis. As BiP has been recently related to cannabinoid type-1 (CB1) receptor function, our work also opens the door to future studies on a possible link between BiP and the neuroprotective effects of cannabinoids that have been widely reported in this neuropathological context. In support of this possibility, preliminary data indicate that CB1 receptor levels are significantly reduced in mSOD1 mice having partial deletion of BiP gene.Item CB2, PPAR-γ and GPR55 as pharmacological targets for an anti-inflammatory and neuroprotective treatment of Parkinson's disease(2023) Burgaz García-Oteyza, Sonia; Fernández Ruiz, José JavierParkinson’s disease (PD) is a chronic neurodegenerative disorder which courses with hypokinetic symptoms due to the selective death of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the consequent dopaminergic denervation of the striatum. This disease is also a proteinopathy, as one of its features is the presence of aggregates of misfolded proteins, mainly α-synuclein, known as Lewy bodies (LB). The etiology of PD remains unknown, but several environmental and genetic risk factors have been described, together with aging as the main one. The main symptoms of PD are bradykinesia, rigidity, and resting tremor, usually determinant for the diagnosis, which appear when more than 50% of the dopaminergic neurons are already dead. However, there are non-motor symptoms such as sleep disturbances, mood symptoms, gastrointestinal problems, and olfactory dysfunction, which may be prodromal and could be useful for an early diagnosis. The pathological events that contribute to the neuronal death include not only protein aggregation, but also neuroinflammation, mitochondrial dysfunction, oxidative stress, and excitotoxicity. These mechanisms are known to be interconnected, worsening the dopaminergic neurodegeneration which disturbs the basal ganglia circuitry, preventing a correct motor functioning. The most frequent treatment is the replacement of dopamine levels, mainly with levodopa (L-DOPA), which recovers the mobility of the patients in the short term but causes irreversible dyskinesias after several years. This makes urgent the need of a disease-modifying treatment, and given the multifactorial pathophysiology of PD, we propose the use of pleiotropic molecules which can be effective at several levels, such as cannabinoids...Item Development of An Oral Treatment with the PPAR-γ-Acting Cannabinoid VCE-003.2 Against the Inflammation-Driven Neuronal Deterioration in Experimental Parkinson’s Disease(Molecules, 2019) Burgaz García-Oteyza, Sonia; García García, María Concepción; Gómez Cañas, María; Muñoz, Eduardo; Fernández Ruiz, JavierIn 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-γ, 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-α, interleukin-1β, 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.