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- Acetyl-L-Carnitine Improves Cell BioenergeticsPublication . Cunha, Lídia; Bravo, Joana; Costa, Pedro; Fernandes, Sílvia; Oliveira, Marta; Castro, Rosa; Metello, Luís F.; Summavielle, TeresaIntroduction: Acetyl-L-Carnitine (ALC), a natural occurring compound in all mammalian species, plays a variety of vital functions in the body. The most important are related to mitochondria, namely the transport of fatty acids for energy production through β oxidation and the control of acyl-CoA/CoA ratio. Due to this close interaction with cell bioenergetics, it plays a role in many diseases, especially those related to the mitochondria. We propose to characterize the action of ALC in mitochondrial bioenergetics and functional integrity.
- Repeated exposure to ketamine in adolescent rats results in persistent anxiety in the adulthoodPublication . Amorim, Manuela; Bravo, Joana; Silva, Ana Isabel; Alves, Cecília Juliana; Monteiro, Pedro; Magalhãess, Ana; Summavielle, TeresaAdolescent development of the prefrontal cortex (PFC) is accompanied by important changes in glutamatergic, GABAergic and dopaminergic circuitries, susceptible to modulation by N-methyl-D-aspartate receptors (NMDAR) antagonists. Repeated ketamine was associated with social and memory deficits, but other relevant factors, such as anxiety, were not sufficiently addressed. The present study aimed to examine the behavioral and molecular consequences of repeated exposure to ketamine with a particular focus in anxiety. Methods. We treated male adolescent Wistar rats, starting postnatal day (PND) 35, with ketamine (30 mg/kg, i.p, 7 days). Behavioral evaluation was conducted in the adulthood (PND 60). The elevated plus maze (EPM) and open field tests were used to evaluate anxiety and locomotion, while sociability and novelty recognition were assessed through the novel object recognition (NOR) and the sociability and social novelty tests. At the end of the behavioral evaluation, brains were dissected and the prefrontal cortex used for biochemical evaluation. Results. Analysis of the elevated plus maze (EPM) data revealed a ketamine-induced anxiety-like profile, corroborated by the open field data. Ketaminetreated rats also failed to increase contact time with a conspecific in the social affiliation test and with an unknown rat in the novelty preference test. At the molecular level, frontal expression levels of tyrosine hydroxylase were found decreased. Conclusion. Altogether, these results show that repeated ketamine-exposure in the adolescent may result in long-term anxiety
- Profiling microglia in a mouse model of Machado–Joseph diseasePublication . Campos, Ana Bela; Silva, Sara Duarte; Fernandes, Bruno; Neves, Sofia Pereira das; Marques, Fernanda; Castro, Andreia Teixeira; Carvalho, Andreia Neves; Fernandes, Daniela Monteiro; Portugal, Camila Cabral; Socodato, Renato; Summavielle, Teresa; Ambrósio, António Francisco; Relvas, João Bettencourt; Maciel, PatríciaMicroglia have been increasingly implicated in neurodegenerative diseases (NDs), and specific disease associated microglia (DAM) profiles have been defined for several of these NDs. Yet, the microglial profile in Machado–Joseph disease (MJD) remains unexplored. Here, we characterized the profile of microglia in the CMVMJD135 mouse model of MJD. This characterization was performed using primary microglial cultures and microglial cells obtained from disease-relevant brain regions of neonatal and adult CMVMJD135 mice, respectively. Machine learning models were implemented to identify potential clusters of microglia based on their morphological features, and an RNA-sequencing analysis was performed to identify molecular perturbations and potential therapeutic targets. Our findings reveal morphological alterations that point to an increased activation state of microglia in CMVMJD135 mice and a disease-specific transcriptional profile of MJD microglia, encompassing a total of 101 differentially expressed genes, with enrichment in molecular pathways related to oxidative stress, immune response, cell proliferation, cell death, and lipid metabolism. Overall, these results allowed us to define the cellular and molecular profile of MJD-associated microglia and to identify genes and pathways that might represent potential therapeutic targets for this disorder.
- Study of Mechanisms for Acetyl-L-Carnitine Neuroprotective ActionPublication . Cunha, Lídia; Damiani, Danira; Alves, Cecília J.; Metello, Luís F.; Summavielle, TeresaIntroduction: Acetyl-L-Carnitine (ALC) has been proposed to have beneficial effects in chronic neurodegenerative disorders caused by production of abnormal proteins, mitochondrial dysfunction and oxidative stress. Recently, our group demonstrated that pre-treatment with ALC confers effective neuroprotection against 3,4- methylenedioximethamphetamine (MDMA)-induced neurotoxicity. These pre-clinical studies reinforce the beneficial potential of ALC as a neuroprotectant in neurodegenerative disorders. However, little is known about the molecular mechanisms underlying ALC action.
