Marielza Nunes | Faculdade de Ciências Médicas da Santa Casa de São Paulo (original) (raw)

Papers by Marielza Nunes

Animals were treated from 2 or 10 months of age (arrow heads). Behavioral experiments (a... more Animals were treated from 2 or 10 months of age (arrow heads). Behavioral experiments (arrows) began when all animals were 6 months old and were repeated every 3 months. When all animals were 18 months old, the last behavioral observations were done, animals were killed and brain tissue was extracted. MA: motor activity; BM: Barnes maze; EPM: elevated plus maze; IA: inhibitory avoidance.</p

Animals were first submitted to Barnes Maze when they were 6 months old, and we used a f... more Animals were first submitted to Barnes Maze when they were 6 months old, and we used a five-day protocol, exposing the animal twice a day to the task (Acquisition Session); latency was recorded. Both WT (n = 12) and TG Ctrl (n = 7) mice learned the task, as there is a reduction in latency to find the escape box in day 5 comparing to day 1 (A). Animals were re-exposed to the protocol every 3 months and TG Ctrl could not retain the memory, as its latency rose in test 2 (at 12 months of age) and kept higher than the latency of WT group up to the end of the experiments (A). We next compared the three TG groups and all of them learned the task, at 6 months of age (Acquisition Session). The treated groups, TG Li8 (n = 7) and TG Li16 (n = 8), did not present increased latency as did TG Ctrl, which means that the treatment with lithium was effective in preventing the loss of memory. Data plotted are mean ± SEM of latency. a: P<0.01, comparing days 1 and 5 within the groups; b: P < 0.01, WT Ctrl vs TG Ctrl. *: P < 0.05, TG Ctrl vs TG Li8 and TG Li16.</p

Brain homogenates were tested to BDNF by ELISA. There was no difference in BDNF levels e... more Brain homogenates were tested to BDNF by ELISA. There was no difference in BDNF levels either in hippocampus (A) or in cortex (C) of TG Ctrl (n = 3) when compared to WT Ctrl (n = 3). In the same way, lithium treatment did not influence in BDNF levels in hippocampus of TG mice (B). In cortex, however, TG Li16 (n = 3) presented higher levels of the neurotrophic factor, compared to TG Ctrl. Although TG Li8 has presented a slight increase in BDNF, it was not significant. Data plotted are median and interquartile range. *: P < 0.05.</p

There was no difference in locomotion when WT and TG mice were compared, at 6 (WT, n = 1... more There was no difference in locomotion when WT and TG mice were compared, at 6 (WT, n = 10; TG, n = 7) and 18 months-old (WT, n = 10; TG, n = 7) (A). In the first evaluation, at 6 months, TG group presented greater rearing behavior than WT (B). Between the transgenic groups, we observed no difference in locomotion in both ages analyzed (C), but TG Ctrl (n = 7) showed more rearing behavior than TG Li8 (n = 9) and TG Li16 (n = 7), at 6 months of age. Data are plotted as mean ± SEM of arbitrary units. * P<0.05.</p

This type of memory was evaluated using an inhibitory avoidance apparatus in which anima... more This type of memory was evaluated using an inhibitory avoidance apparatus in which animals were placed in a light box with access to a dark one, where they received a shock on the paws. The latency (max. 300s) to pass to the dark side was registered. Test session (TS) was performed 24 hours after acquisition session (AS). TG Ctrl (n = 7) showed higher latency in AS than WT (n = 10), and only the latter could remember the task, not passing to the dark side (A). Lithium reverted this result in TG Li8 (n = 8) and TG Li16 (n = 9), as the latency in TS of these groups was higher than in AS. Data plotted are median and interquartile range. *: P < 0.05, a: P < 0.01, #: P < 0.05 in relation to TG Ctrl “AS”.</p

Brains sections were immunolabeled with NeuN antibody. TG Ctrl (n = 5) group had a decre... more Brains sections were immunolabeled with NeuN antibody. TG Ctrl (n = 5) group had a decrease in proportional area stained compared to WT Ctrl (n = 4) (A). Treatment with lithium for 16 months, however, prevented TG Li16 group (n = 5) from this neuronal loss (B). The treatment for 8 months was not enough to produce the same effect, as proportional area stained in TG Li8 (n = 5) was not statistically different from TG Ctrl. In prefrontal cortex (PFC), there was no difference between WT and TG (C), but treatment with lithium resulted in higher proportional area stained in TG Li16, compared to TG Ctrl (D). Data plotted are median and interquartile range. *: P < 0.05.</p

The coronal sections shown are at approximately the same anatomical level (left panels 1... more The coronal sections shown are at approximately the same anatomical level (left panels 1.98 mm and right panels –1.58 from Bregma). Representative images are from samples run in the same batch during immunohistochemistry procedure. Images in each row belong to the same animal and match with the animals showed on panels of thioflavine-S staining figure. Figure abbreviations for cortical areas: Fr3, frontal cortex, area3; M1, primary motor cortex; M2, secondary motor cortex; Cg1, Cingulate cortex, area1; PrL, prelimbic cortex; IL, infralimbic cortex. Anatomical localization and abbreviations of hippocampal structures are described in the line drawing in “panel B” of thioflavine-S staining figure. Scale bar is 400 μm.</p

