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1.
J Neurosci Res ; 102(4): e25334, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38656648

RESUMO

Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an in vitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.


Assuntos
Astrócitos , Diferenciação Celular , Deficiências de Ferro , Oligodendroglia , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Oligodendroglia/metabolismo , Oligodendroglia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Células Cultivadas , Proteínas de Transporte de Cátions/metabolismo , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Ratos , Células Precursoras de Oligodendrócitos/efeitos dos fármacos , Células Precursoras de Oligodendrócitos/metabolismo , Desferroxamina/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Ferro/metabolismo
2.
Int Immunopharmacol ; 105: 108571, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35093689

RESUMO

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-1ß, 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.


Assuntos
Cladribina , Esclerose Múltipla , Apoptose , Cladribina/farmacologia , Cladribina/uso terapêutico , Humanos , Microglia , Esclerose Múltipla/tratamento farmacológico , Fosforilação
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