- MDA in adolescent male rats - decreased serotonin in the amygdala and behavioral effects in the elevated plus-maze testPublication . Faria, Raquel; Magalhães, Ana; Monteiro, Pedro; Silva, Joana Gomes da; Tavares, Maria Amélia; Summavielle, TeresaLong-term behavioral consequences of the neurotoxicity produced by 3,4-methylenedioxymethamphetamine (MDMA) in the adolescent rat are still mostly unknown. Here, adolescent male rats (postnatal day 45 PND [45]) were exposed to 10 mg/kg of MDMA, intraperitoneally, every 2 h for 6 h. Controls were given 0.9% saline in the same protocol. Ten days after exposure, the behavioral effects of MDMA were assessed in the elevated plus-maze (n = 6 per group). After behavioral testing, animals were sacrificed and the amygdalae were dissected and processed for HPLC determination of dopamine (DA), serotonin (5-HT), and metabolites. Results showed a significant decrease in the 5-HT content (P < 0.05), but no significant alterations in DA or its metabolites. Behavioral observation in the elevated plus-maze showed a decreased number of entries in the unprotected arms (P < 0.05), which were correlated to the number of entries and time spent in the central platform. Rearing was also decreased (P < 0.05). No differences were observed in head dips, grooming, or number of entries in the protected arms of the apparatus. Therefore, we conclude that, as in the adult rat, exposure to MDMA in the adolescent rat is associated to long-term depletion of the 5-HT content and increased anxiety-like behavior.
- IL-10 and Cdc42 modulate astrocyte-mediated microglia activation in methamphetamine-induced neuroinflammationPublication . Silva, Ana Isabel; Socodato, Renato; Pinto, Carolina; Terceiro, Ana Filipa; Canedo, Teresa; Relvas, João Bettencourt; Saraiva, Margarida; Summavielle, TeresaMethamphetamine (Meth) use is known to induce complex neuroinflammatory responses, particularly involving astrocytes and microglia. Building upon our previous research, which demonstrated that Meth stimulates astrocytes to release tumor necrosis factor (TNF) and glutamate, leading to microglial activation, this study investigates the role of the anti-inflammatory cytokine interleukin-10 (IL-10) in this process. Our findings reveal that the presence of recombinant IL-10 (rIL-10) counteracts Meth-induced excessive glutamate release in astrocyte cultures, which significantly reduces microglial activation. This reduction is associated with the modulation of astrocytic intracellular calcium (Ca2+) dynamics, particularly by restricting the release of Ca2+ from the endoplasmic reticulum to the cytoplasm. Furthermore, we identify the small Rho GTPase Cdc42 as a crucial intermediary in the astrocyte-to-microglia communication pathway under Meth exposure. By employing a transgenic mouse model that overexpresses IL-10 (pMT-10), we also demonstrate in vivo that IL-10 prevents Meth-induced neuroinflammation. These findings not only enhance our understanding of Meth-related neuroinflammatory mechanisms, but also suggest IL-10 and Cdc42 as putative therapeutic targets for treating Meth-induced neuroinflammation.
- Prenatal exposure to cocaine and enriched environmentPublication . Magalhães, Ana; Summavielle, Teresa; Melo, Pedro; Rosa, Rui; Tavares, Maria Amélia; Sousa, Liliana deExposure to cocaine throughout gestation may produce several deleterious outcomes in the offspring that include effects on neurotransmitter systems and structure of the central nervous system. Such changes are most likely correlated with behavioral alterations. Environmental enrichment (EE) in early stages is a factor that affects structural and behavioral development. This article examines the effects, upon social interactions, of EE during the first month of life in rats prenatally exposed to cocaine. Wistar dams were subcutaneously exposed to 60 mg/kg of cocaine divided in two daily doses from gestational day (GD)8 to GD22. Pair-fed controls were given saline vehicle in the same protocol. Offspring were distributed to the different environments in four experimental groups. Group 1: offspring from dams prenatally exposed to cocaine as previously described and reared in EE from postnatal day (PND)1 to PND28; Group 2: pups from cocaine-exposed dams and reared in a standard environment (SE); Group 3: pups from pair-fed saline-exposed dams and reared in EE; Group 4: offspring from saline-exposed dams and reared in SE. On PND21, 24, and 28, rats were examined in several social behavioral categories (play fighting, social investigation, comfort behaviors, and solicitation to play) for 10 min. Animals reared in SE do not display any differences due to treatment in the behavioral categories analyzed. Control offspring reared in EE presented decreased play fighting, decreased solicitation to play, and decreased social investigation compared to the control SE group, while cocaine-exposed animals reared in EE did not present these variations. These results suggest that EE rearing may unmask hidden effects of prenatal cocaine exposure.
