Introduction

Niacin, also known as vitamin B3, is an essential nutrient obtained through dietary intake, where rich food sources include meat, fish, grains, and vegetables [1]. The importance of maintaining proper niacin levels is clearly established, as niacin-deficient individuals develop pellagra, a disease characterized by dementia, dermatitis, diarrhea, and, ultimately, death [2]. Niacin is thus a medication that is used to treat pellagra [3], and it was commonly indicated for dyslipidemia [4] prior to the advent of statins. In humans, the recommended minimum intake of niacin is between 15 and 20 mg/day [5], while pharmacological doses up to 3000 mg/day have been administered for dyslipidemia, demonstrating its tolerability across a broad range of doses [6].

Recent evidence has posited niacin as an exciting therapeutic option for a range of neurological disorders. Ranked as the third most promising repurposed drug candidate for progressive multiple sclerosis (MS) [7], niacin promotes phagocytosis of inhibitory myelin debris following demyelination in an animal model of MS, leading to remyelination [8]. In animal models of Parkinson’s [9] and Alzheimer’s disease [10], niacin ameliorates neuropathology through mechanisms such as immunomodulation and dopamine supplementation. Furthermore, niacin reduces tumour size and mortality in an animal model of glioblastoma [11] and is currently being investigated in a clinical trial of patients with glioblastoma [12]. Niacin also alleviates motor symptoms in patients with Parkinson’s disease [13], and dietary intake of niacin is associated with reduced incidence of Alzheimer’s disease and cognitive decline [14].

Despite the promise of niacin in neurological diseases, several unanswered questions remain regarding the actions of niacin in the central nervous system (CNS); these include the mechanisms of neuroprotection by niacin and whether it is a pro- or anti-inflammatory agent. In this review, we discuss the biochemistry and activity of niacin, and its receptor-dependent and -independent activities. We then consider the mechanisms of action of niacin within the CNS and explore its potential role as a therapeutic for neurological diseases.

Biology and Chemistry of Niacin

Niacin exists as the vitamers nicotinic acid and nicotinamide, which can give rise to the niacin derivatives nicotinamide riboside and nicotinamide mononucleotide. Niacin generates nicotinamide adenine dinucleotide (NAD+) through a series of metabolic pathways summarized in Fig. 1. In the Preiss-Handler pathway, nicotinic acid is converted into NAD+ in three steps, utilizing the intermediates nicotinic acid mononucleotide and nicotinic acid adenine dinucleotide [15]. The salvage pathway recycles nicotinamide, the by-product of enzymatic activities of NAD+, and dietary nicotinamide riboside to generate NAD+ [16]. Lastly, de novo biosynthesis of NAD+ is accomplished via the kynurenine pathway (Fig. 1), where dietary tryptophan serves as a precursor and is converted to NAD+ through a series of eight enzymatic steps; notably, this is the only NAD+ synthesis pathway that operates independently of niacin [17]. The de novo pathway is the longest and most energy-intensive; as a result, tryptophan is less efficient at increasing NAD+ levels compared to other precursors, and this pathway plays a modest role in NAD+ production [18, 19]. In contrast, the salvage pathway is the chief producer of NAD+ in mammalian cells and is largely responsible for maintaining homeostatic levels of this metabolite [18].

Fig. 1
figure 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

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Once generated, NAD+ serves as a precursor for its phosphorylated form, nicotinamide adenine dinucleotide phosphate (NADP), which is generated via NAD+ kinases [20, 21]. NAD(P) homeostasis involves a balance between biosynthesis and use by NAD+-consuming enzymes. NAD+ and NADP are critical coenzymes for oxidoreductases, and NAD+ also serves as a substrate for redox-independent enzymatic processes in the cell [22]. Thus, NAD(P) homeostasis is essential to the proper metabolic functioning of a cell. In the context of oxidation–reduction reactions such as glycolysis and oxidative phosphorylation, NAD+ serves as a proton acceptor, generating its reduced form NADH. NADH is then oxidized in the electron transport chain, contributing to the mitochondrial proton gradient and allowing for the generation of ATP via ATP synthase [123]. As a result of this promising evidence, a recent study aiming to identify licensed drugs with potential to be repurposed for clinical trials involving progressive MS patients put forth niacin as one of three highly recommended candidate drugs [7]. Future studies will allow us to determine whether niacin has therapeutic effects in people with MS, given its potential remyelinating and immunomodulatory responses (Fig. 5).

Fig. 5
figure 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

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Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disorder primarily caused by a loss of dopaminergic neurons in the substantia nigra pars compactica [124]. This neuropathology leads to dopamine deficiency in the basal ganglia and manifests in patients as bradykinesia, tremor, and/or rigidity, as well as other nonmotor symptoms such as cognitive decline and depression [125]. The first line of treatment for patients with PD is levodopa, a precursor of dopamine. Although levodopa is effective at treating motor symptoms, it does not prevent neurodegeneration and does not impact underlying inflammation; therefore, there is a need for improved therapeutic options [126].

