CAROLINE CRISTIANO REAL GREGORIO
Projetos de Pesquisa
Unidades Organizacionais
LIM/43 - Laboratório de Medicina Nuclear, Hospital das Clínicas, Faculdade de Medicina
26 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 26
- Exercise protects synaptic density in a rat model of Parkinson's disease(2021) BINDA, K. H.; LILLETHORUP, T. P.; REAL, C. C.; BAERENTZEN, S. L.; NIELSEN, M. N.; ORLOWSKI, D.; BROOKS, D. J.; CHACUR, M.; LANDAU, A. M.Background: Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor slowing, rigidity, and tremor. Postural instability and pain are also features. Physical exercise benefits PD patients - possibly by promoting neuroplasticity including synaptic regeneration. Objectives: In a parkinsonian rat model, we test the hypotheses that exercise: (a) increases synaptic density and reduces neuroinflammation and (b) lowers the nociceptive threshold by increasing mu-opioid receptor expression. Methods: Brain autoradiography was performed on rats unilaterally injected with either 6-hydroxydopamine (6OHDA) or saline and subjected to treadmill exercise over 5 weeks. [3H]UCB-J was used to measure synaptic vesicle glycoprotein 2A (SV2A) density. Dopamine D2/3 receptor and mu-opioid receptor availability were assessed with [3H]Raclopride and [3H]DAMGO, respectively, while neuroinflammation was detected with the 18kDA translocator protein (TSPO) marker [3H]PK11195. The nociceptive threshold was determined prior to and throughout the exercise protocol. Results: We confirmed a dopaminegic deficit with increased striatal [3H]Raclopride D2/3 receptor availability and reduced nigral tyrosine hydroxylase immunoreactivity in the ipsilateral hemisphere of all 6-OHDA-injected rats. Sedentary rats lesioned with 6-OHDA showed significant reduction of ipsilateral striatal and substantia nigra [3H]UCB-J binding while [3H]PK11195 showed increased ipsilateral striatal neuroinflammation. Lesioned rats who exercised had higher levels of ipsilateral striatal [3H]UCB-J binding and lower levels of neuroinflammation compared to sedentary lesioned rats. Striatal 6-OHDA injections reduced thalamic mu-opioid receptor availability but subsequent exercise restored binding. Exercise also raised thalamic and hippocampal SV2A synaptic density in 6-OHDA lesioned rats, accompanied by a rise in nociceptive threshold. Conclusion: These data suggest that treadmill exercise protects nigral and striatal synaptic integrity in a rat lesion model of PD - possibly by promoting compensatory mechanisms. Exercise was also associated with reduced neuroinflammation post lesioning and altered opioid transmission resulting in an increased nociceptive threshold.
- Evaluation of exercise-induced modulation of glial activation and dopaminergic damage in a rat model of Parkinson's disease using [C-11]PBR28 and [F-18]FDOPA PET(2019) REAL, Caroline C.; DOORDUIN, Janine; FELTES, Paula Kopschina; GARCIA, David Vallez; FARIA, Daniele de Paula; BRITTO, Luiz R.; VRIES, Erik F. J. deEvidence suggests that exercise can modulate neuroinflammation and neuronal damage. We evaluated if such effects of exercise can be detected with positron emission tomography (PET) in a rat model of Parkinson's disease (PD). Rats were unilaterally injected in the striatum with 6-hydroxydopamine (PD rats) or saline (controls) and either remained sedentary (SED) or were forced to exercise three times per week for 40 min (EX). Motor and cognitive functions were evaluated by the open field, novel object recognition, and cylinder tests. At baseline, day 10 and 30, glial activation and dopamine synthesis were assessed by [C-11]PBR28 and [F-18]FDOPA PET, respectively. PET data were confirmed by immunohistochemical analysis of microglial (Iba-1) / astrocyte (GFAP) activation and tyrosine hydroxylase (TH). [C-11]PBR28 PET showed increased glial activation in striatum and hippocampus of PD rats at day 10, which had resolved at day 30. Exercise completely suppressed glial activation. Imaging results correlated well with post-mortem Iba-1 staining, but not with GFAP staining. [F-18]FDOPA PET, TH staining and behavioral tests indicate that 6-OHDA caused damage to dopaminergic neurons, which was partially prevented by exercise. These results show that exercise can modulate toxin-induced glial activation and neuronal damage, which can be monitored noninvasively by PET.
