The Importance of NAD in Multiple Sclerosis

Enzymes controlling NAD metabolism in professional antigen presenting cells (PAPCs; microglia, macrophages, or dendritic cells) are shown with consideration of pharmacological administration of complementary NAD precursors or effectors of NAD utilizing enzymes (SIRT1 activators / PARP-1 inhibitors) towards rescue NAD deficiency arising from chronic inflammatory disease. Immunomodulatory factors exert a coordinated regulation of NAD levels during autoimmune disease or infection. PAPCs including microglia act as sinks acquiring de novo pathway NAD precursor (tryptophan) or degrading NAD directly via activation of IDO and CD38 respectively. CD38 activity is required for chemotaxis (1). Thus, IFNγ activates IDO to increase intracellular NAD while simultaneously activating tryptophanyl-tRNA (encoded by WRS) to maintain essential tryptophan-dependent protein synthesis (2). All three IFNγ-mediated inductions occur in professional antigen presenting cells. IFNγ-mediated activation of IDO leads to complementary increases in NAD levels in a pyridoxyl phosphate (PLP; derived from vitamin B6) co-factor dependent fashion. The anti-epileptic molecule kynurenate is also produced through this pathway. In the end this pathway is predicted to affect global chromatin structure through NAD dependent SIRT-1 and PARP-1 mediated activities as well as other effects through related Sirtuin/PARP family member proteins (3). During chronic inflammation local extracellular NAD sources become deficient (tryptophan and NAD) and this exerts both an anti-proliferative immunotoleragenic effect on T cells but also decreases PAPC chemotaxis while making neighboring cells more vulnerable (4). Accordingly pharmacological application of NAD precursors provides tremendous cytotrophic benefit in numerous models of autoimmune disease. ADPR from either ROS-PARP1-PAR-PARG or excessive CD38 activity can lead to persistent activation of TRPM2 leading to programmed cell death, PCD (5). Excessive CD38 activity has been observed in type 1 diabetics via excessive autoreactive anti-CD38. Highly expressed in the brain and clearly important in immune function, the role of CD38 in MS is completely unexplored. Peroxynitrate can activate PARP1 leading to nuclear PAR formation that translocates to the mitochondria to promote AIF release which also leads to programmed cell death (PCD). Two R(O/N)S sensitive pathways shown at the bottom include DNA damage-PARP1 activation along with direct activation of the redox sensitive TRPM2 divalent cation channel. (6) Administration of pharmacologic doses of NAD precursors (nicotinic acid/niacin, nicotinamide/niacinamide, or nicotinamide riboside) or pharmacologic targeting of NAD-dependent targets (SIRT1 activators or PARP1 inhibitors) may complement the NAD deficiencies arising from immune activation of IDO and CD38.

Publication

The Importance of NAD in Multiple Sclerosis. () W. Todd Penberthy, et al. Curr Pharm Des. ;15(1):64-99. Figure: F4. Homo sapiens

Disease mentions