Oligodendroglial cells submitted to hypoxia are less vulnerable to damage in the presence of intracellular iron chelators

BERTONE UÑA, ANA; SOTO, EDUARDO; PASQUINI, JUANA; PASQUINI, LAURA

La Falda, Córdoba

Workshop; VIII Taller de Neurociencias; 2007

Taller de Neurociencias

The transcriptional activator Hypoxia Inducible Factor 1 (HIF-1) plays an essential role in oxygen sensing.  HIF-1 registers changes and coordinates appropriate answers that allow cells to survive to hypoxia (H). HIF-1 consists of a and b subunits and its activity are controlled via stability regulation of its aƒn subunit.  HIF-1aƒn degradation is accomplished by prolilhidroxylases (PHD), the activity of which depends on the availability of O2, 2-oxoglutarate and Fe2+. PHDs hydroxylate HIF-1aƒn to facilitate its ubiquitination and poly-ubiquitinated HIF-1a ƒnis then recognized and degraded by the 26S proteasome. Using iron chelators like desferrioxamine (DFO), TPEN, or 2-oxoglutarate analogs like dihidroxibenzoic acid (DHB), it is possible to stabilize HIF-1a. Aim: To study the consequences of hypoxia treatment on oligodendroglial cell viability in cultures at different stages of their maturation in the presence and absence of TPEN, DFO y DHB. Results: Late oligodendroglial progenitor cells (LPCs) are more vulnerable to hypoxia than less differentiated precursors and they are significantly protected by addition to the cultures of the intracellular iron chelator TPEN. Conclusions: the increase in survival rate induced by the treatment with TPEN, in LPCs submitted to hypoxia, could be related to its action as an intracellular iron chelator. The greater vulnerability to hypoxia of LPCs in comparison with that observed in less differentiated precursors agrees with previous data that relate the existence of a temporary ¡§vulnerability window¡¨ in these cells. Works from several laboratories have demonstrated that there is an increase in iron levels in the neonatal rat brain submitted to hypoxia-ischemia and that this increase causes oxidative stress. It is tempting to speculate that a decrease in iron levels trigger protective mechanisms in oligodendroglial cells submitted to hypoxia, as a consequence of a stabilization of HIF-1a and a decreased production of oxidative species.