- 11C-PK11195 plasma metabolization has the same rate in multiple sclerosis patients and healthy controls: a cross-sectional study(2021) SOUZA, Aline Morais de; PITOMBEIRA, Milena Sales; SOUZA, Larissa Estessi de; MARQUES, Fabio Luiz Navarro; BUCHPIGUEL, Carlos Alberto; REAL, Caroline Cristiano; FARIA, Daniele de Paula11C-PK11195 is a positron emitter tracer used for Positron Emission Tomography (PET) imaging of innate immune cell activation in studies of neuroinflammatory diseases. For the image quantitative analysis, it is necessary to quantify the intact fraction of this tracer in the arterial plasma during imaging acquisition (plasma intact fraction). Due to the complexity and costs involved in this analysis it is important to evaluate the real necessity of individual analysis in each 11C-PK11195 PET imaging acquisition. The purpose of this study is to compare 11C-PK11195 plasma metabolization rate between healthy controls and multiple sclerosis (MS) patients and evaluate the interference of sex, age, treatment, and disease phenotype in the tracer intact fraction measured in arterial plasma samples. 11C-PK11195 metabolization rate in arterial plasma was quantified by high performance liquid chromatography in samples from MS patients (n = 50) and healthy controls (n = 23) at 20, 45, and 60 minutes after 11C-PK11195 injection. Analyses were also stratified by sex, age, treatment type, and MS phenotype. The results showed no significant differences in the metabolization rate of healthy controls and MS patients, or in the stratified samples. In conclusion, 11C-PK11195 metabolization has the same rate in patients with MS and healthy controls, which is not affected by sex, age, treatment, and disease phenotype. Thus, these findings could contribute to exempting the necessity for tracer metabolization determination in all 11C-PK11195 PET imaging acquisition, by using a population metabolization rate average. The study procedures were approved by the Ethics Committee for Research Projects Analysis of the Hospital das Clinicas of the University of Sao Paulo Medical School (approval No. 624.065) on April 23, 2014.
- Neuroplasticity induced by the retention period of a complex motor skill learning in rats(2021) SAMPAIO, Adaneuda Silva Britto; REAL, Caroline Cristiano; GUTIERREZ, Rita Mara Soares; SINGULANI, Monique Patricio; ALOUCHE, Sandra Regina; BRITTO, Luiz Roberto; PIRES, Raquel SimoniLearning complex motor skills is an essential process in our daily lives. Moreover, it is an important aspect for the development of therapeutic strategies that refer to rehabilitation processes since motor skills previously acquired can be transferred to similar tasks (motor skill transfer) or recovered without further practice after longer delays (motor skill retention). Different acrobatic exercise training (AE) protocols induce plastic changes in areas involved in motor control and improvement in motor performance. However, the plastic mechanisms involved in the retention of a complex motor skill, essential for motor learning, are not well described. Thus, our objective was to analyze the brain plasticity mechanisms involved in motor skill retention in AE . Motor behavior tests, and the expression of synaptophysin (SYP), synapsin-I (SYS), and early growth response protein 1 (Egr-1) in brain areas involved in motor learning were evaluated. Young male Wistar rats were randomly divided into 3 groups: sedentary (SED), AE, and AE with retention period (AER). AE was performed three times a week for 8 weeks, with 5 rounds in the circuit. After a fifteen-day retention interval, the AER animals was again exposed to the acrobatic circuit. Our results revealed motor performance improvement in the AE and AER groups. In the elevated beam test, the AER group presented a lower time and greater distance, suggesting retention period is important for optimizing motor learning consolidation. Moreover, AE promoted significant plastic changes in the expression of proteins in important areas involved in control and motor learning, some of which were maintained in the AER group. In summary, these data contribute to the understanding of neural mechanisms involved in motor learning in an animal model, and can be useful to the construction of therapeutics strategies that optimize motor learning in a rehabilitative context.
