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

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.

Low-Dose Aspirin Augments the Anti-Inflammatory Effects of Low-Dose Lithium in Lipopolysaccharide-Treated Rats

“…Aspirin-treated rats presented lower NF-κB levels as compared to control rats, indicating suppressed NF-κB activity. Consistently, several studies suggested that COX-1 is imperative to microglial activation and consequent neuroinflammation [ 100 , 101 ], and that genetic deletion or pharmacological inhibition of COX-1 activity mitigates the inflammatory response [ 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ]. Triflusal, a COX-1 inhibiting agent, decreased glial cell activation and proinflammatory cytokine production in a transgenic mouse model of Alzheimer’s disease [ 102 ].…”

“…Indeed, this finding is in line with the now recognized notion suggesting low-dose aspirin use in treating neuroinflammatory diseases [ 58 , 96 , 97 ]. A recent study found that treatment with low-dose aspirin reduces neuroinflammation in an animal model of multiple sclerosis [ 98 ]. Jung et al [ 99 ] tested the effect of low-dose aspirin on activation of NF-κB in aged rats.…”

Hemostasis Components as Therapeutic Targets in Autoimmune Demyelination

“…Vogelsang et al 33 . using quantitative real‐time polymerase chain reaction investigated the role of low‐ and high‐dose of ASA during neuroinflammation in mice subjected to EAE compared with a control condition.…”

“…In details, the percentages of CD4+ T cells, CD8+ T cells, and B cells were significantly reduced in mice treated with low-or high-dose of ASA compared with controls, but the reduction was not statistically different between doses as well as in the EAE scores and the degree of demyelination. 33 The production of thromboxane B2 (TxB2) by platelets, was significantly reduced in EAE mice by low-dose ASA compared with control treatment; in contrast, the pro-inflammatory platelet alpha-granule protein PF4 and the platelet collagen receptors Glycoprotein VI (GPVI) levels were not affected by ASA treatment.…”

“…Vogelsang et al 33 using quantitative real-time polymerase chain reaction investigated the role of low-and high-dose of ASA during neuroinflammation in mice subjected to EAE compared with a control condition. As compared with the control condition, prophylactic treatment with both high-and low-dose ASA significantly alleviated disease severity with no difference between doses; similarly, disease incidence was the same for the two ASA doses but lower than control condition; the histological examination of sections of the lumbar spinal cord, showed reduced CNS infiltration, as well as less demyelination.…”