An essential micronutrient, niacin (nicotinic acid or vitamin B3) has important roles in supporting metabolism, energy production, and general health. It also helps regulate biological functions, including gene expression, the progression of the cell cycle, DNA repair, and cell death [1]. Importantly, niacin can be used to reduce the risk of adverse cardiovascular events, improve cholesterol levels, and help produce nicotinamide adenine dinucleotide (NAD+), a vital molecule in cellular function [2]. Lastly, niacin also garnered considerable attention as a promising therapeutic for neurological disorders such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis [3].
Given the potential impact of niacin on these neurological conditions, the question arises as to how niacin can reach the brain by crossing the blood-brain barrier if indeed it is possible. As we have previously discussed GABA and the blood-brain barrier, we will be discussing niacin in a similar vein!
What is the blood-brain barrier?
The blood-brain barrier (BBB) is a protective filter that tightly regulates and controls the movement of ions, molecules, and cells between the blood and the brain [4,5]. It allows essential nutrients to pass through while blocking harmful pathogens and other toxins. Some molecules pass through with relative ease, whereas others require specific transporters. Before a medication or substance can exert an effect on the central nervous system, it must cross the BBB.
The precise and delicate control of the central nervous system allows for the proper function of neurons whilst also protecting the brain tissue from attack. When the healthy parameters of the BBB are altered or impaired, neurological diseases can arise. You can read more on leaky or impaired BBBs and ways to repair them here.
The physiological nature of the BBB itself is underpinned by the physical, transport, and metabolic properties of the endothelial cells that form the walls of blood vessels. These work in tandem with different vascular, immune, and neural cells [4].
How does niacin cross the blood-brain barrier?
Niacin exists in different forms, comprising nicotinic acid, nicotinamide, and nicotinamide riboside (NR).
In the brain, the percentage of total niacin that turns over daily is about 8% [6]. In blood plasma and cerebrospinal fluid (CSF), the majority of total niacin exists in the form of nicotinamide [7]. In the brain, nicotinamide is taken up and converted to nicotinamide adenine dinucleotide (NAD) as well as nicotinamide adenine dinucleotide phosphate (NADP), NADH, and NADPH mainly through nicotinamide mononucleotide. All of these compounds have essential roles in metabolism and cellular respiration. Nicotinic acid is rapidly converted in the body and brain to nicotinamide and NAD [8]. NAD and its chemical constituents serve as cofactors for a range of essential enzymatic reactions in the body.
At the BBB, nicotinamide is rapidly transferred across the cerebral capillaries in a bidirectional manner by a very low-affinity, high-capacity facilitated diffusion system [6]. Once within the CSF and the extracellular space of the brain, nicotinamide is drawn into brain cells by facilitated diffusion. The control of brain tissue levels of total niacin is contingent on the entry/exit of nicotinamide into brain cells and its subsequent incorporation into NAD, binding, compartmentalization, and the like. Unlike other vitamins, including folates and inositol, plasma nicotinamide levels are a good approximation of what the brain cells "see" [6]. Brain and CSF nicotinamide returns to the blood by transport across the blood vessels and, to a lesser degree, by the flow of CSF into venous blood.
There has been a considerable amount of interest in trying to enhance or manipulate the levels of NAD in the brain for neuroprotection purposes [9]. This is because increasing brain NAD seems to have protective qualities in rodents [10]. Manipulating NAD levels in these animal models, particularly concerning Alzheimer’s disease and aging, has been an active area of research for some time.
What does animal and human research show?
Studies in mice have shown a significant increase in brain nicotinic acid levels following oral administration with niacin [11]. In addition, several preclinical studies with nicotinamide riboside supplementation in rodents have shown increases in NAD+ levels in the brain and other tissues. They have also shown improvements in brain function in preclinical models of Alzheimer's disease for example, as well as beneficial effects on neuroinflammation, mitochondrial dysfunction, and peripheral insulin resistance [12].
Research in human volunteers and patients with neurodegenerative disease has shown that cerebral uptake of nicotinic acid and nicotinamide can be detected using positron emission topography following the provision of intravenous niacin [6]. When administered orally, NR augments neuronal levels of NAD+ and influences biomarkers related to neurological diseases in humans [13].
More recently, evidence using novel non-invasive detection techniques has found that supplementation with nicotinamide riboside (900 mg) increased cerebral NAD+ levels in humans by 16% compared to baseline measures [14]. Encouraging findings have also been obtained by looking at nicotinamide riboside treatments in newly diagnosed Parkinson’s disease patients, again using novel testing methods. Supplementation was well tolerated and led to a significant if variable increase in cerebral NAD levels as well as related metabolites in the CSF [15]. NR recipients that showed increased brain NAD levels had altered cerebral metabolism that was associated with mild clinical improvement, as well as decreased inflammatory cytokines in blood serum and CSF. Although this work is in its early stages, NR could represent a potential neuroprotective therapy for Parkinson’s disease and will no doubt be further examined in future trials.
What are the effects of niacin on the brain?
The above research findings imply that ultimately niacin helps the brain to produce NAD+, which protects brain cells from damage and could be vitally important in preventing neurodegenerative diseases like Alzheimer’s and Parkinson’s. In other words, it could be a neuroprotective agent in this setting.
Low dietary niacin levels (niacin deficiency) cause cognitive decline, particularly in older people [16], and supplementing with nicotinamide could support memory and brain function in this regard [17].
