030 – Probenecid and its various targets in the treatment of multiple sclerosis: A single player or an orchestra of all?
Lea Müller (1) – Nadine Hainz (1) – Carola Meier (1)
Institute of Anatomy, Saarland University, Homburg, Germany (1)
Probenecid (PBN) is an approved drug for the treatment of gout, which was recently shown to prevent the development of clinical symptoms as well as to arrest progression of pronounced clinical symptoms in experimental autoimmune encephalomyelitis (EAE). EAE is a murine model of multiple sclerosis (MS), which mimics the inflammatory component of the disease as well as the resulting demyelination. However, the precise target of PBN in view of its effects in the treatment of EAE still needs to be identified. There are several conceivable pathways, which were analyzed in this study. The fundamental idea was that PBN acts via the inhibition of Pannexin1 (Px1) channels and therefore prevents the activation of an inflammatory cascade, particularly of the inflammasome. To verify this hypothesis, we induced EAE in Px1-deficient mice. Astonishingly, these mice developed clinical EAE-symptoms comparable to those observed in EAE-induced C57BL/6 mice. Postulating an additive effect of PBN, we treated immunized Px1-deficient mice with PBN. Indeed, this additional treatment with PBN protected from the development of clinical EAE symptoms. This result was further supported by the fact that brilliant blue FCF, a highly specific Px1 channel inhibitor, did not change the clinical outcome when applied to EAE-induced C57BL/6 mice. Thus, there is clear evidence for additional targets of PBN other than the Px1 channel, which might mediate its therapeutic effect in EAE. As organic anion transporters (OAT) are known targets of PBN, we next applied an OAT-inhibitor to EAE mice which showed that the OAT inhibition attenuated clinical symptoms. In patients, optic neuritis is frequently one of the first sign of MS, with patients initially reporting pain during eye movements and a visual reduction. The inflammatory lesions in the optic nerve disturb the speed of nerve conduction. It has been assumed that this type of early manifestation occurs due to different local permeabilities at the blood-brain barrier (BBB). Thus, we analyzed if the optic nerves had histopathological changes. The LFB staining showed mild demyelination. One great advantage of PBN might be the fact that PBN can cross the BBB. So PBN might be able to act exactly where it is needed, at neural cells.ÊIt has become clear that PBN has pharmacological targets additional to Px-1.