Drug repurposing of Pirlindole for Multiple Sclerosis
figureposted on 2017-02-23, 09:08 authored by Spyros N. Deftereos, Eftychia LekkaEftychia Lekka, Christos AndronisChristos Andronis, Andreas Persidis
Pirlindole, a reversible inhibitor of Monoamine Oxidase subtype A (MAO-A) is used in the treatment of depression and of disorders with a depressive component, as well as anxiety disorders and fibromyalgia syndrome. We used our Project ProdigyTM Big Data / Artificial Intelligence (AI) platform in Drug Repositioning (DR) mode to reposition pirlindole for the treatment of Multiple Sclerosis (MS).
Our Project ProdigyTM platform works by creating multi-dimensional profiles of biologically relevant concepts and supports the generation of unanticipated and novel biomedical inferences. Project ProdigyTM includes the Clinical Outcome Search SpaceTM database and AI analytics. Unlike other AI approaches and so-called cognitive engines which work by finding already known links in existing data, Project ProdigyTM is unique in taking existing data and re-combining them into previously unanticipated outcomes.
MS is an immune-driven chronic inflammatory disease of the central nervous system (CNS) with varied clinical presentations and heterogeneous histopathological features. In MS, permanent neurological disability accumulates as the disease progresses; the inflammatory processes that underlie the early relapsing-remitting phenotype are gradually replaced by neurodegeneration, which manifests as neuronal and axonal loss and leads to accumulating neurological dysfunction. Neurodegeneration is a hallmark feature of primary and secondary progressive MS.
Although immunosuppressive or immunomodulatory drugs provide a significant reduction in the rate of relapses (in the order of 30%-67%), they are associated with mild-to-often fatal adverse events, such as in the case of Natalizumab which induces Progressive Multifocal Leukoencephalopathy (PML), a rare, but life-threatening disease. This highlights the need for developing drugs that could tackle neuronal dysfunction in MS.
Based on in silico and animal model experiments, we sought to test our hypothesis that Pirlindole would reduce neuronal dysfunction in MS. In in vivo experiments using the MOG (Myelin Oligodendrocyte Glycoprotein)-induced Experimental Autoimmune Encephalomyelitis (EAE) murine model of progressive MS, pirlindole (BVA-201), at 30mg/kg (a pharmaceutically relevant dose) induced a sizeable improvement in disease progression, as represented by EAE severity clinical scores (Figure 1). Moreover, histological data showed that the drug’s MoA is not anti-inflammatory, but rather, pirlindole protects neuronal cells and myelin in a direct manner (Figure 2). The above data is supported by previous observations that Pirlindole acts not only as a MAO-A inhibitor, but is also involved in the reduction of oxidative stress and inhibition of lipid peroxidation.
In terms of safety, Pirlindole exhibits a favorable pharmacokinetics and Adverse Event (AE) profile with only mild and transient AEs recorded from clinical trials and post-marketing surveillance.
Overall, our observations lead to the validation of the hypothesis involving repositioning of pirlindole as a neuroprotectant in MS. The use of pirlindole in MS as a new indication is protected by international patent applications. The patent applications also cover administration in several different dose ranges, routes of administration, as well as a number of drug combinations.
We used Vizit, a free visual bibliographic search and science communication tool that is part of the Project ProdigyTM platform to identify genes, pathways and biosystems that would explain the role of Pirlindole in MS.
The graph is fully interactive. It can be reached at:
and can be modified and shared, forming the basis of an open platform for science communication in the relevant biomedical research fields.