Protecting Axonal Degeneration by Increasing Nicotinamide Adenine Dinucleotide Levels in Experimental Autoimmune Encephalomyelitis Models

Abstract

Axonal damage is a major morphological alteration in the CNS of patients with multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the underlying mechanism for the axonal damage associated with MS/EAE and its contribution to the clinical symptoms remain unclear. The expression of a fusion protein, named "Wallerian degeneration slow" (Wld s ), can protect axons from degeneration, likely through a ␤-nicotinamide adenine dinucleotide (NAD)-dependent mechanism. In this study, we find that, when induced with EAE, Wld s mice showed a modest attenuation of behavioral deficits and axon loss, suggesting that EAE-associated axon damage may occur by a mechanism similar to Wallerian degeneration. Furthermore, nicotinamide (NAm), an NAD biosynthesis precursor, profoundly prevents the degeneration of demyelinated axons and improves the behavioral deficits in EAE models. Finally, we demonstrate that delayed NAm treatment is also beneficial to EAE models, pointing to the therapeutic potential of NAm as a protective agent for EAE and perhaps MS patients.

NAD + and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents

“…Treatment of axons with 5-20 mM NAD + markedly delays the axon degenerative process (9). Additionally, animals that express the Wallerian degeneration slow (Wld S ) protein, a fusion of the NAD + biosynthetic enzyme Nicotinamide mononucleotide adenylyl transferase 1 and Ube4a, exhibit markedly delayed degeneration of the distal axonal fragment after axonal transection (10), and expression of Wld S mitigates disease phenotypes in several neurodegenerative disease models (11)(12)(13)(14). Thus, understanding the intracellular pathways regulated by NAD + may be important for understanding the pathogenesis of numerous disorders.…”

WldS, Nmnats and axon degeneration-progress in the past two decades

“…In disease models, Wld S mice show resistance to the 6-hydroxydopamine-induced dopamine fiber loss in Parkinson disease (Sajadi et al, 2004) or the MPTP-induced nigrostriatal axon degeneration (Hasbani and O'Malley, 2006). In addition, the protective roles of Wld S have been observed in mouse models of different neurodegenerative diseases, including progressive motor neuropathy (pmn mice) (Ferri et al, 2003), multiple sclerosis (experimental autoimmune encephalomyelitis) (Kaneko et al, 2006), myelin-related axonapathy (myelin protein zero null mutants) (Samsam et al, 2003), gracile axonal dystrophy (gad mutant mice) (Mi et al, 2005) and glaucoma (Beirowski et al, 2008). However, Wld S fails to protect axon degeneration in other degenerative disease models, such as the SOD1 transgenic mouse model of ALS (Vande Velde et al, 2004;Fischer et al, 2005), the proteolipid protein (Plp) null animal model of hereditary spastic paraplegia, an spinal muscular atrophy model (Kariya et al, 2009) and prion infected models (Gultner et al, 2009).…”

“…These enzymes include nicotiamide phosphoribosyltransferase, nicotinamide phosphoribosyltransferase (Nampt) and nicotinic acid phosphoribosyl transferase (Sasaki et al, 2006). In addition, exogenous application the substrate or intermediates of the NAD synthesis pathway, including nicotinamide, NAD, nicotinic acid mononucleotide and nicotinamide mononucleotide all promoted axonal protection (Araki et al, 2004;Wang et al, 2005;Kaneko et al, 2006;Sasaki et al, 2006). Exogenously pyruvate, a critical intermediate product of glycolysis, could partially protect axon degeneration .…”

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

“…Cytoprotection through Akt also can involve control of inflammatory cell activation [33, 41,61], transcription factor regulation [118], maintenance of mitochondrial membrane potential (ΔΨ m ), prevention of cytochrome c release [45,61,105], and blockade of caspase activity [45,61,110] In addition to targeting the activity of membrane PS exposure and microglial activation, nicotinamide inhibits several pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, interleukin-8, tissue factor, and tumor necrosis factor-α (TNF-α) [119][120][121][122]. Nicotinamide also can alter major histocompatibility complexes [123], inhibit intracellular adhesion molecule expression [124], and modulate the production of TNF in vascular cells [123] that may be responsible for the ability of nicotinamide to reduce demyelination in models of multiple sclerosis [125]. However, translation of these experimental studies to clinical efficacy appears to require further work, since some studies show that oral nicotinamide administration following endotoxin challenge in healthy volunteers did not demonstrate a significant effect upon serum cytokine levels [126].…”