- Antinociceptive effects of treadmill exercise in a rat model of Parkinson's disease: The role of cannabinoid and opioid receptors(2020) BINDA, K. H.; REAL, C. C.; FERREIRA, A. F. F.; BRITTO, L. R.; CHACUR, M.In addition to motor symptoms, Parkinson's disease (PD) presents high prevalence of painful symptoms responsible for worsening quality of life of PD patients. Physical exercise can improve such painful symptoms. This study evaluated the effects of exercise on nociceptive threshold using an unilateral rat model of PD, as well as the role played by cannabinoid and opioid receptors in areas responsible for pain pathways. For PD induction, Wistar rats were injected with 6-OHDA. 15?days after, rats either remained sedentary or were forced to exercise three times a week for 40 min. Motor and nociceptive behaviors were evaluated through cylinder and mechanical hyperalgesia tests, respectively. The animals were euthanized for analysis of cannabinoid receptor type 1 (CB1) and type 2 (CB2), and mu-opioid receptor (MOR) in the anterior cingulate cortex (ACC), periaqueductal gray matter (PAG), and thalamus areas by immunohistochemistry (IHC) and Western blotting. Our data revealed a decrease in the nociceptive threshold in both forepaws after surgery; in contrast, there was improvement in painful symptoms after the exercise protocol. For cannabinoid system there were an increase in CB2 expression in the ACC and PAG, and in CB1 levels in the PAG. And for opioid system there was an increase of MOR expression in the thalamus. Thus, modulation of those receptors by physical exercise can be an important non-pharmacological intervention to reduce painful symptoms in a rat model of PD, contributing to knowledge and promotion of better treatment aimed at improving the quality of life of PD patients.
- Physical exercise protects against mitochondria alterations in the 6-hidroxydopamine rat model of Parkinson's disease(2020) FERREIRA, Ana Flavia Fernandes; BINDA, Karina Henrique; SINGULANI, Monique Patricio; PEREIRA, Carolina Parga Martins; FERRARI, Gustavo Duarte; ALBERICI, Luciane Carla; REAL, Caroline Cristiano; BRITTO, Luiz RobertoParkinson's disease (PD) is typicaly caractherized by loss of dopaminergic neurons, as well as the presence of mitochondrial impairments. Although physical exercise is known to promote many beneficial effects in healthy subjects, such as enhancing mitocondrial biogenesis and function, it is not clear if these effects are evident after exercise in individuals with PD. The aim of this study was to investigate the effects of two different protocol durations on motor behavior (aphomorphine and gait tests), mitochondrial biogenesis signaling (PGC-1 alpha, NRF-1 and TFAM), structure (oxidative phosphorylation system protein levels) and respiratory chain activity (complex I) in a unilateral PD rat model. For this, male Wistar rats were injected with 6-hydroxydopamine unilaterally into the striatum and submitted to an intermitent moderate treadmill exercise for one or four weeks. In the gait test, only stride width data revealed an improvement after one week of exercise. On the other hand, after 4 weeks of the exercise protocol all gait parameters analyzed and the aphomorphine test demonstrated a recovery. Analysis of protein revealed that one week of exercise was able to prevent PGC-1 alpha and NRF-1 expression decrease in PD animals. In addition, after four weeks of physical exercise, besides PGC-1 alpha and NRF-1, reduction in TFAM and complex I protein levels and increased complex I activity were also prevented in PD animals. Thus, our results suggest a neuroprotective and progressive effect of intermittent treadmill exercise, which could be related to its benefits on mitochondrial biogenesis signaling and respiratory chain modulation of the dopaminergic system in PD.
- Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer's Disease Rat Model: A Proof-of-Concept Study(2022) FARIA, Daniele de Paula; SOUZA, Larissa Estessi de; DURAN, Fabio Luis de Souza; BUCHPIGUEL, Carlos Alberto; BRITTO, Luiz Roberto; CRIPPA, Jose Alexandre de Souza; FILHO, Geraldo Busatto; REAL, Caroline CristianoAn early and persistent sign of Alzheimer's disease (AD) is glucose hypometabolism, which can be evaluated by positron emission tomography (PET) with F-18-2-fluoro-2-deoxy-D-glucose ([F-18]FDG). Cannabidiol has demonstrated neuroprotective and anti-inflammatory properties but has not been evaluated by PET imaging in an AD model. Intracerebroventricular (icv) injection of streptozotocin (STZ) is a validated model for hypometabolism observed in AD. This proof-of-concept study evaluated the effect of cannabidiol treatment in the brain glucose metabolism of an icv-STZ AD model by PET imaging. Wistar male rats received 3 mg/kg of STZ and [F-18]FDG PET images were acquired before and 7 days after STZ injection. Animals were treated with intraperitoneal cannabidiol (20 mg/kg-STZ-cannabidiol) or saline (STZ-saline) for one week. Novel object recognition was performed to evaluate short-term and long-term memory. [F-18]FDG uptake in the whole brain was significantly lower in the STZ-saline group. Voxel-based analysis revealed a hypometabolism cluster close to the lateral ventricle, which was smaller in STZ-cannabidiol animals. The brain regions with more evident hypometabolism were the striatum, motor cortex, hippocampus, and thalamus, which was not observed in STZ-cannabidiol animals. In addition, STZ-cannabidiol animals revealed no changes in memory index. Thus, this study suggests that cannabidiol could be an early treatment for the neurodegenerative process observed in AD.
- [C-11]PIB PET imaging can detect white and grey matter demyelination in a non-human primate model of progressive multiple sclerosis(2019) CARVALHO, Robert H. F.; REAL, Caroline C.; CININI, Simone; GARCEZ, Alexandre T.; DURAN, Fabio L. S.; MARQUES, Fabio L. N.; MELLO, Luiz Eugenio; BUSATTO FILHO, Geraldo; VRIES, Erik F. J. de; BRITTO, Luiz R. G. de; BUCHPIGUEL, Carlos A.; FARIA, Daniele de PaulaBackground: Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system. Its diagnosis is clinical, often confirmed by magnetic resonance imaging. This image modality, however, is not ideal for discrimination of demyelination in grey and white matter regions from inflammatory lesions. Positron Emission Tomography (PET), using specific radiopharmaceuticals, can be a tool to differentiate between these processes. The radiopharmaceutical [C-11]PIB is widely used for detection of beta-amyloid plaques, but has also been suggested for the analysis of myelin content due to its consistent uptake in white matter. The aim of this study was to evaluate [C-11]PIB PET imaging as a tool for detecting demyelinated regions in white and grey matter of non-human primate model of progressive MS. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in marmosets by injection of re-combinant human myelin oligodendrocyte glycoprotein (rhMOG) emulsified in either Incomplete Freund's Adjuvant (IFA) or Complete Freund's Adjuvant (CFA). [C-11]PIB PET images were acquired prior to immunization (baseline) and after symptoms were present (end of experiment). Brain tissue was isolated for histochemical analysis. Results: All rhMOG/IFA-treated and rhMOG/CFA-treated animals showed clinical signs of EAE. The rhMOG/CFA group presented a significant [C-11]PIB uptake reduction only in the left motor cortex (9%, P = 0.011). For the rhMOG/IFA group, significant decrease in [C-11]PIB uptake was observed in the whole brain (15%, P = 0.015), in the right hemisphere of body of corpus callosum (34%, P = 0.02), splenium of corpus callosum (38%, P = 0.004), hippocampus (19%, P = 0.036), optic tract (13%, P = 0.025), thalamus (14%, P = 0.041), Globus pallidus (23%, P = 0.017), head of caudate nucleus (25%, P = 0.045), tail of caudate nucleus (29%, P = 0.003), putamen (28%, P = 0.047) and left hemisphere of body of corpus callosum (14%, P = 0.037) and head of caudate nucleus (23%, P = 0.023). [C-11]PIB uptake significantly correlated with luxol fast blue histology (myelin marker), both in the rhMOG/IFA (r(2) = 0.32, P < 0.0001) and the rhMOG/CFA group (r(2) = 0.46, P < 0.0001). Conclusion: [C-11]PIB PET imaging is an efficient tool for detecting demyelination in grey and white matter, in a non-human primate model of progressive MS.