There are several mechanisms through which niacin may act to ameliorate PD pathology, the first of which is through immune modulation. Aberrant neuroinflammation is increasingly being recognized as a key driver of PD pathogenesis. Activated microglia are enriched in the post-mortem brains of people with PD, particularly in affected areas such as the substantia nigra [127, 140, 141], and in people with PD, low-dose niacin supplementation over the course of 12 months improves the Unified Parkinson’s Disease Rating Scale, a measure of motor disability [13]. Furthermore, a case study demonstrated reduced rigidity and bradykinesia in a PD patient administered niacin for dyslipidemia [142].

Table 1 Ongoing and completed trials of niacin in neurological disorders
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Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia, and its prevalence and burden on the healthcare system will only increase as our population ages. The pathological hallmarks of AD include amyloid-β plaques and neurofibrillary tangles [147], and people with AD experience reduced cognition including memory, language, and executive functions [148]. Current treatment options for individuals with AD are limited and primarily focus on symptom management without affecting neuropathology [149].

The mechanisms through which niacin may act in AD have similarities to those employed in MS, particularly its regulation of liver X receptor expression and lipid recycling (Fig. 5). Altered lipid dynamics have been implicated in the pathogenesis of AD [150]. For instance, the ApoE gene is strongly implicated in AD pathology; while the ApoE ε4 allele is the strongest genetic risk factor for AD development, individuals carrying the ε2 allele experience protection from the disease [151]. Furthermore, neuronal cholesterol levels control amyloid-β production by regulating the cleavage of amyloid precursor protein [152, 153]. In addition, ABCA1- and ABCG1-mediated cholesterol efflux is impaired in the CSF of AD patients, when compared to healthy and non-AD dementia controls [154]. Thus, the lipid-modifying actions of niacin, where niacin promotes cholesterol efflux and regulates CNS cholesterol and lipid homeostasis (Fig. 4), may allow it to modulate AD pathogenesis.

In addition to its lipid-modifying properties, niacin alters AD pathology by promoting a rejuvenated microglia/macrophage phenotype, enhancing the phagocytosis of pathological amyloid-B plaques. In the 5xFAD transgenic mouse model of AD, treatment with slow-release niacin (niaspanR) increases microglia engagement with plaques, reduces plaque number and area, and promotes expression of microglial genes related to phagocytosis [10]. This, in turn, has a positive effect on clinical aspects, reducing cognitive deficits [10].

Gene expression analysis has also been performed to identify novel mechanisms of action for niacin in the context of AD. In the APP/PS1 transgenic model of AD, mice that received niacin supplementation had enhanced cognition. Niacin-supplemented AD mice also had elevated expression of genes including Ctnnb1, Mdm2, and Pten, which are involved in processes such as Wnt signalling, posttranslational modifications, and regulation of mTOR signalling [155].

Longitudinal studies suggest that niacin may have therapeutic potential in the context of people with AD. For example, previous work has established that increased intake of dietary niacin is associated with improved cognition [156] and reduced risk of AD later in life [14]. Whether or not niacin is an effective treatment in patients with AD remains to be investigated but is a promising avenue for future research.

Glioblastoma

Glioblastomas (GBMs) are the most common primary tumours in the CNS in adults, and they affect approximately 2.3 people per 100,000 [157]. The current treatment involves surgical resection followed by radiation and chemotherapy with temozolomide, yet GBMs are one of the deadliest forms of cancer, with a median survival time of less than 15 months following diagnosis [158]. Treatment advances are in part halted by the self-renewing capacity of brain tumour initiating cells (BTICs), an immunosuppressive tumour microenvironment, and limited CNS access due to the BBB [159, 160]. Indeed, treatment of GBM has not improved since 2005 with the introduction of temozolomide into the therapeutic regimen, despite research efforts [161].

BTICs are a subclass of cancer cells that initiate glioblastoma growth and development due to their capacity for self-renewal and proliferation [162]; engraftment of as few as 100 human BTICs is sufficient to generate an identical tumour in recipient mice [163]. These cells have highly efficient DNA repair machinery, making them resistant to traditional radiation treatment that induces cell death by causing double-stranded DNA breaks [164]. BTICs have also demonstrated resistance to chemotherapy, although the mechanisms involved are not as clear [165]. Effective GBM treatment is further hindered by the presence of an immunosuppressive tumour microenvironment. Tumour-associated macrophages are the most abundant nontransformed cells in the tumour microenvironment, and they demonstrate a clear protumour phenotype, releasing anti-inflammatory cytokines and failing to initiate T cell responses [166]. Furthermore, tumour-infiltrating immune cells display an exhausted phenotype with reduced activity and fail to mount a proper immune response towards tumour cells [167]. Thus, a potential treatment for GBM would ably cross the BBB and stimulate immune activity, counteracting immune suppression and promoting recognition of BTICs by immune cells.

