New Therapeutic Strategies Using Modified Digoxin Nanocompounds for Alternating Hemiplegia of Childhood (AHC)

• Grant number: 22/15745-0
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2024
• End date: February 28, 2026
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Cristoforo Scavone
• Grantee: Cristoforo Scavone
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Jacqueline Alves Leite ; Leandro Augusto de Oliveira Barbosa ; Luciana Biagini Lopes
• Associated scholarship(s): 24/05172-9 - Synthesis of DB15 and formulations based on nanocarriers for the development of the project: New therapeutic strategies using carbon nanotubes functionalized with modified digoxin (DB15) for Alternating Hemiplegia of Childhood (AHC)"., BP.TT

Abstract

Cardiotonic steroids (ECTs) are substances capable of interacting with Na/K-ATPase and activating signaling pathways involved in cell survival. This enzyme is responsible for the main ionic transport in the brain, maintaining ideal intracellular conditions. Ouabain (OUA) is one of the most studied ECTs in the CNS, where its ability to reduce LPS-induced neuroinflammation has been observed via inhibition of the activation of the nuclear factor NF-KB leading to a reduction of pro-inflammatory cytokines such as, IL-1B and TNF-alpha. Furthermore, studies have observed that OUA has the ability to modulate the immune system, reducing peripheral inflammation. Interestingly, recent work carried out by our group with synthetic derivatives of digoxin, BD-21 and BD-15, demonstrated at low doses and concentrations, respectively, an anti-inflammatory and neuroprotective effect in in vivo and in vitro models. Furthermore, BD-14 and BD-15 showed selectivity for the alpha3 isoform, and were able to stimulate activity in the alpha3 isoforms of rat NKA transfected into Sf9 cells through the baculovirus expression system. Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by episodes of hemiplegia on any side of the body and paroxysmal events. The etiology of the disease stems from mutations in the ATP1A3 gene, which encodes the alpha3-Na/K-ATPase isoform. The treatment of AHC still remains palliative, and one of the challenges of developing pharmacological and genetic therapies for the treatment of AHC results from the inability of drugs and biomolecules with selectivity for action on NKA to effectively cross the blood-brain barrier (BBB). This challenge of crossing the BBB could be overcome through the use of new therapeutic nano-delivery systems to safely and efficiently deliver pharmacologically active agents (drugs or genes) to the brain. Furthermore, exploring the synergy between nanomedicine and pharmacological and genetic therapies could be a major advance in the treatment of various diseases, including AHC and neurodegenerative diseases. Thus, considering the lipophilicity of the BD-15 molecule and its derivatives and the advantages of oral administration (which include comfort and patient acceptance), its incorporation into nanostructured lipid carriers with surface modified by polysorbate 80 is proposed. development of a product for oral use can even be used in the nasal form, which would be interesting for use by children. (AU)

Scientific publications

(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)

MAGALHAES, DANIEL WILSON A.; SIDRONIO, MARIA GABRIELLA S.; NOGUEIRA, NOEMIA N. A.; CARVALHO, DEYSE CRISTINA MADRUGA; DE FREITAS, MARIA EUGENIA G.; OLIVEIRA, ERICKE CARDOSO; LIMA, GUSTAVO F. DE FRAZAO; DE ARAUJO, DEMETRIUS A. M.; SCAVONE, CRISTOFORO; DE SOUZA, THALISSON AMORIM; et al. Evaluation of the Anti-Mycobacterial and Anti-Inflammatory Activities of the New Cardiotonic Steroid γ-Benzylidene Digoxin-15 in Macrophage Models of Infection. MICROORGANISMS, v. 13, n. 2, p. 17-pg., 2025-02-01. (21/06009-6, 22/15745-0)