Sildenafil ameliorates EAE by decreasing apoptosis in the spinal cord of C57BL/6 mice

Author(s):Show less -

Duarte-Silva, Eduardo ^{[1, 2]} ; da Rocha Araujo, Shyrlene Meiry ^[1] ; Oliveira, Wilma Helena ^[1] ; de Los, Deniele Bezerra ^[3] ; Rocha de Franca, Maria Eduarda ^[4] ; Bonfanti, Amanda Pires ^[5] ; Peron, Gabriela ^[5] ; Thomaz, Livia de Lima ^[5] ; Verinaud, Liana ^[5] ; de Santana Nunes, Ana Karolina ^[4] ; Peixoto, Christina Alves ^{[1, 6]}

Affiliation

^[1] Aggeu Magalhaes Inst IAM, Lab Ultrastruct, Recife, PE - Brazil

^[2] Aggeu Magalhaes Inst IAM, Postgrad Program Biosci & Biotechnol Hlth PPGBBS, Oswald Cruz Fdn FIOCRUZ PE, Recife, PE - Brazil

^[3] Fed Univ Pernambuco UFPE, Postgrad Program Biotechnol, Northeast Network Biotechnol RENORBIO, Recife, PE - Brazil

^[4] Fed Univ Pernambuco UFPE, Postgrad Program Biol Sci, Ctr Biosci, Recife, PE - Brazil

^[5] Univ Campinas UNICAMP, Dept Struct & Funct Biol, Campinas, SP - Brazil

^[6] Inst Sci & Technol Neuroimmunomodulat INCT NIM, Rio De Janeiro - Brazil

• Document type: Journal article
• Source: Journal of Neuroimmunology; v. 321, p. 125-137, AUG 15 2018.
• Web of Science Citations: 4

Abstract

Apoptosis is one form of cell death that is intimately related to health and pathological conditions. In most neuroinflammatory and/or neurodegenerative diseases, apoptosis is associated with disease development and pathology and inhibition of this process leads to considerable amelioration. It is becoming evident that apoptosis also participates in the pathogenesis of Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). Drugs such as Sildenafil, a Phosphodiesterase type 5 Inhibitor (PDESI), have proven to be neuroprotective in MS models. However, it is not known whether Sildenafil is able to modulate cell death, specifically apoptosis, in EAE mice. Therefore, the aim of this study was to determine the effects of Sildenafil on extrinsic and intrinsic apoptosis pathways in the spinal cord of C57BL/6 mice with EAE. TUNEL analysis showed that EAE mice had elevated number of TUNEL+ cells and that treatment with Sildenafil led to reduced number of dying cells, indicating that Sildenafil was able to inhibit cell death. We observed that both extrinsic and intrinsic pathways of apoptosis were governing the dynamics of EAE progression. We showed that in EAE mice there were increased levels of extrinsic (Caspase-8, -3, TNF-alpha, FADD) and intrinsic (Caspase-9, Bax and Cytochrome C) apoptosis markers. Bcl-2, an anti-apoptotic protein, was downregulated in EAE mice. We also demonstrated that EAE mice had increased levels of non-caspase mediators of cell survival/cell death (p-I kappa B alpha and p-MAPK-p38). Besides, EAE mice presented augmented demyelination. Nevertheless, this is the first research to demonstrate that Sildenafil, when administered concomitant to disease induction, modulated the expression of pro- and antiapoptotic proteins of the extrinsic and intrinsic pathways, as well as diminished the expression of non-caspase mediators and promoted remyelination in the spinal cord, indicating neuroprotective effects. Thus, the present study demonstrated that Sildenafil inhibits apoptosis by two distinct, although interconnected, mechanisms: directly by modulating caspase expression (through extrinsic and intrinsic pathways) and indirectly by modulating the expression of molecules involved in cell death and/or cell survival. (AU)

• FAPESP's process: 16/15827-6 - Identification of new molecules with chemotherapeutic effect in human glioma and characterization of the mechanism
• Grantee: Catarina Raposo Dias Carneiro
• Support Opportunities: Scholarships in Brazil - Young Researchers