In a rodent model of GBM, treatment with niacin promotes beneficial immune modulation, rejuvenating immunosuppressive myeloid cells and increasing their tumour-fighting abilities (Fig. 5). Indeed, niacin activates myeloid cells derived from GBM patients in vitro, leading to their enhanced release of cytokines such as TNFα and IL-6, and niacin-treated monocytes attenuate the growth of GBM patient-derived BTICs [11]. Furthermore, niacin treatment in BTIC-implanted mice reduces brain tumour growth and prolongs survival. Following these promising preclinical results, the addition of slow-release niacin (niacinCRT) to standard of care entered a Phase I/IIa clinical trial in individuals with GBM (clinicaltrials.gov NCT04677049) (Table 1). Results from this ongoing trial will increase our knowledge on the potential of niacin to promote antitumour immune functions in a clinical setting.

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, characterized by the loss of both upper and lower motor neurons. Current treatments target symptoms such as muscle spasticity, sialorrhea, and pain, but disease-modifying therapies are nonexistent [168]. Recently, the gut microbiome has been implicated in the pathogenesis of many disorders, including ALS [169], with a particular interest being paid to the microbiota-gut-brain axis [170]. In animal models of ALS, impaired tight junction integrity and enhanced gut permeability are observed [171], and microbiome dysbiosis precedes motor deficits [172]. Furthermore, ALS patients have significantly altered gut microbiota composition compared to controls [173], and repeated antibiotic use is associated with increased risk of develo** ALS [174]. Notably, the recent work described below suggests that niacin may exert its therapeutic effects in part through modulation of the gut microbiome.

In the Sod1 transgenic mouse model of ALS, supplementation of Akkermansia muciniphila increases the serum levels of nicotinamide and leads to improvements in motor and neurological function, suggesting that nicotinamide released from gut microbiota has a beneficial effect on ALS pathogenesis [175]. Further, ALS patients have altered serum levels of molecules involved in nicotinamide synthesis, and increased serum nicotinamide correlates with better functional status [175]. Beyond the ALS literature, in obese humans, low levels of dietary niacin intake are correlated with low alpha-diversity and reduced Bacteroidetes abundance [176], a microbe that is largely considered to be beneficial [177]. Administration with delayed-release nicotinic acid leads to a significant increase in Bacteroidetes abundance, indicating that niacin administration can modulate composition of the microbiome [176]. In ACE2 knockout mice, which are prone to colitis and experience altered microbiome ecology, nicotinamide administration restores the microbiome composition to control levels and ameliorates gastrointestinal symptoms of colitis [178]. Thus, by modulating the gut microbiome, niacin may serve as a promising therapeutic option for ALS and other CNS disorders (Fig. 5).

Conclusion and Remaining Questions

In conclusion, niacin is an essential vitamin that has long served as a well-tolerated treatment for a variety of disorders. While its canonical role is as a precursor for NAD+/NADP, niacin has additional mechanisms of action, including agonistic activity at the GPCR Hcar2, and modulation of the microbiome. Due to the expression of Hcar2 on immune cells, niacin is emerging as a potent modulator of the immune system and has been shown to promote a beneficial immune cell phenotype, enhancing phagocytosis of harmful debris and reducing neuropathology in several neurological disorders. Niacin also plays a role in regulating cholesterol recycling, which is critical following the uptake of lipid-rich debris such as myelin by CNS macrophages. The recent work is establishing niacin as a promising therapeutic option in a range of neurological diseases such as MS, Alzheimer’s disease, and glioblastoma.

Several questions remain about the mechanisms and utility of niacin. At what doses are its effects due solely to metabolism such as conversion to NAD+? When high pharmacological doses are used where Hcar2 stimulation is thought to be engaged, to what extent is the benefit conferred by metabolic mechanisms? Are there as yet unidentified receptors for niacin? Is niacin anti-inflammatory or pro-inflammatory, and is there a concentration range that separates these potentially divergent activities? Would long-term use in chronic conditions such as MS run into risks of pro-inflammatory responses? Can niacin be combined with other therapeutic agents, such as direct agonists at LXRs, for a more efficacious outcome? Are there additional neurological conditions that may benefit from niacin therapy? Future studies will elucidate the role of niacin as a neuroprotective agent, allowing for its widespread adoption into clinical practice.