"Cell" sub-issue: Nicotinamide riboside may have neuroprotective effects!

Anyone who is interested in skin care may have heard the name of nicotinamide riboside (NR) in recent years, because it is a derivative of vitamin B3.
The handle is often added to some cosmetic skin care products
.

 However, in addition to skin care, NR has also been found to have neuroprotective properties in recent years, or can be used to treat neurodegenerative diseases such as dementia and Parkinson's disease
.

So, is NR's magical brain-protecting function a commercial tout, or is it true? Recently, the team of Charalampos Tzoulis from Horkland University Hospital in Norway and the University of Bergen published important research results in Cell Metabolism [1]
.

They found in the first phase I clinical trial that oral nicotinamide riboside (NR) significantly increased the level of nicotinamide adenine dinucleotide (NAD) in the brain of patients with Parkinson's disease, altered brain metabolism, and reduced the serum levels of the subjects.
and inflammatory cytokine levels in cerebrospinal fluid, thereby improving the clinical symptoms of patients
.

Screenshot of the paper's homepage The incidence of Parkinson's disease in people over the age of 65 has been as high as 1% to 2% [2]
.

However, the current treatment methods for Parkinson's disease are all "treating the symptoms but not the root cause", which can only relieve some symptoms, and have not substantially changed the death of dopamine neurons and the overall progression of the disease [3]
.

Although several candidate neuroprotective therapies have shown promising preclinical results, these therapies fail as soon as they reach clinical trials
.

 Currently, there is increasing evidence that increasing the level of NAD in cells may have neuroprotective effects on aging and neurodegeneration [4]
.

 As an important cofactor in redox reactions, NAD can be reversibly converted between oxidative (NAD+) and reduced (NADH) states, thereby participating in a variety of important physiological activities, such as regulating mitochondrial respiration and participating in DNA repair [5]
.

In addition, NAD+ is an important substrate for deacylation reactions of histones and other proteins
.

These reactions consume NAD+ at high rates, and the body needs to constantly replenish it through NAD biosynthesis
.

While NAD levels have been shown to decline with age, NAD deficiency may contribute to the development of age-related diseases [6]
.

 It has been reported that NAD supplementation by NR supplementation or enhancement of NADH/NAD+ ratio by calorie restriction has neuroprotective effects in various neurodegenerative animal models [7]
.

Enhanced NAD supplementation may help improve several major processes involved in the pathogenesis of Parkinson's disease, including mitochondrial respiratory dysfunction, neuroinflammation, epigenome dysregulation, and neuronal DNA damage [8]
.

 But will NR supplementation end in clinical trials like other neurotherapies? And is NR well tolerated in Parkinson's disease patients? To answer these questions, Tzoulis' team conducted a double-blind, randomized, placebo-controlled Phase I clinical study (Clinicaltrials.
gov: NCT03816020) in 30 newly diagnosed Parkinson's disease patients who had not received other treatments
.

 First, the Tzoulis team gave half of the patients 1,000 mg of NR orally per day, while the other half received the same amount of placebo.
Metabolite content, it was found that the ratio of NAD/ATP-α was significantly higher in the NR group than in the placebo group
.

The 31P-MRS assay showed that NAD levels were significantly higher in the NR group than in the placebo group.
On an individual level, brain NAD responses were heterogeneous, with 10 of 13 patients showing increases, 9 of which increased beyond baseline levels.
10%
.

Because this heterogeneity raises the possibility of heterogeneity in treatment effects, Tzoulis' team defined the 10 patients with significantly increased brain NAD levels as a subgroup, MRS responders, to assess downstream neurometabolic and clinical assessments.
Perform stratified analysis
.

 Using the new version of the World Movement Disorders Society-Parkinson's Disease Comprehensive Rating Scale (MDS-UPDRS), the Tzoulis team evaluated the clinical scores of patients and found that compared with the placebo group, NR treatment did improve the clinical symptoms of patients to a certain extent.

.

At the same time, the researchers found that NR was safe and well tolerated in the study population by evaluating the frequency and severity of adverse events, changes in vital signs and other indicators
.

Assessing patients' clinical scores after taking NR or placebo by MDS-UPDRS Next, Tzoulis' team used fluorodeoxyglucose-positron emission tomography (FDG-PET) to examine whether oral NR affects the patients' brain metabolism
.

The results showed that the NR-related metabolic pattern (NRRP) in the brains of patients with Parkinson's disease was significantly reduced in the caudate and putamen on both sides of the nucleus and extended to the adjacent globus pallidus and thalamus
.

