Abstract
While it has been established that Probenecid (PBN) prevents the onset of experimental autoimmune encephalomyelitis (EAE) in mice, it is not clear whether it has any effect on already manifest EAE. The aim of this study was therefore to analyze the therapeutic effect of PBN in pronounced EAE. Mice with manifest clinical symptoms of EAE were either treated with PBN or solvent for 20 days, or they were left untreated. The clinical symptoms were monitored daily. Inflammation, demyelination and oligodendrocyte numbers were determined in the spinal cord. We were able to demonstrate that PBN not only significantly prolonged survival but also prevented the progression of clinical symptoms in the EAE model of multiple sclerosis. In addition, we were able to show that PBN reduced inflammation, T cell infiltration and oligodendrocyte cell loss. PBN was previously shown to inhibit – among other targets – pannexin channels. As pannexin channels provide conduits for ATP, are associated with the inflammasome, and act as “find me-signals” in the process of apoptosis, inhibition of pannexins via PBN might contribute to the PBN-effects observed in this study. The beneficial and therapeutic effects of PBN in the context of EAE demonstrate an intriguing link between PBN and neuroinflammation, which might foster translational interest.
Highlights
Characteristic pathologic features of multiple sclerosis (MS) are inflammation and demyelination resulting, along with other symptoms, in the loss of motor function
EAE was induced in all mice and clinical symptoms were monitored daily from the start of immunization
General estimated equation (GEE) analysis confirmed that differences between these two groups, EAE and solvent, were not significant (p = 0.836)
Summary
Characteristic pathologic features of MS are inflammation and demyelination resulting, along with other symptoms, in the loss of motor function. Extracellular ATP released by Panx[1] channels was shown to modulate both the initiation and the clearance of inflammatory responses[6]. Probenecid (PBN) is a clinically-approved drug, which – among other targets – inhibits the Panx[1] channel and prevents activation of the inflammasome[2,7]. In EAE, PBN prevented the onset of clinical symptoms in mice[9]. It is not clear whether PBN has any effect on already manifest EAE. We show that EAE does not progress in PBN-treated animals and that these effects are associated with reduced inflammation and increased numbers of oligodendrocytes
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