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Therapeutic potential of NAD+ Boosters in Rheumatoid Arthritis

Carlos Pérez-Sánchez

NAD+ is an important cofactor/second messenger for key cellular processes whose modulation might have a therapeutic role in Rheumatoid Arthritis (RA).
Aims: 1- To study the NAD+ metabolism in RA patients. 2- To analyze the effect of NAD+ boosters in leukocytes from active RA patients. Plasma and PBMCs were purified from 100 RA patients and 50 healthy donors (HDs). NAD+ levels were determined by using the NAD/NADH-Glo Assay. NAD+-consuming genes expression were analyzed by RT-PCR. In parallel, PBMCs from six HDs and six active RA patients were treated ex vivo with 1 mM of NAD+ boosters including nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). After 24 hours, intracellular reactive oxygen species (ROS) levels (DFCHDA) and the percentage of apoptotic PBMCs (annnexin V/PI) were assessed by flow cytometry. Finally, a panel of pro-inflammatory genes were evaluated by RT-PCR. NAD+ levels were significantly reduced in plasma of RA patients compared with HDs and directly related to disease activity. Accordingly, the expression levels of genes involved in the consumption of NAD+ such as SIRT-1, CD38 and PARP-1 were found up-regulated in RA PBMCs. PBMCs isolated from RA patients showed an increased oxidative, apoptotic and proinflammatory status compared with HDs. The in vitro treatments with NAD+ boosters significantly increased the NAD+ levels and promoted a deep reduction of intracellular ROS, the percentage of apoptotic cells and the expression levels of key inflammatory mediators, such as IL-6, IL-8, IL-1b, TNF-α, CCL2, IL-23, and STAT-3.
Conclusions: 1. NAD+ metabolism is altered in RA, involving both, reduced NAD+ levels and increased expression of NAD+-consuming genes. 2. NAD+ boosters reduced the oxidative, apoptotic and inflammatory profile of RA leukocytes through the parallel increase of intracellular NAD+ levels. Thus, NAD+ boosters might be considered novel therapeutic tools for RA patients.