International Journal of

Molecular Sciences

Review
Niacin in the Central Nervous System: An Update of
Biological Aspects and Clinical Applications
Valeria Gasperi *,† , Matteo Sibilano † , Isabella Savini and Maria Valeria Catani *
Department of Experimental Medicine, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy;
matteosibilano@libero.it (M.S.); savini@uniroma2.it (I.S.)
* Correspondence: gasperi@med.uniroma2.it (V.G.); catani@uniroma2.it (M.V.C.);
Tel.: +39-06-72596465 (V.G. & M.V.C.)
† These authors contributed equally to this work.




Received: 30 January 2019; Accepted: 20 February 2019; Published: 23 February 2019


Abstract: Niacin (also known as “vitamin B3 ” or “vitamin PP”) includes two vitamers (nicotinic acid
and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD)
and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for
oxidative reactions crucial for energy production, but they are also substrates for enzymes involved
in non-redox signaling pathways, thus regulating biological functions, including gene expression,
cell cycle progression, DNA repair and cell death. In the central nervous system, vitamin B3 has
long been recognized as a key mediator of neuronal development and survival. Here, we will
overview available literature data on the neuroprotective role of niacin and its derivatives, especially
focusing especially on its involvement in neurodegenerative diseases (Alzheimer’s, Parkinson’s,
and Huntington’s diseases), as well as in other neuropathological conditions (ischemic and traumatic
injuries, headache and psychiatric disorders).

Keywords: central nervous system; diet; NAD(P); neurodegenerative diseases; niacin; nicotinamide;
nicotinic acid; vitamin B3

1. Introduction
Niacin (also known as “vitamin B3 ” or “vitamin PP”) is the generic descriptor for two vitamers,
nicotinic acid (pyridine-3-carboxylic acid) and nicotinamide (nicotinic acid amide), that give rise to the
biologically active coenzymes, nicotinamide adenine dinucleotide (NAD) and its phosphate analog,
the nicotinamide adenine dinucleotide phosphate (NADP) [1] (Figure 1). The two coenzymes take part
in redox reactions crucial for energy production: in particular, the pyridinic ring can accept and donate
a hydride ion (:H− , the equivalent of a proton and two electrons), thus acting as an electron carrier.
Nonetheless, NAD and NADP play different metabolic roles in the cytosol: the NADH/NAD+ ratio
is small (about 8 × 10−4 ), thus favoring oxidative catabolism, whereas the NADPH/NADP+ ratio is
higher (about 75), thus providing a strongly reducing environment for biosynthetic reactions [2,3].
Maintenance of the intracellular NAD pool is not only important to fuel redox metabolism,
but also to support NAD-dependent, non-redox signaling pathways. NAD is indeed a substrate
of ADP-ribosyltransferases that catalyze ADP-ribose transfer reactions, thus breaking down NAD
to nicotinamide and ADP-ribosyl products, which play a key role in cellular signaling cascades
regulating gene expression, cell cycle progression, insulin secretion, DNA repair, apoptosis and
aging [4–6]. Finally, NAD has also been recognized as an endogenous agonist of purinergic P2Y1 and
P2Y11 membrane subtype receptors, through which it inhibits neurotransmission in visceral smooth
muscles [7] and activates immune cells [8,9], respectively.

Int. J. Mol. Sci. 2019, 20, 974; doi:10.3390/ijms20040974 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2019, 20, 974 2 of 26
Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 27

Figure
Figure 1. 1.Chemical
Chemical structures
structures of
of niacin
niacinvitamers
vitamers(A)(A)
and active
and coenzymatic
active formsforms
coenzymatic (B). NAD:
(B). NAD:
nicotinamide
nicotinamide adenin
adenin dinucleotide. NADP:
dinucleotide. NADP: nicotinamide
nicotinamide adenin dinucleotide
adenin phosphate.
dinucleotide phosphate.

2. NiacinMaintenance
Sources of the intracellular NAD pool is not only important to fuel redox metabolism, but
also to support NAD-dependent, non-redox signaling pathways. NAD is indeed a substrate of ADP-
Humans obtain niacin
ribosyltransferases from both
that catalyze endogenous
ADP-ribose transferand exogenous
reactions, thus sources. Only 2%
breaking down NADof todietary
tryptophan (Trp)and
nicotinamide is converted
ADP-ribosylinto niacin via
products, a multistep
which pathway
play a key role in (see in next
cellular sections),
signaling occurring
cascades
mainly in the gene
regulating liverexpression,
[10]. Diet cell
provides the vitamininsulin
cycle progression, as nicotinic acid,
secretion, DNAnicotinamide andand
repair, apoptosis Trp,aging
as well as
the active coenzymatic forms of niacin.
[4–6]. Finally, NAD has also been recognized as an endogenous agonist of purinergic P2Y1 and P2Y11
membrane subtype receptors, through which it inhibits neurotransmission in visceral smooth
2.1. muscles
Exogenous Sources
[7] and activates immune cells [8,9], respectively.

