HIF-1 neuroprotection through erythropoietin increase in hypoxia: a role for A1 adenosine receptors

Several reports suggest that neuronal death is an important mechanism in neuropathic pain and neurotrophic factors have been demonstrated to possess potent neuroprotective activity. Unfortunately, these factors are limited therapeutically because they have a tendency to induce hyperalgesia. Erythropoietin (Epo), by contrast, does not induce hyperalgesia and is a neuroprotective agent for primary sensory neurons, spinal neurons and their supporting glial cells. Hypoxia induces genes that have been shown to be associated with neuroprotection. One of the key genes involved is HIF-1. HIF induces a series of genes one of which is Epo. Adenosine is an endogenous nucleoside modulator released from almost all cells and is generated in the extracellular space by breakdown of ATP through a series of ectoenzymes, including the ENTDase (CD39) and 5’-nucleotidase (CD73). Adenosine modulates HIF-1α in different cancer cell lines and in foam cells (Gessi et al., 2008; Gessi et al., 2010). In particular this nucleoside, through A1 receptor activation, plays an essential role in protecting the embryo from hypoxia by regulating HIF-1 (Wendler et al., 2007; Gessi et al., in press), suggesting a possible involvement of A1 adenosine receptor also in HIF-mediated neuroprotective effects. In this project we have evaluated the involvement of A1 adenosine receptors on the modulation of HIF-1, Epo, tumor necrosis factor (TNF)-alpha and IL-6, in a panel of different types of neuronal cells including N9 murine microglial, PC12 rat neuron-like, C8-D1A murine astrocytes and RSC96 rat schwann cells in hypoxic conditions, in the absence or in the presence of stimulation with LPS. These data suggest the importance of A1 adenosine receptors modulation in neuroinflammation and pain. Gessi et al. Advances in Pharmacology, in press. Gessi et al. (2008). Pharmacol Ther. 117, 123-40 Gessi et al (2010). Arterioscler Thromb Vasc Biol. 30, 90-7. Wendler et al. (2007) Proc Natl Acad Sci U S A. 104, 9697-702.