- Potential of [C-11](R)-PK11195 PET Imaging for Evaluating Tumor Inflammation: A Murine Mammary Tumor Model(2022) SOUZA, Aline Morais de; REAL, Caroline Cristiano; JUNQUEIRA, Mara de Souza; SOUZA, Larissa Estessi de; MARQUES, Fabio Luiz Navarro; BUCHPIGUEL, Carlos Alberto; CHAMMAS, Roger; SAPIENZA, Marcelo Tatit; FARIA, Daniele de PaulaBackground: Breast tumor inflammation is an immunological process that occurs mainly by mediation of Tumor-Associated Macrophages (TAM). Aiming for a specific measurement of tumor inflammation, the current study evaluated the potential of Positron Emission Tomography (PET) imaging with [C-11](R)-PK11195 to evaluate tumor inflammation in a mammary tumor animal model. Methods: Female Balb/C mice were inoculated with 4T1 cells. The PET imaging with [C-11](R)-PK11195 and [F-18]FDG was acquired 3 days, 1 week, and 2 weeks after cell inoculation. Results: The [C-11](R)-PK11195 tumor uptake increased from 3 days to 1 week, and decreased at 2 weeks after cell inoculation, as opposed to the [F-18]FDG uptake, which showed a slight decrease in uptake at 1 week and increased uptake at 2 weeks. In the control group, no significant differences occurred in tracer uptake over time. Tumor uptake of both radiopharmaceuticals is more expressed in tumor edge regions, with greater intensity at 2 weeks, as demonstrated by [C-11](R)-PK11195 autoradiography and immunofluorescence with TSPO antibodies and CD86 pro-inflammatory phenotype. Conclusion: The [C-11](R)-PK11195 was able to identify heterogeneous tumor inflammation in a murine model of breast cancer and the uptake varied according to tumor size. Together with the glycolytic marker [F-18]FDG, molecular imaging with [C-11](R)-PK11195 may provide a better characterization of inflammatory responses in cancer.
- Development of a platform for the production of multiple modal chelating and imaging agents using desferrioxamine and bovine albumin as a model(2021) CORREIA, Lucas Antonio Arias; GARCIA, Rodrigo Santos; REAL, Caroline Cristiano; UZUELI, Daniel Henrique; SA, Ulisses Lacerda de Figueiredo; MARQUES, Fabio Luiz Navarro; COLNAGO, Luiz Alberto; ESPOSITO, Breno PanniaThe linker p-SCN-Bz-desferrioxamine was used as a conjugating agent to bovine serum albumin. The conjugate (BSA-DFO) did not display relevant structural alterations in comparison with the native protein. BSA-DFO was able to bind iron in a high affinity, antioxidant form similar to the native siderophore desferrioxamine. The gadolinium complex of BSA-DFO displayed 7-10 times higher relaxivities compared to the low molecular weight complex. Preparation of the radiotracers(68)Ga(BSA-DFO) and(89)Zr(BSA-DFO) in high radiochemical yields was accomplished quickly in mild conditions. These results indicate that BSA-DFO might be useful as an alternative treatment for iron overload disorders, and as a platform for the production of radiotracers or contrast agents for magnetic resonance imaging.
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