The Importance of NAD in Multiple Sclerosis

Abstract

The etiology of multiple sclerosis (MS) is unknown but it manifests as a chronic inflammatory demyelinating disease in the central nervous system (CNS). During chronic CNS inflammation, nicotinamide adenine dinucleotide (NAD) concentrations are altered by (T helper) Th1-derived cytokines through the coordinated induction of both indoleamine 2,3-dioxygenase (IDO) and the ADP cyclase CD38 in pathogenic microglia and lymphocytes. While IDO activation may keep autoreactive T cells in check, hyper-activation of IDO can leave neuronal CNS cells starving for extracellular sources of NAD. Existing data indicate that glia may serve critical functions as an essential supplier of NAD to neurons during times of stress. Administration of pharmacological doses of non-tryptophan NAD precursors ameliorates pathogenesis in animal models of MS. Animal models of MS involve artificially stimulated autoimmune attack of myelin by experimental autoimmune encephalomyelitis (EAE) or by viral-mediated demyelination using Thieler's murine encephalomyelitis virus (TMEV). The Wld S mouse dramatically resists razor axotomy mediated axonal degeneration. This resistance is due to increased efficiency of NAD biosynthesis that delays stress-induced depletion of axonal NAD and ATP. Although the Wld S genotype protects against EAE pathogenesis, TMEV-mediated pathogenesis is exacerbated. In this review, we contrast the role of NAD in EAE versus TMEV demyelinating pathogenesis to increase our understanding of the pharmacotherapeutic potential of NAD signal transduction pathways. We speculate on the importance of increased SIRT1 activity in both PARP-1 inhibition and the potentially integral role of neuronal CD200 interactions through glial CD200R with induction of IDO in MS pathogenesis. A comprehensive review of immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis is presented. Distinctive pharmacological approaches designed for NADcomplementation or targeting NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, and CD38) are outlined towards determining which approach may work best in the context of clinical application.

Periventricular Demyelination and Axonal Pathology Is Associated with Subependymal Virus Spread in a Murine Model for Multiple Sclerosis

“…In agreement with the present findings, β-APP-positive axons can be detected predominately in acute MS lesions and less frequent associated with chronic plaques [6,44,45]. In TME, the onset of axonopathy in the spinal cord during the initial stage is suggested to be a virus-induced effect [10] while axonal degeneration and loss at the later stages is more related to an immune-mediated attack [8,46,47], and a lack of glial-derived trophic support which induces neurodegenerative mechanisms in vulnerable, demyelinated axons [48]. Axonal degeneration is regarded as an active self-destructive response to TMEV infection to prevent further axonal spread of the virus [49].…”

CD200/CD200R Paired Potent Inhibitory Molecules Regulating Immune and Inflammatory Responses; part I: CD200/CD200R Structure, Activation, and Function

“…ido, whose expression is potentiated by cd200/cd200R interaction, suppresses apc cells to prevent autoreactivity and protects the fetus against spontaneous abortion. however, this IDO activity is penalized by an energy deficit as NAD + is decreased in this way (30). As mentioned above, a significantly higher expression of ido is thought to be associated with inflammation and positively correlates with the severity of inflammation.…”

CNS inflammation and neurodegeneration

“…Dying cells in the brain may release extracellular purinergic metabolites such as ATP and NAD, leading to both innate and adaptive immune activation (85,86). The uptake of double-stranded DNA can induce activation of TLRs.…”