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The role of TNFR1 in the effects of ouabain in the inflammatory signaling in mice hippocampus

Grant number: 14/01435-3
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): August 01, 2014
Effective date (End): October 28, 2018
Field of knowledge:Biological Sciences - Pharmacology
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Cristoforo Scavone
Grantee:Paula Fernanda Kinoshita
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Ouabain is considered an endogenous hormone and it is produced in hypothalamus and in adrenal gland, but little is known about its physiological role. However, many studies show the protective and anti-inflammatory effects of ouabain in the presence of a lesion, for example, kainic acid, Shiga toxin, LPS and in adversal developmental programming and it has also an important role in neuroplasticity by dendritic growth. Ouabain interacts with Na+, K+-ATPase which is a membrane protein which is essential for life, because this enzyme is responsible for osmotic balance regulation, pH control and cell volume by the transport of K+ íons into the cell and Na+ íons out the cell. This process occurs with the hydrolysis of a molecule of ATP. This interaction between NKA and ouabain can also activate signaling cascades which can modulate cell growth, apoptosis, cellular adhesion and motility. It has been shown that mutations in NKA in the central nervous system can cause diseases like familial hemiplegic migraine and rapid-onset dystonia Parkinsonism which emphasize the important role of this enzyme in the CNS. Previous data in our laboratory show that ouabain can increase the Tnf mRNA levels in hippocampus of wistar rats as well as in cerebellar primary cultured cells. Then, we have decided to study what is the role of TNF signaling in the ouabain anti-inflammatory and neuroprotective effect. TNF is mostly related to inflammation, because in the CNS, it activates microglia and astrocytes. Inflammation is an important factor in the neurodegenerative diseases, like Parkinson's and Alzheimer's disease. The interesting point is that the receptors respond differently and activates different cell responses. Firstly, we chose to work with a specific type of TNF receptor, called TNFR1 which is activated only by soluble TNF, while the other receptor (TNFR2) is activated by membrane TNF. To answer our questions, we'll work with KO animals for TNFR1 to evaluate the comportamental and molecular alterations induced by ouabain in an inflammatory response caused by LPS. (AU)