ROLE OF ASTROCYTES AND NEURONS IN THE RESPONSE TO HYPOXIAi IN THE DEVELOPING CNS. HIF1 AND NEUROTROPHINES AS MEDIATING MOLECULES.

FISZER DE PLAZAS S.; BOGETTI, M.E.; BONAFINA, A.

Congreso; Society for Neuroscience; 2012

Society for Neuroscience

Hypoxia is a damage consisting in a decrease in the concentration of oxygen in blood and tissues, which leads to cell death. During development, this insult causes irreversible damage in the CNS. Previous work in our model of acute hypoxia (60 min, 8% O2) in chicken embryos has shown that the cell death by hypoxia (HxCD) in the optic tectum (OT) presents an apoptotic phenotype and affects only a small group of neurons. Embryonic day (ED) 15 was established to carry out the studies because it is a period during which neurotrophins (NTS) play an essential role in the maintenance and survival of neurons and during which astrocytes are present and mature in the OT. Hypoxia-inducible factor-1 (HIF-1) is a key regulator of oxygen homeostasis and is stabilized by insults associated with hypoxia and ischemia. It is known that, within the NTS, Nerve Growth Factor (NGF) plays a role as a neuroprotective factor of various types of injury. In this work, we analyzed the role and modulation of the receptors of this factor (P-TrkA and p75) in response to hypoxic damage in cells neuroprotected by NGF. Our results show that, at the end of hypoxia (Ho), there is a decrease in the expression of the active receptor P-TrkA and an increase in that of p75, and that these values recover to control values as from 12 h post-hypoxia. The presence of NGF half an hour before the injury reverses these patterns, preventing the decrease in P-TrkA and the increase in p75. Ho seems to be a critical and adjustable point, in which the lower expression of active TrkA, together with an increase in the expression of p75, may be related to the cell death evidenced 48 hours later. We also found stabilization of HIF-1 after hypoxia, both in vivo and in primary culture of astrocytes, which is rapidly decreased in the first minutes of re-oxygenation, together with an increase in the mRNA levels. In conclusion, hypoxic cell death is sensitive to the influence of endogenous NTS, and is prevented when NGF is administered before the injury. This may indicate that HxCD occurs by an increase in p75 and a decrease  in P-TrkA. On the other hand, HxCD is regulated by HIF-1, and its expression in astrocytes may be mediating a survival pathway. Taking together, these results show that HxCD is a result of very regulated pathways in both neurons and astrocytes.