Multiple sclerosis is a seriously disabling autoimmune disease—when our immune systems attack our healthy cells. This progressive disorder happens when this self-inflicted response causes inflammation of the nervous system and results in demyelination, the stripping of the protective coating of nerve projections. Finding ways to suppress this inflammation of the nervous system and keep nerves healthy to preserve their function is an attractive therapeutic strategy.

Wang and colleagues show in an article published in International Immunopharmacology that treatment with nicotinamide adenine dinucleotide (NAD+) improved nervous system function in a mouse model of multiple sclerosis. NAD+ significantly reduced brain damage and delayed the onset of neurological symptoms in mice modeling multiple sclerosis. This treatment also alleviated demyelination and levels of inflammatory factors in the spinal cord. These findings highlight NAD+ as a potential therapeutic strategy for the treatment of multiple sclerosis.

NAD+ treatment improved neurologic function in mice with EAE

In the present study, Wang and colleagues observed that NAD+ significantly delayed the onset of neurological symptoms in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. When they evaluated the mice for their neurological functional abilities, EAE mice injected with NAD+ (250 mg/kg) had significantly lower scores compared to the untreated mice. These EAE mice treated with NAD+ had healthier white matter, where the projections of nerves wrapped in myelin—the protective and conductive coating—travel in the nervous system.

“We demonstrated that NAD+ can significantly reduce the functional severity and white matter damage caused by experimental autoimmune encephalomyelitis in mice,” said the researchers in the article. 

(Wang 2020 | Int Immunopharmacol) Daily NAD + treatment alleviated the clinical severity of mice modeling multiple sclerosis. Daily NAD+ significantly delayed the rise in the clinical score (B) and reduced the cumulative score (C, the sum of neurological scores from the 3rd day until the 25th day after EAE induction of each mouse), indicating substantial preservation of neurological function.

NAD+ treatment alleviated demyelination and levels of inflammatory factors in the spinal cord

The researchers saw that the activation of neuroinflammatory cells called microglia was inhibited in EAE mice treated with NAD+. These mice exhibited reduced inflammation in the nervous system and demyelination compared to their untreated counterparts. Along these lines, the spinal cords of untreated EAE mice exhibited considerable inflammatory cell infiltration as well as massive injuries and demyelination to axons—the long cable where electrical impulses from one neuron travel away to be received by other neurons. However, in the spinal cords of EAE mice treated with NAD+, the number of infiltrating inflammatory cells was greatly reduced and fewer signs of demyelination and axonal damage were detected.

(Wang 2020 | Int Immunopharmacol) NAD+ alleviated the disease signs of EAE-induced inflammation, axonal injury, and demyelination. NAD+ treatment reduced the number of infiltrating inflammatory cells as well as the areas of axonal damage and demyelination compared to the untreated EAE group. NAD+ treatment reduced microglial activation compared to the untreated EAE group.

The researchers think that NAD+ alleviated the detrimental effects of EAE in part by shifting the cytokine profile to a more anti-inflammatory state. This is because they saw that NAD+ significantly reduced levels of the inflammation marker NLRP3 as well as pro-inflammatory factors like IL-17 in the spinal cord of EAE mice. The researchers suggest this all may lead to the prevention of large scale infiltration of immune cells into the nervous system’s white matter, limiting the severity of the disease.

Inhibition of autophagy aggravated clinical symptoms and worsened inflammation and demyelination

In addition to reducing NLRP3 levels and demyelination injury, NAD+ promoted the levels of proteins involved in autophagy—the process cells use to remove unnecessary or dysfunctional components for degradation and recycling.

“We show that induction of autophagy is essential for these NAD+-induced benefits, at least in part by suppressing the inflammasome and downstream pro-inflammatory cytokine signaling.”

This is supported by other studies showing that autophagy blocks inflammation to prevent the harmful amplification of inflammatory factors that promote demyelination.

Blockade of autophagy attenuated the protective effects of NAD+ in EAE mice

Studies have shown that dysregulation of autophagy can prolong and make persisting inflammatory responses, possibly leading to autoimmune and inflammatory diseases. Consistent with this previous research, when Wang and colleagues blocked autophagy with a chemical called 3-MA, they observed aggravated clinical symptoms, worsened inflammation and demyelination, and attenuated protective effects of NAD+ in EAE mice. They saw that inflammatory cell infiltration was greatly enhanced in mice that were treated with both the autophagy blocker 3-MA and NAD+ compared to those only treated with NAD+. Further, the reduced levels of inflammation and pro-inflammatory markers NLRP3 and IL-17, respectively, in the spinal cords of NAD+ treated EAE mice were significantly reversed by 3-MA.

“Our results indicate that NAD+ suppresses the NLRP3 inflammasome at least in part through the activation of autophagy to relieve the symptoms of experimental autoimmune encephalomyelitis,” said the researchers in the article.

(Wang 2020 | Int Immunopharmacol) Blockade of autophagy attenuated the beneficial effects of NAD+ on EAE pathology. Levels of inflammation marker NLRP3 and pro-inflammatory marker IL-17 in the spinal cord of EAE mice are decreased by NAD+ to levels seen in mice without EAE (CON). Blockade of autophagy by 3-MA reversed the suppression of these inflammation-related factors by NAD+.

Future directions of NAD+ treatment in multiple sclerosis

These findings suggest that the regulation of autophagy by NAD+ treatment may be an effective therapeutic strategy for multiple sclerosis. More research is needed to unravel how autophagy suppressed neuroinflammation affects multiple sclerosis. Importantly, clinical trials testing the effectiveness of NAD+ treatment in multiple sclerosis patients are necessary to see if these results translate to humans.