Platelet Inhibition by Low-Dose Acetylsalicylic Acid Reduces Neuroinflammation in an Animal Model of Multiple Sclerosis.

Anna Vogelsang,Karin Loser,Kerstin Göbel,Sven G Meuth,Hannes Böhnlein,Susann Eichler,Niklas Huntemann,Lars Masanneck,Bernhard Nieswandt,Beate E Kehrel,Alexander Zarbock,Lisa Schüngel,Alice Willison

doi:10.3390/ijms22189915

Abstract

Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4+ T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28% in ASA-treated mice compared to 56.11 ± 1.46% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A2 were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS.

Highlights

Multiple sclerosis (MS) is the most common immune-mediated inflammatory disease of the central nervous system (CNS) [1,2]
Using established therapies for new indications, instead of searching for novel therapeutic approaches for disease pathologies that are not yet fully understood, is known as “repurposing”. This method is becoming increasingly popular in translational science, as it has the clear advantage of side effects already well-studied in human clinical trials, thereby increasing patient safety and accelerating the approval process for new indications
We demonstrate that the pharmacologic blockade of platelets using both low- and high-dose acetylsalicylic acid (ASA), a well-known antiplatelet drug, renders EAE mice less susceptible to neuroinflammation

Summary

Introduction

Multiple sclerosis (MS) is the most common immune-mediated inflammatory disease of the central nervous system (CNS) [1,2]. As already demonstrated for cells of the immune system, platelets, as part of the coagulation system, seem to infiltrate the CNS and aggregate within MS and EAE lesions [6,7,8,9,10,11]. Platelet depletion during the effector phase of EAE reduces the disease severity and is associated with a reduction in CNS-infiltrating immune cells from the periphery [6,10]. Recent studies demonstrated that platelets are chronically activated in the early stages of EAE [8]. Platelets obtained from MS patients, especially in relapsing-remitting and secondary progressive MS, show a chronically activated status [12,13,14]. The critical role of platelets in MS and EAE pathophysiology still needs to be clarified in more detail

Methods

Results

Conclusion