The importance of NAD in multiple sclerosis

Area of Science:

• Neuroimmunology
• Neuroinflammation
• Metabolic pathways in CNS disease

Background:

• Multiple Sclerosis (MS) is a chronic CNS inflammatory demyelinating disease with unknown etiology.
• Th1-derived cytokines alter nicotinamide adenine dinucleotide (NAD) concentrations in CNS inflammation via indoleamine 2,3-dioxygenase (IDO) and CD38 induction.
• IDO hyper-activation can lead to neuronal NAD starvation, while glia may supply NAD to stressed neurons.

Purpose of the Study:

• To contrast the role of NAD in experimental autoimmune encephalomyelitis (EAE) and Thieler's murine encephalomyelitis virus (TMEV) models of MS pathogenesis.
• To explore the pharmacotherapeutic potential of NAD signal transduction pathways in MS.
• To review immunomodulatory control of NAD biosynthesis and degradation in MS pathogenesis.

Main Methods:

• Review of existing literature on NAD metabolism in MS animal models (EAE and TMEV).
• Analysis of the Wld(S) mouse model's differential resistance/exacerbation in EAE versus TMEV.
• Discussion of NAD-centric proteins (SIRT1, SIRT2, PARP-1, GPR109a, CD38) and NAD-complementation strategies.

Main Results:

• The Wld(S) genotype protects against EAE but exacerbates TMEV-mediated pathogenesis, highlighting distinct roles of NAD metabolism.
• IDO induction, potentially mediated by glial CD200R interactions, may play a role in MS pathogenesis.
• Pharmacological NAD precursor administration ameliorates MS pathogenesis in animal models.

Conclusions:

• Understanding NAD's differential roles in various MS models is crucial for targeted pharmacotherapy.
• Targeting NAD signal transduction pathways, including SIRT1 activity and PARP-1 inhibition, holds therapeutic promise.
• Further investigation into NAD-complementation and NAD-centric protein modulation is warranted for clinical application in MS.