ROLE OF ADENOSINE A2B RECEPTORS DURING CUPRIZONE-INDUCED DEMYELINATION IN AN IN VIVO MOUSE MODEL

Demyelinating diseases are characterized by the progressive loss of myelin in the central nervous system (CNS). Myelin recovery can be achieved by fostering the differentiation of oligodendrocyte progenitor cells to mature oligodendrocytes, the only myelinating cells in the brain. Oligodendrocytes maturation is sustained, among others, by the neuromodulator adenosine through the activation of its specific receptors: A₁, A_2A, A_2B, A₃, all expressed in the brain on neurons and glial cells. The role of A_2B receptors (A2BRs) in a cuprizone- induced demyelination model in male C57BL/6 mice was investigated by administering the selective A2BR agonist BAY60-6583 or antagonist PSB603 every other day during the last 2 weeks of a 5-week cuprizone-based diet. We evaluated body weight, behavioral responses with the Hole board test and Rotarod test to assess motility and anxiety and performed immunofluorescence analyses. Cuprizone-fed mice showed significant decrease in body weight, motor impairment, reduced spontaneous motility and increased anxiety-like behavior. These effects were associated with a decrease in myelin levels, an increase in LDN neurons (a form of damaged neurons), reactive astrogliosis and microgliosis in corpus callosum medialis, striatum and motor cortex. PSB603, but not BAY60-6583, prevented the latter effects, also promoting a partial recovery in motor deficits. Both drugs reverted the increase of LDN neurons and were able to promote the increase of a protective phenotype of microglia, rod microglia. The antagonism of A2BRs might represent an attractive strategy to alleviate myelin damage and glial activation in the CNS under conditions of demyelination.