- Chronic ketamine administration impairs mitochondrial complex I in the rat liverPublication . Venâncio, Carlos; Antunes, Luis; Félix, Luís; Rodrigues, Paula; Summavielle, Teresa; Peixoto, FranciscoKetamine can induce hepatotoxicity which has been suggested to be dependent on mitochondrial impairment. This study investigated the long-term effects of chronic low-dose ketamine on liver mitochondrial function, oxidative stress parameters, liver histology and glycogen content. Adult rats were administered with saline or ketamine (5 or 10 mg/kg) twice a day for a fourteen-day period in order to mimic chronic treatments. Effects between groups were compared ten days after the treatment had ended. Liver mitochondrial function was monitored in isolated mitochondrial extracts through evaluation of respiration parameters and activity of respiratory complexes, as well as oxidative stress, through lipid peroxidation, protein oxidation and superoxide dismutase activity. The hepatic histology and liver glycogen content were also evaluated. Ketamine groups showed a decreased evolution in body weight gains during the treatment period. Ketamine had no effect either on serum liver enzymes or on the oxidative stress parameters of liver mitochondria. Ketamine decreased the hepatic glycogen content, inhibited mitochondrial complex I and oxygen consumption when glutamate–malate substrate was used. These findings reflect a long-term mitochondrial bioenergetic deterioration induced by ketamine, which may explain the increased susceptibility of some patients to its prolonged or repeated use.
- 3D vs 2D Cell Cultures in the Evaluation of Radiobiological Effects of Exposition to Low Doses - Medical Imaging Levels - of Ionizing RadiationPublication . Costa, Pedro; Caires, Hugo; Lemos, Joana; Cunha, Lídia; Bravo, Joana; Bravo, Isabel; Silva, Regina; Summavielle, Teresa; Metello, Luís F.Pretending to develop advanced biological models to study biological effects of low doses of ionizing radiation and following the actual policies on Animal Sciences, based on 3 R’s Rule (to Reduce, Refine and Replace) – that limits as much as possible the application of animal models – scientific research using cellular models is constantly increasing. Nevertheless, the intrinsic limitations of actual cellular models quite often had been recognized on a significant number of papers pointing a significant number of non-concordances between results obtained using in vitro and in vivo studies. Actually, an increasing number of authors admit that three-dimensional cell culture (and spheroid cell culture in particular) could represent an interesting solution and a step further on use of cellular models. The work here to be presented reflects the first phase on the use of this methodology on the study, evaluation and quantification of cellular effects of low doses – starting on medical imaging level - of exposition to ionizing radiation.
- Maternal stress and vulnerability to depression: coping and maternal care strategies and its consequences on adolescent offspringPublication . Alves, Renata L.; Portugal, Camila C.; Lopes, Igor M.; Oliveira, Pedro; Alves, Cecília J.; Barbosa, Fernando; Summavielle, Teresa; Magalhães, AnaDepressive mothers often find mother-child interaction to be challenging. Maternal stress may further impair mother-child attachment, which may increase the risk of negative developmental consequences. We used rats with different vulnerability to depressive-like behavior (Wistar and Kyoto) to investigate the impact of stress (maternal separation-MS) on maternal behavior and adolescent offspring cognition. MS in Kyoto dams increased pup-contact, resulting in higher oxytocin levels and lower anxiety-like behavior after weaning, while worsening their adolescent offspring cognitive behavior. Whereas MS in Wistar dams elicited higher quality of pup-directed behavior, increasing brain-derived neurotrophic factor (BDNF) in the offspring, which seems to have prevented a negative impact on cognition. Hypothalamic oxytocin seems to affect the salience of the social environment cues (negatively for Kyoto) leading to different coping strategies. Our findings highlight the importance of contextual and individual factors in the understanding of the oxytocin role in modulating maternal behavior and stress regulatory processes.