Details

Autor(en) / Beteiligte

• Aybar, Florencia
• Julia Perez, María
• Silvina Marcora, María
• Eugenia Samman, María
• Marrodan, Mariano
• María Pasquini, Juana
• Correale, Jorge

Titel

2-Chlorodeoxyadenosine (Cladribine) preferentially inhibits the biological activity of microglial cells

Ist Teil von

• International immunopharmacology, 2022-04, Vol.105, p.108571-108571, Article 108571

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2022

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• [Display omitted] •Cladribine is a pro-drug requiring intracellular phosphorylation to be activated.•Cladribine induces apoptosis and inhibits the proliferation of microglial cells.•Cladribine inhibits pro-inflammatory cytokine secretion by microglial cells.•Astrocytes are resistant to cladribine effects.•Differences in the phosphorylation state can explain these features. Cladribine (2CdA) is a synthetic chlorinated purine nucleoside analogue which acts as a pro-drug requiring intracellular phosphorylation to be activated. It is biologically active in selected cell types, which results in a reduction of circulating T and B lymphocytes implicated in multiple sclerosis (MS) pathogenesis. In addition, 2CdA shows good central nervous system (CNS) penetration and can therefore exert its action on microglia and astrocytes. Therefore, we studied the effects of 2CdA on microglial cells and astrocytes, both emerging as potential targets for MS therapy. Other than its effects on the peripheral immune system, 2CdA induced the apoptosis of microglial cells, inhibited their proliferation and reduced the production of cytokines, particularly pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. These represent additional mechanisms of 2CdA that may contribute to limiting inflammatory pathways. By contrast, astrocytes showed resistance to the action of 2CdA, which may be explained by differences in its intracellular phosphorylation. Insights into the mechanism of action of and resistance to 2CdA in CNS-resident cells may prove crucial for its optimal use.