The Promise of Niacin in Neurology

Abstract

Niacin (vitamin B3) is an essential nutrient that treats pellagra, and prior to the advent of statins, niacin was commonly used to counter dyslipidemia. Recent evidence has posited niacin as a promising therapeutic for several neurological disorders. In this review, we discuss the biochemistry of niacin, including its homeostatic roles in NAD⁺ supplementation and metabolism. Niacin also has roles outside of metabolism, largely through engaging hydroxycarboxylic acid receptor 2 (Hcar2). These receptor-mediated activities of niacin include regulation of immune responses, phagocytosis of myelin debris after demyelination or of amyloid beta in models of Alzheimer's disease, and cholesterol efflux from cells. We describe the neurological disorders in which niacin has been investigated or has been proposed as a candidate medication. These are multiple sclerosis, Alzheimer's disease, Parkinson's disease, glioblastoma and amyotrophic lateral sclerosis. Finally, we explore the proposed mechanisms through which niacin may ameliorate neuropathology. While several questions remain, the prospect of niacin as a therapeutic to alleviate neurological impairment is promising.

Keywords: Hydroxycarboxylic acid receptor (Hcar)2; Immunomodulation; NAD+/NADP; Neurological diseases; Niacin treatment; Phagocytosis.

Fig. 1

NAD⁺ biosynthesis pathways. In the kynurenine pathway, dietary tryptophan is first converted to N-formylkynurenine via tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO). Through a series of four enzymatic steps, N-formylkynurenine generates quinolinic acid, which gives rise to nicotinic acid mononucleotide in a reaction catalyzed by quinolinic acid phosphoribosyl transferase (QPRT). In the final steps, nicotinic acid mononucleotide is converted to nicotinic acid adenine dinucleotide, which generates NAD⁺. In the Preiss-Handler pathway, dietary nicotinic acid (niacin) is converted to nicotinic acid mononucleotide via nicotinate phosphoribosyltransferase (NAPRT). Nicotinic acid mononucleotide is then converted to nicotinic acid adenine dinucleotide in a nicotinamide mononucleotide adenylyl transferase (NMNAT)-catalyzed reaction, and this gives rise to NAD⁺ via NAD⁺ synthase (NADS). In the salvage pathway, nicotinamide that has been recycled from the enzymatic activities of NAD⁺ is used to generate nicotinamide mononucleotide via nicotinamide phosphoribosyltransferase (NAMPT). Dietary nicotinamide riboside can produce either nicotinamide mononucleotide, or nicotinamide. In the final step of this pathway, nicotinamide mononucleotide gives rise to NAD⁺. Once generated, NAD⁺ is consumed by several enzymes, including sirtuins (SIRTs), poly(ADP-ribose) polymerases (PARPs), and sterile alpha and TIR motif-containing 1 (SARM1), as well as the cyclic ADP-ribose (cADPR) synthases CD38 and CD157. These enzymes generate nicotinamide as a by-product. Figure created using BioRender

Fig. 2

Homeostatic roles of niacin as a precursor to NAD⁺. Through the activity of NAD⁺-consuming enzymes, niacin is involved in the maintenance of cellular processes such as the DNA damage response and Ca²⁺ signalling. NAD⁺ is reduced to form NADH, which serves as a proton donor in the electron transport chain, generating the mitochondrial proton gradient and leading to the production of ATP. NAD⁺ is also phosphorylated to generate NADP. NADP serves as a precursor for ribose-5-phosphate, which gives rise to nucleic acids such as DNA and RNA. Finally, NADP is reduced to generate NADPH. NADPH is then used as a reducing agent in the generation of biological molecules such as fatty acids, sterols, and nucleotides. Figure created using BioRender

Fig. 3

Activity of niacin at Hcar2 in adipocytes and immune cells. In adipocytes, niacin acts through hydroxycarboxylic acid receptor (Hcar2) to inhibit adenylyl cyclase activity. Under normal conditions, adenylyl cyclase generates cAMP, which activates protein kinase A. Protein kinase A phosphorylates and activates hormone-sensitive lipase, which increases lipolysis. By inhibiting adenylyl cyclase, niacin reduces activity of this pathway and leads to suppression of lipolysis. In immune cells, niacin binding to Hcar2 leads to an increase in intracellular Ca^2+. Although the precise mechanism has yet to be elucidated, one model suggests that Hcar2 agonism activates phospholipase C (PLC), promoting the release of Ca²⁺ from intracellular stores within the endoplasmic reticulum. Ca²⁺ then acts as a second messenger, inhibiting the phosphorylation of p65 which is downstream from inflammatory NF-κB activation. Conversely, it is thought that the transient increase in Ca²⁺ could originate from extracellular sources. This would stabilize the intracellular Ca²⁺ stores found within the endoplasmic reticulum, making the cell more resistant to stress. Cellular stress leads to the activation of the NLRP3 inflammasome, which promotes cholesterol accumulation within macrophages and leads to a proinflammatory, detrimental immune cell phenotype. In the figure, the step of inhibition of inflammatory activity in immune cells subsequent to niacin/Hcar2 interaction is depicted by the red T sign. Figure created using BioRender

Fig. 4

Cholesterol recycling in the CNS and impact of niacin. Demyelination often occurs as a result of CNS insult or injury, producing myelin debris which is phagocytosed by microglia/macrophages in the CNS. This uptake of debris is promoted by niacin [8]. Following phagocytosis, myelin debris is partially degraded in the lysosome. Cholesterol, which cannot be broken down, is either esterified for storage in lipid droplets, or effluxed out of the cell. Impaired cholesterol processing leads to sustained cholesterol accumulation and the formation of cholesterol crystals, which promote an inflammatory macrophage phenotype. Cholesterol efflux is mediated by the ABCA1 and ABCG1 transporters, which transfer free cholesterol onto lipid-poor ApoE particles. There is evidence that niacin promotes the mRNA level of ABCA1 and ABCG1 [107, 108] and cholesterol efflux [106] although whether the latter is due to passive diffusion or through an ABCA1-dependent mechanism is unresolved. Together, cholesterol and ApoE generate an HDL-like particle, which distributes cholesterol throughout the CNS. Oligodendrocytes are one cell type that receives this free cholesterol, using it in the generation of new myelin. In the nucleus, cholesterol derivatives (e.g., oxysterol) bind to LXR. LXR forms a heterodimer with RXR and serves as a transcription factor, promoting transcription of ApoE, ABCA1 and ABCG1. Figure created using BioRender

Fig. 5

Mechanisms of niacin in neurological disease. Niacin may act through a variety of mechanisms to alleviate pathology in neurological and neurodegenerative diseases. These putative mechanisms based on preclinical studies include enhanced phagocytosis and lipid recycling, immunomodulation, and ameliorated oxidative stress. Figure created using BioRender