Conclusion
In this article, we have discussed how niacin, especially in the form of nicotinamide, crosses the BBB through specialized transporters and significantly contributes to brain and central nervous system health. Niacin and its related compounds can help boost NAD+ in the brain, which can influence brain function, protect against disease, reduce inflammation, and enhance cognitive health. Although questions remain as to the optimal dosage, form, and delivery method, niacin represents a promising therapeutic for neurological impairment.
References
[1] V. Gasperi, M. Sibilano, I. Savini, M.V. Catani, Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications, IJMS 20 (2019) 974. https://doi.org/10.3390/ijms20040974.
[2] M. Romani, D.C. Hofer, E. Katsyuba, J. Auwerx, Niacin: an old lipid drug in a new NAD+ dress, Journal of Lipid Research 60 (2019) 741–746. https://doi.org/10.1194/jlr.S092007.
[3] E. Wuerch, G.R. Urgoiti, V.W. Yong, The Promise of Niacin in Neurology, Neurotherapeutics 20 (2023) 1037–1054. https://doi.org/10.1007/s13311-023-01376-2.
[4] R. Daneman, A. Prat, The blood-brain barrier, Cold Spring Harb Perspect Biol 7 (2015) a020412. https://doi.org/10.1101/cshperspect.a020412.
[5] H. Kadry, B. Noorani, L. Cucullo, A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity, Fluids Barriers CNS 17 (2020) 69. https://doi.org/10.1186/s12987-020-00230-3.
[6] R. Spector, C.E. Johanson, REVIEW: Vitamin transport and homeostasis in mammalian brain: focus on Vitamins B and E, Journal of Neurochemistry 103 (2007) 425–438. https://doi.org/10.1111/j.1471-4159.2007.04773.x.
[7] R. Spector, NIACIN AND NIACINAMIDE TRANSPORT IN THE CENTRAL NERVOUS SYSTEM. IN VIVO STUDIES, Journal of Neurochemistry 33 (1979) 895–904. https://doi.org/10.1111/j.1471-4159.1979.tb09919.x.
[8] W.-P. Sun, M.-Z. Zhai, D. Li, Y. Zhou, N.-N. Chen, M. Guo, S.-S. Zhou, Comparison of the effects of nicotinic acid and nicotinamide degradation on plasma betaine and choline levels, Clinical Nutrition 36 (2017) 1136–1142. https://doi.org/10.1016/j.clnu.2016.07.016.
[9] P. Belenky, K.L. Bogan, C. Brenner, NAD+ metabolism in health and disease, Trends in Biochemical Sciences 32 (2007) 12–19. https://doi.org/10.1016/j.tibs.2006.11.006.
[10] M.R. Hoane, A.A. Tan, J.L. Pierce, G.D. Anderson, D.C. Smith, Nicotinamide Treatment Reduces Behavioral Impairments and Provides Cortical Protection after Fluid Percussion Injury in the Rat, Journal of Neurotrauma 23 (2006) 1535–1548. https://doi.org/10.1089/neu.2006.23.1535.
[11] M. Moutinho, S.S. Puntambekar, A.P. Tsai, I. Coronel, P.B. Lin, B.T. Casali, P. Martinez, A.L. Oblak, C.A. Lasagna-Reeves, B.T. Lamb, G.E. Landreth, The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer’s disease, Sci. Transl. Med. 14 (2022) eabl7634. https://doi.org/10.1126/scitranslmed.abl7634.
[12] D. Ozaydin, P.K. Bektasoglu, T. Koyuncuoglu, S.C. Ozkaya, A.K. Koroglu, D. Akakin, C. Erzik, M. Yuksel, B.C. Yegen, B. Gurer, Antioxidant, Neuroprotective, and Anti-Inflammatory Effects of Niacin on Mild Traumatic Brain Injury in Rats, Turk Neurosurg 33 (2023) 1028–1037. https://doi.org/10.5137/1019-5149.JTN.42563-22.3.
[13] M. Vreones, M. Mustapic, R. Moaddel, K.A. Pucha, J. Lovett, D.R. Seals, D. Kapogiannis, C.R. Martens, Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin, Aging Cell 22 (2023) e13754. https://doi.org/10.1111/acel.13754.
[14] R.P.R. Nanga, C.E. Wiers, M.A. Elliott, N.E. Wilson, F. Liu, Q. Cao, S. Swago, P.S. Jacobs, R. Armbruster, D. Reddy, J.A. Baur, W.R. Witschey, J.A. Detre, R. Reddy, Acute nicotinamide riboside supplementation increases human cerebral NAD+ levels in vivo, Magnetic Resonance in Med (2024) mrm.30227. https://doi.org/10.1002/mrm.30227.
[15] B. Brakedal, C. Dölle, F. Riemer, Y. Ma, G.S. Nido, G.O. Skeie, A.R. Craven, T. Schwarzlmüller, N. Brekke, J. Diab, L. Sverkeli, V. Skjeie, K. Varhaug, O.-B. Tysnes, S. Peng, K. Haugarvoll, M. Ziegler, R. Grüner, D. Eidelberg, C. Tzoulis, The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease, Cell Metabolism 34 (2022) 396-407.e6. https://doi.org/10.1016/j.cmet.2022.02.001.
[16] X. Shen, L. Yang, Y.Y. Liu, L. Jiang, J.F. Huang, Association between dietary niacin intake and cognitive function in the elderly: Evidence from NHANES 2011–2014, Food Science & Nutrition 11 (2023) 4651–4664. https://doi.org/10.1002/fsn3.3428.
[17] G. Rennie, A.C. Chen, H. Dhillon, J. Vardy, D.L. Damian, Nicotinamide and neurocognitive function, Nutritional Neuroscience 18 (2015) 193–200. https://doi.org/10.1179/1476830514Y.0000000112.
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