ROLE OF ADENOSINE A2B RECEPTOR AGONISM AND ANTAGONISM IN AN IN VIVO MOUSE MODEL OF SEVERE DEMYELINATION

The aim of our study was to characterize the effect of selective adenosine A2B receptor (A2BR) agonist BAY60-6583 and antagonist PSB603 on a murine model of severe demyelination induced by a 7 weeks diet enriched with cuprizone (CPZ). Drugs were administered i.p. every other day for the last 2 weeks of the diet. Body weight was monitored and Hole board test was performed to assess anxiety. Immunohistochemistry of neurons and glia was performed on corpus callosum medialis, cortex and striatum.
Body weight was influenced neither by diet nor treatments. In Hole board test, CPZ increased anxiety and BAY60-6583, but not PSB603, reverted this effect. Immunohistochemistry demonstrated that CPZ increased LDN neurons (low density nucleus neurons, a form of damaged neurons) in cortex and striatum, effect reverted by both drugs. CPZ induced astrogliosis and microgliosis. Neither PSB603 nor BAY60-6583 reverted completely astrogliosis and microgliosis. CPZ increased rod microglia (a protective phenotype of microglia), and PSB603 and BAY60-6583 enhanced this effect.
Summarizing: both drugs prevented the increase of damaged LDN neurons and promoted the increase of protective rod microglia. In in vivo experiments BAY60-6583 demonstrated a protective effect in the Hole board test. In accordance with the literature, we hypothesize that BAY60-6583 agonism on neuronal A2BRs, may increase the firing and promote the release of pro-myelination factors, while PSB603 antagonism on A2BRs of oligodendrocyte precursor cells, may promote oligodendrogenesis. Both effects may help the recovery of the tissue and confirm the importance of the modulation of the adenosinergic system to counteract demyelination.