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Study of the neuroprotective role of kinin B2 receptor in the Alzheimer's Disease

Grant number: 13/13656-1
Support Opportunities:Regular Research Grants
Duration: September 01, 2014 - February 28, 2017
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Hudson de Sousa Buck
Grantee:Hudson de Sousa Buck
Host Institution: Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP). Fundação Arnaldo Vieira de Carvalho. São Paulo , SP, Brazil
Associated researchers:Ariadiny de Lima Caetano ; Fernand Gobeil Jr ; Hélene Girouard ; Luciana Malavolta Quaglio ; Mariana da Silva Araujo ; Tânia Araújo Viel


The Kallikrein-Kinin System (KKS) has been associated to inflammatory and immunogenic responses in the peripheral and central nervous system by the activation of two receptors, namely B1 receptor and B2 receptor. The B1 receptor is absent or under-expressed in physiological conditions, being up-regulated during tissue injury or in the presence of cytokines. The B2 receptor is constitutive and mediates most of the biological effects of kinins. Some authors suggest a link between the KKS and the neuroinflammation in Alzheimer's disease, which is characterized by cognitive decline, presence of amyloid beta peptide (A²) aggregates and neurofibrillary tangles. We have recently described an increase in bradykinin (BK) in the cerebrospinal fluid and in densities of B1 and B2 receptors in brain areas related to memory, after chronic infusion of amyloid-beta (A²) peptide in rats, which was accompanied by memory disruption and neuronal loss. Similar memory impairment was observed in C57BL/6 mice (WTA²) but occurred earlier in mice lacking B2R (KOB2RA²) and was absent in mice lacking B1R (KOB1RA²). An increase in B2R density was observed in both WTA² and KOB1RA² in memory processing related areas. Also, increases in synapses density in KOB1RA² and in A² deposits in KOB2RA² were observed. The memory preservation observed in KOB1RA², could be due to the increase in densities of B2R and synapses suggesting a neuroprotective role for B2R, reinforced by the increased number of A² plaques in KOB2RA², which could be involved in the "in vivo" A² degradation. Additionally, it was show recently that exposure of BV2, N9, and primary microglia cells to BK or endothelin increased A² incorporation, in a dose dependent manner, due to increased A² fagocitosis. Very recently it was show a selective upregulation of astroglial B1R in the amiloyd precursor protein (APP) mouse brain, and the capacity of the B1R antagonist to abrogate amyloidosis, cerebrovascular and memory deficits in this AD transgenic model. This effect of kinin B1 blockade could be due to a preferential activation of B2 receptor by circulating kinins.Thus, the aim of this study is evaluate the participation of kinin B2 receptor in AD, using transgenic mice hyperexpressing human APP. Mice will be treated with selective B2 agonist (NG294) and antagonist (R1004), and B1 antagonist N2031, all of them resistant to degradation, and memory process evaluated. Also, will be evaluated neuroinflammatory markers, neuronal and synaptic plasticity, and cellular and sub-cellular colocalization of kinin B2 receptor. In a non-treated group, density of kinin receptors and neurodegenerative process will be evaluated along aging. These data will give the pharmacological and neuroanatomical substrate for a better understanding of the kinin B2 receptor role in AD. (AU)

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Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
NUNES, MARIELZA ANDRADE; TORICELLI, MARIANA; SCHOWE, NATALIA MENDES; MALERBA, HELENA NASCIMENTO; DONG-CRESTE, KARIS ESTER; AZEVEDO TUMA FARAH, DANIELA MOURA; DE ANGELIS, KATIA; IRIGOYEN, MARIA CLAUDIA; GOBEIL, FERNAND; VIEL, TANIA ARAUJO; et al. Kinin B2 Receptor Activation Prevents the Evolution of Alzheimer's Disease Pathological Characteristics in a Transgenic Mouse Model. PHARMACEUTICALS, v. 13, n. 10, . (13/13656-1, 17/21655-6, 16/07115-6)
BALTHAZAR, JANAINA; SCHOWE, NATALIA MENDES; CIPOLLI, GABRIELA CABETT; BUCK, HUDSON SOUSA; VIEL, TANIA ARAUJO. Enriched Environment Significantly Reduced Senile Plaques in a Transgenic Mice Model of Alzheimer's Disease, Improving Memory. FRONTIERS IN AGING NEUROSCIENCE, v. 10, . (16/07115-6, 13/19999-8, 13/06935-1, 13/13656-1)
CAETANO, A. L.; DONG-CRESTE, K. E.; AMARAL, F. A.; MONTEIRO-SILVA, K. C.; PESQUERO, J. B.; ARAUJO, M. S.; MONTOR, W. R.; VIE, T. A.; BUCK, H. S.. Kinin B2 receptor can play a neuroprotective role in Alzheimer's disease. Neuropeptides, v. 53, p. 51-62, . (09/08049-3, 07/04800-0, 13/13656-1)
MORZELLE, MARESSA CALDEIRA; SALGADO, JOCELEM MASTRODI; TELLES, MILENA; MOURELLE, DANILO; BACHIEGA, PATRICIA; BUCK, HUDSON SOUSA; VIEL, TANIA ARAUJO. Neuroprotective Effects of Pomegranate Peel Extract after Chronic Infusion with Amyloid-beta Peptide in Mice. PLoS One, v. 11, n. 11, . (12/12917-3, 13/08989-1, 13/13656-1)
TORICELLI, MARIANA; EVANGELISTA, SEBASTIANA RIBEIRO; OLIVEIRA, LARISSA ROLIM; VIEL, TANIA ARAUJO; BUCK, HUDSON SOUSA. Neuroprotective Effects of Kinin B2 Receptor in Organotypic Hippocampal Cultures of Middle-Aged Mice. FRONTIERS IN AGING NEUROSCIENCE, v. 11, . (13/13656-1, 17/21655-6, 16/07115-6)

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