Association between inflammation, reward processing, and ibuprofen-induced increases of miR-23b in astrocyte-enriched extracellular vesicles: A randomized, placebo-controlled, double-blind, exploratory trial in healthy individuals

Ibuprofen, a non-steroidal, anti-inflammatory drug, modulates inflammation but may also have neuroprotective effects on brain health that are poorly understood. Astrocyte-enriched extracellular vesicles (AEEVs) facilitate cell-to-cell communication and – among other functions - regulate inflammation and metabolism via microribonucleic acids (miRNAs). Dysfunctions in reward-related processing and inflammation have been proposed to be critical pathophysiological pathways in individuals with mood disorders. This investigation examined whether changes in AEEV cargo induced by an anti-inflammatory agent results in inflammatory modulation that is associated with reward-related processing. Data from a double-blind, randomized, repeated-measures study in healthy volunteers were used to examine the effects of AEEV miRNAs on brain activation during reward-related processing. In three separate visits, healthy participants (N = 20) received a single dose of either placebo, 200 mg, or 600 mg of ibuprofen, completed the monetary incentive delay task during functional magnetic resonance imaging, and provided a blood sample for cytokine and AEEV collection. AEEV miRNA content profiling showed that ibuprofen dose-dependently increased AEEV miR-23b-3p expression with greater increase following the 600 mg administration than placebo. Those individuals who received 600 mg and showed the highest miR-23b-3p expression also showed the (a) lowest serum tumor necrosis factor (TNF) and interleukin-17A (IL-17A) concentrations; and had the (b) highest striatal brain activation during reward anticipation. These results support the hypothesis that ibuprofen alters the composition of miRNAs in AEEVs. This opens the possibility that AEEV cargo could be used to modulate brain processes that are important for mental health.