After oral administration of NR, NRRP scores were significantly up-regulated, and changes in NRRP were significantly correlated with UPDRS motor scores recorded by PET (r = 0.
59, p = 0.
026)
.

NR subjects with the greatest increase in NRRP had the greatest improvement in motor scores
.

FDG-PET detected the effect of oral NR on brain metabolism of patients.
At the same time, the researchers performed metabolomic analysis on the cerebrospinal fluid, skeletal muscle and peripheral blood mononuclear cells of the subjects.
A large amount of nicotinamide metabolism was detected in the cerebrospinal fluid and muscle tissue.
Significant changes in related substances, such as NAD+, NADH, nicotinamide mononucleotide (NMN), nicotinamide adenine dinucleotide (NAAD), methylnicotinamide (Me-Nam), n-methyl-2- Pyridone-5-carboxamide (Me-2-PY) etc.

.

Metabolic changes in peripheral blood mononuclear cells were not extensive, but increases in NAAD and Me-Nam were also found
.

 In addition, to investigate the effect of NR treatment on gene expression, Tzoulis' team further performed RNA-seq analysis on muscle tissue and peripheral blood mononuclear cells of all subjects to evaluate the difference between the NR group and the placebo group
.

 In muscle tissue, the expression of 58 genes was significantly up-regulated after oral administration of NR, including the transcription factor KLF2 related to oxidative damage, the gene PARP15 related to NADD degradation, and the genes FARS2 and TMEM242 related to mitochondrial translation and respiratory complex assembly
.

Gene set enrichment analysis revealed that NR-induced up-regulated biological processes mainly included proteasome function, RNA transport and stability
.

 In peripheral blood mononuclear cells, a total of 13 genes were significantly associated with NR replenishment, including BLOC1S2, a gene involved in lysosomal biogenesis and trafficking
.

Functional enrichment analysis revealed that multiple biological processes were significantly upregulated, such as ribosomal, proteasome, lysosome and mitochondrial (oxidative phosphorylation) pathways
.

Considering that mitochondrial dysfunction and inflammation are closely related to the pathology of Parkinson's disease, Tzoulis' team sought to identify changes in relevant biomarkers in patients' serum and cerebrospinal fluid
.

The researchers assessed the levels of genes FGF21 and GDF15 associated with mitochondrial dysfunction, as well as 35 inflammatory cytokines
.

The test results showed that the level of GDF15 in serum was significantly decreased, and several common inflammatory cytokines (such as MIP-1β, IL-7) were decreased in serum and cerebrospinal fluid
.

 Above, the research results of Tzoulis team show that daily oral NR can increase the level of NAD in the brain, change brain metabolism, and reduce the level of inflammatory factors in cerebrospinal fluid and serum, which is an effective neuroprotective therapy
.

However, given the relatively small sample size of this trial, the short observation time of the subjects, and the large inter-individual variability in MDS-UPDRS scores, the observed trend of clinical improvement brought about by elevated brain NAD levels should be interpreted with caution, with only Phase II trials provide conclusive clinical evidence
.

 The researchers are currently conducting a Phase II clinical study (Clinicaltrials.
gov: NCT03568968)
.

Let's wait and see
.

References: [1] Brakedal, B.
, Do¨lle, C.
, Riemer, F.
, Ma,Y.
, .
.
.
and Tzoulis, C.
(2022).
The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.
Cell Metabolism.
34, 396–407.
[2] Gooch, CL, Pracht, E.
, and Borenstein, AR (2017).
The burden of neurological disease in the United States: a summary report and call to action.
Ann.
Neurol.
81, 479–484.
[3] Bloem, BR, Okun, MS, and Klein, C.
(2021).
Parkinson's disease.
Lancet 397, 2284–2303.
[4] Lautrup, S .
, Sinclair, DA, Mattson, MP, and Fang, EF (2019).
NAD+ in brain aging and neurodegenerative disorders.
Cell Metab.
30, 630–655.
[5] Katsyuba, E.
, Romani, M.
, Hofer, D.
, and Auwerx, J.
(2020).
NAD+ homeostasis in health and disease.
Nat.
Metab.
2, 9–31.
[6] Johnson, S.
, and Imai, S.
-I.
(2018).
NAD+ biosynthesis, aging, and disease.
F1000Res.
7,132.
[7] Braidy, N.
, and Liu, Y.
(2020).
NAD+ therapy in age-related degenerative disorders: a benefit/risk analysis.
Exp.
Gerontol.
132, 110831.
[8] Gonzalez-Hunt, CP , and Sanders, LH (2021).
DNA damage and repair in Parkinson's disease: recent advances and new opportunities.
J.
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99, 180–189.
Editor-in-Chief | Ying Yuyan