Brains sections were stained with Thioflavine-S and plaques were counted in the whole se... more Brains sections were stained with Thioflavine-S and plaques were counted in the whole section. The ratio of plaques/slice is plotted. WT Ctrl (n = 4) did not present any plaques. Treatment with lithium during 16 months reduced the number of plaques in TG Li16 (n = 5) compared to TG Ctrl (n = 6). TG Li8 (n = 5) also presented a reduction but it was not statistically different. Data were plotted in median and interquartile range. *: P < 0.01.</p

The coronal sections shown are at approximately the same anatomical level (-1.58 from Br... more The coronal sections shown are at approximately the same anatomical level (-1.58 from Bregma). Representative images are from samples run in the same batch during staining procedure. Images match with the animals showed on <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142267#pone.0142267.g008" target="_blank">Fig 8</a>. Hippocampal areas are described on line draw from “A” and the dotted square depicts the approximated area shown on panels “B” to “E”. Structure abreviations were cited according to Franklin and Paxinos, 2008 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0142267#pone.0142267.ref069" target="_blank">69</a>]. Figure Abbreviations: cg, cingulum; CA1, field CA1 of hippocampus; CA3, field CA3 of hippocampus; Lmol, stratum lacunosum moleculare of the hippocampus; CA2, field CA2 of hippocampus; Py, pyramidal cells of field CA1 of hippocampus; PoDG, polymorphic layer of the dentate gyrus; GrDG, granular layer of the dentate gyrus; MoDG, molecular layer of the dentate gyrus; fi, fimbria. Scale bar is 160 μm.</p

☯ These authors contributed equally to this work.

Background: Alzheimer’s disease is mainly characterized by remarkable neurodegeneration in brain ... more Background: Alzheimer’s disease is mainly characterized by remarkable neurodegeneration in brain areas related to memory formation. This progressive neurodegeneration causes cognitive impairment, changes in behavior, functional disability, and even death. Our group has demonstrated changes in the kallikrein–kinin system (KKS) in Alzheimer’s disease (AD) experimental models, but there is a lack of evidence about the role of the KKS in Alzheimer’s disease. Aim: In order to answer this question, we evaluated the potential of the kinin B2 receptors (BKB2R) to modify AD characteristics, particularly memory impairment, neurodegeneration, and Aβ peptide deposition. Methods: To assess the effects of B2, we used transgenic Alzheimer’s disease mice treated with B2 receptor (B2R) agonists and antagonists, and performed behavioral and biochemical tests. In addition, we performed organotypic hippocampal culture of wild-type (WT) and transgenic (TG) animals, where the density of cytokines, neurot...

PLOS ONE, 2015

The use of lithium is well established in bipolar disorders and the benefits are being demonstrat... more The use of lithium is well established in bipolar disorders and the benefits are being demonstrated in neurodegenerative disorders. Recently, our group showed that treatment with microdose lithium stabilized the cognitive deficits observed in Alzheimer's disease (AD) patients. In order to verify the lithium microdose potential in preventing the disease development, the aim of this work was to verify the effects of chronic treatment with microdose lithium given before and after the appearance of symptoms in a mouse model of a disease similar to AD. Transgenic mice (Cg-Tg(PDGFB-APPSwInd)20Lms/2J) and their non-transgenic litter mate genetic controls were treated with lithium carbonate (1.2 mg/Kg/day in drinking water) for 16 or 8 months starting at two and ten months of age, respectively. Similar groups were treated with water. At the end of treatments, both lithium treated transgenic groups and non-transgenic mice showed no memory disruption, different from what was observed in the water treated transgenic group. Transgenic mice treated with lithium since two months of age showed decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice. It is suitable to conclude that these data support the use of microdose lithium in the prevention and treatment of Alzheimer's disease, once the neurohistopathological characteristics of the disease were modified and the memory of transgenic animals was maintained.

Current Alzheimer Research, 2013

A lower incidence of dementia in bipolar patients treated with lithium has been described. This m... more A lower incidence of dementia in bipolar patients treated with lithium has been described. This metal inhibits the phosphorylation of glycogen-synthase-kinase 3-α and β, which are related to amyloid precursor protein processing and tau hyperphosphorylation in pathological conditions, respectively. Following the same rationale, a group just found that lithium has disease-modifying properties in amnestic mild cognitive impairment with potential clinical implications for the prevention of Alzheimer&amp;amp;amp;#39;s Disease (AD) when a dose ranging from 150 to 600 mg is used. As lithium is highly toxic in regular doses, our group evaluated the effect of a microdose of 300 μg, administered once daily on AD patients for 15 months. In the evaluation phase, the treated group showed no decreased performance in the mini-mental state examination test, in opposition to the lower scores observed for the control group during the treatment, with significant differences starting three months after the beginning of the treatment, and increasing progressively. This data suggests the efficacy of a microdose lithium treatment in preventing cognitive loss, reinforcing its therapeutic potential to treat AD using very low doses.

☯ These authors contributed equally to this work.

PLOS ONE, 2015

Current Alzheimer Research, 2013