Publications by authors named "Paula Maria Quaglio Bellozi"

11 Publications

  • Page 1 of 1

PI3K, mTOR and GSK3 modulate cytokines' production in peripheral leukocyte in temporal lobe epilepsy.

Neurosci Lett 2021 Jun 9;756:135948. Epub 2021 May 9.

Neuroscience Program, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil; Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. Electronic address:

Introduction: Epilepsy is a common pathological condition that predisposes individuals to seizures, as well as cognitive and emotional dysfunctions. Different studies have demonstrated that inflammation contributes to the pathophysiology of epilepsy. Indeed, seizures change the peripheral inflammatory pattern, which, in turn, could contribute to seizures. However, the cause of the altered production of peripheral inflammatory mediators is not known. The PI3K/mTOR/GSK3β pathway is important for different physiological and pharmacological phenomena. Therefore, in the present study, we tested the hypothesis that the PI3K/mTOR/GSK3β pathway is deregulated in immune cells from patients with epilepsy and contributes to the abnormal production of inflammatory mediators.

Methods: Patients with temporal lobe epilepsy presenting hippocampal sclerosis and controls aged between 18 and 65 years-old were selected for this study. Peripheral blood was collected for the isolation of peripheral mononuclear blood cells (PBMC). Cells were pre-incubated with different PI3K, mTOR and GSK-3 inhibitors for 30 min and further stimulated with phytohaemaglutinin (PHA) or vehicle for 24 h. The supernatant was used to evaluate the production of IL-1β, IL-6, IL-10, TNF e IL-12p70.

Results: Non-selective inhibition of PI3K, as well as inhibition of PI3Kγ and GSK-3, reduced the levels of TNF and IL-10 in PHA-stimulated cells from TLE individuals. This stimulus increased the production of IL-12p70 only in cells from TLE individuals, while the inhibition of PI3K and mTOR enhanced the production of this cytokine. On the other hand, inhibition of GSK3 reduced the PHA-induced production of IL-12p70.

Conclusions: Herein we demonstrated that the production of cytokines by immune cells from patients with TLE differs from non-epileptic patients. This differential regulation may be associated with the altered activity and responsiveness of intracellular molecules, such as PI3K, mTOR and GSK-3, which, in turn, might contribute to the inflammatory state that exists in epilepsy and its pathogenesis.
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http://dx.doi.org/10.1016/j.neulet.2021.135948DOI Listing
June 2021

Cannabidiol anticonvulsant effect is mediated by the PI3Kγ pathway.

Neuropharmacology 2020 10 20;176:108156. Epub 2020 Jun 20.

Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil. Electronic address:

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt)/mechanistic target of rapamycin (mTOR) signaling pathway has been associated with several pathologies in the central nervous system (CNS), including epilepsy. There is evidence supporting the hypothesis that the PI3Kγ signaling pathway may mediate the powerful anticonvulsant properties associated with the cannabinoidergic system. This work aims to investigate if the anticonvulsant and neuroprotective effects of cannabidiol (CBD) are mediated by PI3Kγ. In vitro and in vivo experiments were performed on C57Bl/6 wild-type (WT) and PI3Kγ mice. Behavioral seizures were induced by bilateral intra-hippocampal pilocarpine microinjection. Twenty-four hours after the first behavioral seizure, animals were perfused and their brains removed and processed, for histological analysis of neurodegeneration, microgliosis and astrocytosis. Primary cultures of hippocampal neurons were used for glutamate-induced cell death assay. CDB increased latency and reduced the severity of pilocarpine-induced behavioral seizures, as well as prevented postictal changes, such as neurodegeneration, microgliosis and astrocytosis, in WT animals, but not in PI3Kγ. CBD in vivo effects were abolished by pharmacological inhibition of cannabinoid receptor or mTOR. In vitro, PI3Kγ inhibition or deficiency also changed CBD protection observed in glutamate-induced cell death assay. Thus, we suggest that the modulation of PI3K/mTOR signaling pathway is involved in the anticonvulsant and neuroprotective effects of CBD. These findings are important not only for the elucidation of the mechanisms of action of CBD, which are currently poorly understood, but also to allow the prediction of therapeutic and side effects, ensuring efficacy and safety in the treatment of patients with epilepsy.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108156DOI Listing
October 2020

NVP-BEZ235 (Dactolisib) Has Protective Effects in a Transgenic Mouse Model of Alzheimer's Disease.

Front Pharmacol 2019 13;10:1345. Epub 2019 Nov 13.

Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Alzheimer's disease (AD) is a neurodegenerative disease and the main cause of dementia. Its major symptom is memory loss, which is a result of neuronal cell death, which is accompanied by neuroinflammation. Some studies indicate the overactivation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway in this disease, being, thus, a potential target for pharmacological treatment. Here, we used a transgenic mouse model of AD that expresses a mutant amyloid-β precursor protein (T41 mice) to investigate the effects of dactolisib (alternative name: NVP-BEZ235, abbreviation BEZ), a dual PI3K/mTOR inhibitor. Ten-months-old T41 animals were treated for 14 days with BEZ or vehicle oral gavage and then submitted to social memory, open field and contextual conditioned fear tests. Hippocampal slices were prepared and Aβ content, NeuN, Iba-1, CD68 and GFAP were evaluated. Tissues were further processed to evaluate cytokines levels through cytometric bead array. The treatment with BEZ (5 mg/kg) reduced social memory impairment in T41 mice. However, BEZ did not have any effect on altered Aβ levels, NeuN, or GFAP staining. The drug reduced the CD68/Iba-1 ratio in CA3 region of hippocampus. Finally, BEZ diminished IL-10 levels in T41 mice. Thus, although its mechanisms are not clear, BEZ protects against memory impairment, reduces microglial activation and reestablishes IL-10 levels, revealing beneficial effects, which should be further investigated for the treatment of AD.
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http://dx.doi.org/10.3389/fphar.2019.01345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864823PMC
November 2019

Minocycline treatment prevents depression and anxiety-like behaviors and promotes neuroprotection after experimental ischemic stroke.

Brain Res Bull 2020 02 19;155:1-10. Epub 2019 Nov 19.

Laboratório de Patologia Celular e Molecular do Departamento de Patologia Geral, Instituto de Ciências Biológicas, UFMG, Brazil; Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, MG, Brazil. Electronic address:

Depression and anxiety have been reported as the major neuropsychiatric consequences following stroke. Minocycline, a neuroprotective drug has minimized depressive symptoms in patients with major depressive disorders and anxiety-like symptoms. In addition, minocycline demonstrated efficacy and seemed a promising neuroprotective agent in acute stroke patients. The present studied evaluated the effects of minocycline treatment on the depression and anxiety-like behaviors, brain damage and expression of inflammatory and neuroprotective mediators after transient global cerebral ischemia in C57BL/6 mice. Brain ischemia was induced by bilateral occlusion of the common carotids (BCCAo) for 25 min and subsequent reperfusion. Sham and BCCAo animals received minocycline at a dose of 30 mg/kg by intraperitoneal injection during 14 days. The locomotor activity, depression and anxiety-like behaviors were assessed by open field, forced swim and elevated plus maze tests, respectively. Then, the brains were removed and processed to evaluate brain damage by histological and morphometric analysis, hippocampal neurodegeneration using Fluoro-Jade C histochemistry, microglial activity using iba-1 immunohistochemistry, brain levels of TNF, IFN-γ, IL-6, IL-10, IL-12p70 and CCL2 by CBA, CX3CL1 and BDNF by ELISA assays. The animals developed depression and anxiety-like behaviors post-stroke and minocycline treatment prevented those neurobehavioral changes. Moreover, minocycline-treated BCCAo animals showed less intense brain damage in the cerebral cortex, brainstem and cerebellum as well as significantly reduced hippocampal neurodegeneration. BCCAo groups exhibited up-regulation of some cytokines at day 14 after ischemia and brain levels of CX3CL1 and BDNF remained unaltered. Our data indicate that the depression and anxiety-like behavioral improvements promoted by minocycline treatment might be related to its neuroprotective effect after brain ischemia in mice.
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http://dx.doi.org/10.1016/j.brainresbull.2019.11.009DOI Listing
February 2020

A positive allosteric modulator of mGluR5 promotes neuroprotective effects in mouse models of Alzheimer's disease.

Neuropharmacology 2019 12 18;160:107785. Epub 2019 Sep 18.

Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil. Electronic address:

Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder. Despite advances in the understanding of its pathophysiology, none of the available therapies prevents disease progression. Excess glutamate plays an important role in excitotoxicity by activating ionotropic receptors. However, the mechanisms modulating neuronal cell survival/death via metabotropic glutamate receptors (mGluRs) are not completely understood. Recent data indicates that CDPPB, a positive allosteric modulator of mGluR5, has neuroprotective effects. Thus, this work aimed to investigate CDPPB treatment effects on amyloid-β (Aβ) induced pathological alterations in vitro and in vivo and in a transgenic mouse model of AD (T41 mice). Aβ induced cell death in primary cultures of hippocampal neurons, which was prevented by CDPPB. Male C57BL/6 mice underwent stereotaxic surgery for unilateral intra-hippocampal Aβ injection, which induced memory deficits, neurodegeneration, neuronal viability reduction and decrease of doublecortin-positive cells, a marker of immature neurons and neuronal proliferation. Treatment with CDPPB for 8 days reversed neurodegeneration and doublecortin-positive cells loss and recovered memory function. Fourteen months old T41 mice presented cognitive deficits, neuronal viability reduction, gliosis and Aβ accumulation. Treatment with CDPPB for 28 days increased neuronal viability (32.2% increase in NeuN cells) and reduced gliosis in CA1 region (Iba-1 area by 31.3% and GFAP area by 37.5%) in transgenic animals, without inducing hepatotoxicity. However, it did not reverse cognitive deficit. Despite a four-week treatment did not prevent memory loss in aged transgenic mice, CDPPB is protective against Aβ stimulus. Therefore, this drug represents a potential candidate for further investigations as AD treatment.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107785DOI Listing
December 2019

Inflammation as a Possible Link Between Dyslipidemia and Alzheimer's Disease.

Neuroscience 2018 04 14;376:127-141. Epub 2018 Feb 14.

Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil. Electronic address:

Alzheimer's disease (AD) is the leading cause of dementia worldwide. This pathological condition is characterized not only by Aβ and tau accumulation in the central nervous system (CNS), but also by inflammation, processes that can lead to neurodegeneration. Besides that, other factors may contribute to the development of AD, such as dyslipidemias. Changes in lipid levels can either influence the activity of enzymes related to the protein deposition that occurs in this pathological condition, or enhance the peripheral and CNS immune responses. Furthermore, cholesterol-associated genes are frequently associated with AD. Here, we extensively reviewed the literature and, based on the existing evidences, we suggest inflammation as an important link between dyslipidemias and AD.
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http://dx.doi.org/10.1016/j.neuroscience.2018.02.012DOI Listing
April 2018

Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl-acylhydrazone derivatives as donepezil hybrids: Discovery of novel multi-target anti-alzheimer prototype drug candidates.

Eur J Med Chem 2018 Mar 31;147:48-65. Epub 2018 Jan 31.

Institute of Biological Sciences, Federal University of Minas Gerais, MG 31270-901, Brazil.

A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AβO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AβO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.
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http://dx.doi.org/10.1016/j.ejmech.2018.01.066DOI Listing
March 2018

Postictal alterations induced by intrahippocampal injection of pilocarpine in C57BL/6 mice.

Epilepsy Behav 2016 11 11;64(Pt A):83-89. Epub 2016 Oct 11.

Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil. Electronic address:

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults. The pilocarpine (PILO) experimental model of TLE portrays behavioral and pathophysiological changes in rodents that are very similar to those found in humans with TLE. However, this model is associated with an unfortunate high mortality rate. Studies have shown that intrahippocampal injection of PILO, while having a much smaller mortality rate, induces status epilepticus (SE) that secondarily leads to TLE. To the best of our knowledge, the present study was the first to evaluate the cognitive and histological alterations 72h after intrahippocampal microinjection of PILO in C57BL/6 mice. Seventy percent of mice developed status epilepticus (SE) after PILO administration, and all animals survived after SE. Seventy-two hours after SE, mice presented memory impairment in both Novel Object Recognition (recognition index - vehicle: 67.57±4.46% vs PILO: 52.33±3.29%) and Contextual Fear Conditioning (freezing time - vehicle: 203±20.43 vs PILO: 107.80±25.17s) tasks. Moreover, using Nissl and NeuN staining, we observed in PILO-treated mice a significant decrease in cell viability and an increase in neuronal loss in all three hippocampal regions analyzed, cornus ammonis (CA) 1, CA3, and dentate gyrus (DG), in comparison with the control group. Additionally, using Iba-1 staining, we observed in PILO-treated mice a significant increase in microglial proliferation in CA1, CA3, and DG of the hippocampus. Therefore, intrahippocampal PILO microinjection is an efficient route to induce SE and acute postictal epileptogenic-like alterations in C57BL/6 mice.
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http://dx.doi.org/10.1016/j.yebeh.2016.08.003DOI Listing
November 2016

Neuroprotective effects of the anticancer drug NVP-BEZ235 (dactolisib) on amyloid-β 1-42 induced neurotoxicity and memory impairment.

Sci Rep 2016 05 4;6:25226. Epub 2016 May 4.

