Evaluation of the effects of BD-15 on hippocampal neurogenesis

• Grant number: 22/13996-6
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): April 01, 2023
• Effective date (End): August 31, 2024
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Cristoforo Scavone
• Grantee: Letícia Pavan dos Anjos
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 21/06009-6 - Neuroplasticity -induced by challenge Na, K-ATPase, Klotho, glutamate, and neuroinflammation signaling cascades to reveal new therapeutic targets for aging and neurodegenerative diseases, AP.TEM

Abstract

Adult hippocampal neurogenesis (AHN), a process that adds new neurons in the hippocampus,tends to increase hippocampal plasticity, assisting in pattern separation, spatial memory, learning, and with direct participation in mood regulation. Neural precursor (or progenitor) stem cells, known by NSCs, have the ability to differentiate into astrocytes, oligodendrocytes, or new neurons depending on the niche in which they are located. This process, called neurogenesis, is classified as a process involving the proliferation, migration, and differentiation of these stem cells in the central nervous system (CNS). The impairment of adult neurogenesis is directly related to cognitive disorders and neurodegenerative diseases. Neuroinflammation, also associated with neuroinflammatory disorders, affects neurogenesis and can have detrimental or beneficial consequences that can result in enhancement and/or inhibition of the neurogenic process, depending on the duration of inflammation. Both neuroinflammation and AHN can be effectively reversed by the use of nonsteroidal anti-inflammatory drugs. Stimulation of neurogenesis comes from tasks that incite learning, such as studying a new language or new content and performing long-term medium-intensity physical activity, and decreased neurogenesis is directly related to the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's, and depression. Previous resultsfrom our study groups show that ouabain (OUA), a cardiotonic steroid that inhibits Na,K-ATPaseand has neuroprotective potential, is responsible for modulating and increasing BDNF expression,modulating ERK, AKT and Wnt/²-Catenin pathways, and inducing morphological changes in CA1region neurons, increased dendritic arborization after 7 and 14 days of administrationand improved spatial memory in treated animals. A cardiotonic steroid analog of OUA, a benzylidene digoxin derivative, called 15-benzylidene digoxin (BD-15), has been widely studied and related to neuroprotection. When tested in membrane preparations it showed higher affinity forthe ±3 isoform of the enzyme Na,K-ATPase (PESSÔA et al, 2018) and both in studies in neuroblastoma cells and in experiments against partial chemical ischemia, this drug attenuated the damaging effects, suggesting that this substance presents neuroprotective effects (DE SOUZA et al,2019). Thus, the aim of this project is to evaluate the neuroprotective effects of BD-15 on neural precursor cells of the subgranular zone as well as its correlation with the neurogenic process.