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listelement.badge.dso-type Item , Myo-Inositol Levels in the Dorsal Hippocampus Serve as Glial Prognostic Marker of Mild Cognitive Impairment in Mice(Universidade Federal de Minas Gerais, 2021) Tim Ebert; Daniel Heinz; Suellen Almeida-Corrêa; Renata Cruz; Frederik Dethloff; Tibor Stark; Thomas Bajaj; Oriana Maria Maurel; Fabiola Mara Ribeiro; Silvio Calcagnini; Kathrin Hafner; Nils Gassen; Christoph Turck; Benoit Boulat; Michael Czisch; Carsten WotjakDementia is a devastating age-related disorder. Its therapy would largely benefit from the identification of susceptible subjects at early, prodromal stages of the disease. To search for such prognostic markers of cognitive impairment, we studied spatial navigation in male BALBc vs. B6N mice in combination with in vivo magnetic resonance spectroscopy (1H-MRS). BALBc mice consistently showed higher escape latencies than B6N mice, both in the Water Cross Maze (WCM) and the Morris water maze (MWM). These performance deficits coincided with higher levels of myo-inositol (mIns) in the dorsal hippocampus before and after training. Subsequent biochemical analyses of hippocampal specimens by capillary immunodetection and liquid chromatography mass spectrometry-based (LC/MS) metabolomics revealed a higher abundance of glial markers (IBA-1, S100B, and GFAP) as well as distinct alterations in metabolites including a decrease in vitamins (pantothenic acid and nicotinamide), neurotransmitters (acetylcholine), their metabolites (glutamine), and acetyl-L-carnitine. Supplementation of low abundant acetyl-L-carnitine via the drinking water, however, failed to revert the behavioral deficits shown by BALBc mice. Based on our data we suggest (i) BALBc mice as an animal model and (ii) hippocampal mIns levels as a prognostic marker of mild cognitive impairment (MCI), due to (iii) local changes in microglia and astrocyte activity, which may (iv) result in decreased concentrations of promnesic molecules.listelement.badge.dso-type Item , Negative Modulation of the Metabotropic Glutamate Receptor Type 5 as a Potential Therapeutic Strategy in Obesity and Binge-Like Eating Behavior(Universidade Federal de Minas Gerais, 2021) Tadeu Oliveira; Bruno Daniel Correia Gonçalves; Bruna da Silva Oliveira; Antonio Carlos Pinheiro De Oliveira; Helton José dos Reis; Claudia Natalia Ferreira; Daniele Cristina de Aguiar; Aline Silva Miranda; Fabiola Mara Ribeiro; Erica Vieira; András Palotás; Luciene Bruno VieiraObesity is a multifactorial disease, which in turn contributes to the onset of comorbidities, such as diabetes and atherosclerosis. Moreover, there are only few options available for treating obesity, and most current pharmacotherapy causes severe adverse effects, while offering minimal weight loss. Literature shows that metabotropic glutamate receptor 5 (mGluR5) modulates central reward pathways. Herein, we evaluated the effect of VU0409106, a negative allosteric modulator (NAM) of mGluR5 in regulating feeding and obesity parameters. Diet-induced obese C57BL/6 mice were treated for 14 days with VU0409106, and food intake, body weight, inflammatory/hormonal levels, and behavioral tests were performed. Our data suggest reduction of feeding, body weight, and adipose tissue inflammation in mice treated with high-fat diet (HFD) after chronic treatment with VU0409106. Furthermore, a negative modulation of mGluR5 also reduces binge-like eating, the most common type of eating disorder. Altogether, our results pointed out mGluR5 as a potential target for treating obesity, as well as related disorders.listelement.badge.dso-type Item , mGluR5 regulates REST/NRSF signaling through N-cadherin/β-catenin complex in Huntington’s disease(Universidade Federal de Minas Gerais, 2020) Jéssica Mabelle de Souza; Khaled Abd-Elrahman; Fabiola Mara Ribeiro; Stephen FergusonRepressor element 1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a transcription repressor and its expression is regulated by the Wnt pathway through β-catenin. Metabotropic glutamate receptor 5 (mGluR5) signaling plays a key role in controlling neuronal gene expression. Interestingly, REST/NRSF nuclear translocation and signaling, as well as mGluR5 signaling are altered in the presence of mutant huntingtin. It remains unclear whether mGluR5 can modulate Wnt and REST/NRSF signaling under physiological conditions