Protective effects of adenosine A2B receptor antagonism in a cuprizone-induced demyelination model

Demyelinating diseases are characterized by the progressive loss of myelin in the central nervous system (CNS). Myelin protection 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 PSB 603 during the last 2 weeks of a 5-week cuprizone-based diet. We performed body weight evaluation, behavioural tests and immunofluorescence analysis. Cuprizone-fed mice showed a significant decrease in body weight gain, a motor impairment and a reduced spontaneous mobility. These effects were associated with a decrease in myelin levels, a reactive astrogliosis and microgliosis in corpus callosum medialis, striatum and motor cortex. PSB 603, was able to prevent cuprizone effects on glia, whereas both compounds promoted a significant recovery in motor deficits. The antagonism of A2BRs might represent an attractive strategy to alleviate myelin damage and glial activation in the CNS under conditions of demyelination.