Abstract
Our previous data revealed that the signaling pathways associated with ±-Klotho, glutamate, mediators of the inflammatory response in the central nervous system (CNS) and that related to different isoforms of the Na, K-ATPase (NKA) protein as a pump and receptor for endogenous steroids ( ouabain-like hormones) are associated with neuroplasticity and neuroprotection. This effect induced by pharmacologic (cardiosteroids, Klotho, Curcumin, PTEN (Phosphatase and Tensin Homolog on Chromosome Ten), Rotenone (an electron transport chain complex I inhibitor), cannabinoid receptor inverse agonist (CB1), GPNMB (glycoprotein nonmetastatic melanoma protein B), and by non-pharmacologic strategies (intermittent fasting, physical exercise) involves glial and neuronal cell crosstalk through activation of different intracellular pathways involving mediators, such as glutamate and cytokines, transcription factors, and gene expression which will exert a marked influence on the adaptive processes (neuroplasticity) that prevent premature aging, in addition to playing an essential role in cognition and neurodegenerative processes. The general objective is to continue evaluating the effect of these agents on the CNS (FAPESP Process 2016/07427-8) exploring changes in neuroplasticity -induced by these mediators in the presence of a modified expression or signaling of the ±-Klotho, and of the isoforms of NKA. The studies involve in vitro approaches using models of neuronal and glial cells, as well as in vivo studies with a behavioral and biochemical approach in the presence (or absence) of changes in the expression of these proteins (by using vectors, interference RNA, transgenic animals with specific protein modified expression), in different models of inflammation (obesity and asthma), and in Hemodialysis Patients. Finally, there are perspectives of approaching molecular, morphological, and functional changes in the cortical neurons of patients through the induction of pluripotent stem cells (iPSCs) that helps to unravel the mechanisms involved with the emergence of cognitive decline as revealed in previous studies of our groups associated with chronic kidney disease aiming to discover possible pharmacological targets and biological markers. (AU)
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