and whether this modulation is altered in Huntington’s disease (HD). Using primary corticostriatal neurons derived from wild type mouse embryos, we find that targeting mGluR5 using the agonist, DHPG, or the negative allosteric modulator, CTEP, modulates REST/NRSF expression by regulating the assembly of N-cadherin/ β-catenin complex in a Src kinase-dependent manner. We have validated our in vitro findings in vivo using two HD mouse models. Specifically, we show that pharmacological inhibition of mGluR5 in zQ175 mice and genetic ablation of mGluR5 in BACHD mice corrected the pathological activation of Src and rescued REST/NRSF-dependent signaling. Together, our data provide evidence that mGluR5 regulates REST/NRSF expression via the Wnt pathway and highlight the contribution of impaired REST/ NRSF signaling to HD pathology.listelement.badge.dso-type Item , Zika Virus Transmission Through Blood Tissue Barriers(Universidade Federal de Minas Gerais, 2019) Svetlana Khaiboullina; Fabiola Mara Ribeiro; Timsy Uppal; Ekaterina Martynova; Alberto Rizvanov; Subhash VermaA recente epidemia do vírus Zika (ZIKV) nas Américas e no Caribe revelou uma nova cepa mortal do vírus transmitido por mosquitos, nunca antes associada a surtos anteriores na Ásia. Pela primeira vez, demonstrou-se que a infecção generalizada por ZIKV causa microcefalia e morte de recém-nascidos, provavelmente devido à mutação adquirida durante o grande surto registrado na Polinésia Francesa em 2013-2014. A replicação e persistência produtivas do ZIKV foram demonstradas na placenta e no cérebro fetal. A possível associação entre o ZIKV e a microcefalia e morte fetal foi confirmada utilizando modelos de camundongos imunocompetentes in vitro e in vivo . Após atravessar a placenta, o ZIKV atinge diretamente as células progenitoras neurais (CPNs) no feto humano em desenvolvimento e desencadeia apoptose. As células endoteliais embrionárias são excepcionalmente suscetíveis à infecção por ZIKV, que causa morte celular e necrose tecidual. Em contrapartida, a infecção por ZIKV não afeta a morfologia das células microvasculares do cérebro adulto nem a função da barreira hematoencefálica. O ZIKV é transmitido principalmente pela picada do mosquito Aedes e é introduzido na placenta/sangue por meio de replicação no local de entrada. O vírus também pode ser transmitido por meio de relações sexuais desprotegidas. Embora múltiplas vias de infecção viral tenham sido identificadas, o(s) mecanismo(s) exato(s) utilizado(s) pelo ZIKV para atravessar a placenta ainda permanecem em grande parte desconhecidos. Nesta revisão, resumimos o conhecimento atual sobre a infecção e transmissão do ZIKV através das barreiras placentária e cerebral.listelement.badge.dso-type Item , Alterations of Calcium Channels in a Mouse Model of Huntington’s Disease and Neuroprotection by Blockage of CaV1 Channels(Universidade Federal de Minas Gerais, 2019) Artur Santos Miranda; Pablo Leal Cardozo; Flavia Rodrigues da Silva; Jessica Mabelle de Souza; Isabella Guimarães Olmo; Jader Santos Cruz; Marcus Vinícius Gomez; Fabiola Mara Ribeiro; Luciene Bruno VieiraHuntington’s disease (HD) is a neurodegenerative autosomal dominant disorder, characterized by symptoms of involuntary movement of the body, loss of cognitive function, psychiatric disorder, leading inevitably to death. It has been previously described that higher levels of brain expression of Cav1 channels are involved in major neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. Our results demonstrate that a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD mice) at the age of 3 and 12 months exhibits significantly increased Cav1.2 protein levels in the cortex, as compared with wild-type littermates. Importantly, electrophysiological analyses confirm a significant increase in L-type Ca2+ currents and total Ca2+ current density in cortical neurons from BACHD mice. By using an in vitro assay to measure neuronal cell death, we were able to observe neuronal protection against glutamate toxicity after treatment with Cav1 blockers, in wild-type and, more importantly, in BACHD neurons. According to our data, Cav1 blockers may offer an interesting strategy for the treatment of HD. Altogether, our results show that mutant huntingtin (mHtt) expression may cause a dysregulation of Cav1.2 channels and we hypothesize that this contributes to neurodegeneration during HD.