Department of Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, 31270-901, Brazil.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the main cause of dementia. Substantial evidences indicate that there is over-activation of the PI3K/Akt/mTOR axis in AD. Therefore, the aim of the present study was to investigate the effects of NVP-BEZ235 (BEZ; dactolisib), a dual PI3K/mTOR inhibitor that is under phase I/II clinical trials for the treatment of some types of cancer, in hippocampal neuronal cultures stimulated with amyloid-β (Aβ) 1-42 and in mice injected with Aβ 1-42 in the hippocampus. In cell cultures, BEZ reduced neuronal death induced by Aβ. BEZ, but not rapamycin, a mTOR inhibitor, or LY294002, a PI3K inhibitor that also inhibits mTOR, reduced the memory impairment induced by Aβ. The effect induced by Aβ was also prevented in PI3Kγ(-/-) mice. Neuronal death and microgliosis induced by Aβ were reduced by BEZ. In addition, the compound increased IL-10 and TNF-α levels in the hippocampus. Finally, BEZ did not change the phosphorylation of Akt and p70s6K, suggesting that the involvement of PI3K and mTOR in the effects induced by BEZ remains controversial. Therefore, BEZ represents a potential strategy to prevent the pathological outcomes induced by Aβ and should be investigated in other models of neurodegenerative conditions.
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http://dx.doi.org/10.1038/srep25226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855228PMC
May 2016

Pereskia aculeata: A plant food with antinociceptive activity.

Pharm Biol 2015 18;53(12):1780-5. Epub 2015 Jun 18.

Laboratory of Bioactive Natural Products, Department of Biochemistry, Institute of Biological Science of Federal University of Juiz de Fora , Juiz de Fora, MG , Brazil and.

Context: Pereskia aculeata Miller (Cactaceae) is a cactus distributed from south to northeast of Brazil, where its leaves are commonly used as a vegetable, in skin wound healing, and to treat inflammation.

Objectives: The objective of this study was to perform the chemical characterization and to evaluate the antinociceptive activity of the hydromethanolic fraction obtained from the methanol extract of P. aculeata leaves.

Materials And Methods: Chemical characterization was performed by UPLC-MS analysis. The antinociceptive activity was evaluated by the acetic acid-induced writhing, formalin, and tail-flick tests in mice, administering the single oral doses of 100, 200, and 300 mg/kg 1 h before each test.

Results: Tryptamine, abrine, mescaline, hordenine, petunidin, di-tert-butylphenol isomers, and quercetin were identified. The antinociceptive activity was inversely proportional to the administered doses in the acetic acid test, as the dose of 100 mg/kg reduced by 78% the number of writhings, while the doses of 200 and 300 mg/kg reduced by 64% and 41%, respectively. In the formalin test, the dose of 300 mg/kg inhibited by 50% and 86% the licking paw time in the first and second phases, respectively, while the doses of 200 mg/kg (45% and 62%, respectively) and 100 mg/kg (15% and 48%, respectively) were less effective. The sample did not respond to the tail-flick test. Those results suggested a peripheral and central antinociception devoid of an opioid effect.

Conclusion: Pereskia aculeata not only is a plant food with high nutritional value but also presents analgesic potential. It is the first time that this bioactivity is reported for this species.
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http://dx.doi.org/10.3109/13880209.2015.1008144DOI Listing
May 2016

Anti-inflammatory, antinociceptive and cytotoxic effects of the methanol extract of Cecropia pachystachya Trécul.

Phytother Res 2013 Jun 30;27(6):926-30. Epub 2012 Aug 30.

Departamento de Bioquímica-ICB, Universidade Federal de Juiz de Fora, Campus Universitário, Martelos, Juiz de Fora, MG, Brasil.

Cecropia pachystachya is widely used in the traditional medicine as anti-inflammatory, antitusive, expectorant, antiasthmatic and hypoglycemic. It is also commercially available to treat skin cancer. To validate some of the popular uses of this species, its methanol leaves extract (CPM) was tested for anti-inflammatory, antinociceptive and cytotoxic effects. The anti-inflammatory activity was evaluated by croton oil-induced ear edema test. When used orally, the anti-inflammatory effect of CPM at 300 mg/kg was similar to that of indomethacin with 53% inhibition of the ear edema. Also, results on topical treatment were similar to that of dexamethasone with 83% inhibition of the edema. To evaluate the antinociceptive activity, acetic acid-induced writhing and formalin-induced pain tests were employed. CPM (100 and 300 mg/kg) reduced the number of writhing by 61% and 67%, respectively. In both doses, the activity was comparable to the reference drug, indomethacin. The oral administration of CPM was ineffective in the first phase of formalin test but exhibited great effects on the second phase decreasing the licking time by 85% at 300 mg/kg. The cytotoxic potential of CPM was also investigated against HL60, HL60.bcl2 and Jurkat tumor cell lines and showed an inhibition of more than 50% of cell proliferation. The flavones orientin and isoorientin were detected in CPM.
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http://dx.doi.org/10.1002/ptr.4811DOI Listing
June 2013