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Study of the possible neuroprotective effects of the TRPV1 antagonism in an animal model of Alzheimer's Disease

Grant number: 17/11465-5
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): February 01, 2018
Effective date (End): August 29, 2018
Field of knowledge:Biological Sciences - Pharmacology - Neuropsychopharmacology
Principal Investigator:Leonardo Resstel Barbosa Moraes
Grantee:Davi Campos La Gatta
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Alzheimer's Disease (AD) is a neurodegenerative disorder that may occur on account of an increased production of amyloid-beta (AB) protein, which deposits in the synapses. It leads to an alteration in the glutamate release/capitation kinetics, the main excitatory neurotransmitter of the central nervous system. In this context, glutamate accumulates in the synaptic cleft, inducing neurotoxic pathways activation, such as Tau protein hiperphosphorilation as well as production of inflammatory and oxidant compounds. As a consequence, the synapses disintegrate in areas involved with episodic memory and memory extinction processes, such as the medial prefrontal cortex (MPFC) and hippocampus (Hpc). In these brain areas, the glutamate release can be reduced by the endocannabinoids through CB1 receptors activation by anandamide. In addition, the repeated treatment with a CB1 receptors agonist displayed a neuroprotective effect and improved the cognitive function of transgenic mice, that express some characteristics of AD. Additionally, anandamide is able to activate other classes of receptors, the so called TRPV1 receptors. They favor calcium influx to the neuronal cells and increase glutamate release in the MPFC and Hpc. The pharmacological blockade of such receptors in astrocytes culture prevented the increased gene expression of enzymes and pro-inflammatory compounds induced by A² application. However, the role of the TRPV1 channels in vivo models of familial AD has never been tested. Therefore, the hypothesis of this project is that the MPFC and Hpc TRPV1 receptors could exert a neurotoxic effect and damage neuroplastic processes during the evolution of the disease. In order to test this assumption, 4 months-old male transgenic APP/PS1 mice will be used. These animals present some AD-like characteristics, such as MPFC and Hpc AB deposition and cognitive impairment. APP/PS1 mice along with their littermates wild-type will be submitted to a repeated treatment during 21 consecutive days, with the TRPV1 receptors antagonist, SB366791, or vehicle. 24 hours after the end of the treatment, they will undergo the object recognition task, as well as the sound or contextual fear conditioning to assess fear extinction. After the end of the behavioral tests the MPFC and Hpc will be dissected for the molecular assays. (AU)

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