2.Niacin
NiacinisSources
found in animal and vegetable foods. In meat and fish, the vitamin is present as NAD(P),
whose amounts are higher in unprepared foods compared to processed foods (enzymatic hydrolysis of
Humans obtain niacin from both endogenous and exogenous sources. Only 2% of dietary
the coenzymes can occur during food preparation).
tryptophan (Trp) is converted into niacin via a multistep pathway (see in next sections), occurring
In mature cereal grains (particularly in corn), niacin is largely present as niacin-glycoside and, in
mainly in the liver [10]. Diet provides the vitamin as nicotinic acid, nicotinamide and Trp, as well as
a minor proportion,
the active peptide-bound
coenzymatic niacin, compounds collectively termed “niacinogens” [11]. When
forms of niacin.
complexed in niacinogens, niacin is poorly available (only ~ 30%), as intestinal enzymes are not able to
free 2.1.
niacin; nonetheless,
Exogenous Sources alkali treatment of the grain increases niacin bioavailability [11].
Once ingested,
Niacin is foundfreeinniacin
animalcanand
be adsorbed in the stomach,
vegetable foods. In meat and although thevitamin
fish, the small intestine
is presentabsorbs
as it
faster. The mechanism of transport across the enterocyte brush border membrane
NAD(P), whose amounts are higher in unprepared foods compared to processed foods (enzymatic is not fully clarified
yet. hydrolysis
Several transporters,
of the coenzymes indeed, appear
can occur to be
during foodinvolved in intestinal niacin uptake; among them,
preparation).
the mostIncommon are the
mature cereal grainshuman organicinanion
(particularly transporter-10
corn), niacin (hOAT-10,
is largely present a proton-driven
as niacin-glycoside and,carrier
thatinalso
a minor
mediatesproportion, peptide-bound
the transport of urateniacin, compounds collectively
and p-aminohippurate) [12],termed “niacinogens”
responsible [11].uptake
for niacin
at physiological concentrations [13], and the sodium-coupled monocarboxylate transporterare
When complexed in niacinogens, niacin is poorly available (only ~ 30%), as intestinal enzymes (SMCT1
not able to
or SLC5A8, free niacin; nonetheless,
a transporter for lactate,alkali treatment
pyruvate and of the grain increases
short-chain niacinspecifically
fatty acids), bioavailability [11].at high
active
Once ingested, free niacin can be adsorbed in the stomach, although the small intestine absorbs
pharmacological doses of nicotinic acid [14,15].
it faster. The mechanism of transport across the enterocyte brush border membrane is not fully
NAD and NADP are quickly hydrolyzed, by intestinal mucosa and liver glycohydrolases,
clarified yet. Several transporters, indeed, appear to be involved in intestinal niacin uptake; among
to nicotinamide
them, the most that is subsequently
common transported
are the human to tissues,
organic anion where it(hOAT-10,
transporter-10 is converted into coenzymatic
a proton-driven
forms as necessary.
carrier It seemsthe
that also mediates noteworthy
transport ofthat nicotinamide
urate moves freely
and p-aminohippurate) [12],into or out offorthe
responsible brain [16]
niacin
and,uptake
as discussed in the next
at physiological sections, such
concentrations [13],aand
property has importantmonocarboxylate
the sodium-coupled neurobiologicaltransporter
implications.
(SMCT1 or SLC5A8, a transporter for lactate, pyruvate and short-chain fatty acids), specifically active
2.2. at
Endogenous Synthesis doses of nicotinic acid [14,15].
high pharmacological
Starting from dietary Trp, niacin is synthesized via the kynurenine pathway (KP) (Figure 2),
occurring mainly in the liver and, to a lesser extent, in extrahepatic tissues (especially upon immune
cell activation) [17–19].
2.2. Endogenous Synthesis
Starting from dietary Trp, niacin is synthesized via the kynurenine pathway (KP) (Figure 2),
occurring mainly in the liver and, to a lesser extent, in extrahepatic tissues (especially upon immune
Int. J. Mol. Sci. 2019, 20, 974 3 of 26
cell activation) [17–19].

Figure 2. De novo synthesis of NAD(P) from tryptophan, nicotinamide and nicotinic acid. (1) Two
Figure 2. De novo synthesis of NAD(P) from tryptophan, nicotinamide and nicotinic acid. (1) Two
iron porphyrin metalloproteins, tryptophan 2,3 dioxygenase (TDO, in the liver) and indolamine-pyrrole
iron porphyrin metalloproteins, tryptophan 2,3 dioxygenase (TDO, in the liver) and indolamine-
2-3 dioxygenase (IDO, in extrahepatic tissues), oxidize the pyrrole moiety of Tryptophan (Trp), thus
pyrrole 2-3 dioxygenase (IDO, in extrahepatic tissues), oxidize the pyrrole moiety of Tryptophan
forming N-L-formylkynurenine. (2) Arylformamidase (AFMID) hydrolytically removes the formyl
(Trp), thus forming N-L-formylkynurenine. (2) Arylformamidase (AFMID) hydrolytically removes
group producing kynurenine and is then (3) hydroxylated to 3-hydroxykynurenine by kynurenine-3
the formyl group producing kynurenine and is then (3) hydroxylated to 3-hydroxykynurenine by
monooxygenase (KMO), a mitochondrial flavo-enzyme that uses O2 as a substrate and NADPH
kynurenine-3
as a cofactor. monooxygenase
The action of (KMO), a mitochondrial
(4) kynureninase flavo-enzyme
B (KYNU, a vitaminthat uses O2 as a enzyme)
B6 -dependent substrate andand
NADPH as a cofactor. The action of (4) kynureninase B (KYNU, a vitamin B 6-dependent enzyme) and
(5) 3-hydroxyanthranilic dioxygenase (HAAO, a nonheme iron-dependent dioxygenase) leads to
(5) 3-hydroxyanthranilic
production dioxygenase (HAAO, a nonheme
of 2-amino-3-carboxymuconic-6-semialdehyde acid, aniron-dependent
unstable productdioxygenase) leads to
that (6) spontaneously
production of 2-amino-3-carboxymuconic-6-semialdehyde acid, an unstable product
condensates and rearranges to form quinolinic acid; then, (7) quinolinic acid is decarboxylated and that (6)
spontaneously
converted condensates
to nicotinic and rearranges by
acid mononucleotide to form quinolinic
quinolinic acid; then, (7) quinolinic (QPRT).
acid phosphoribosyltransferase acid is
Nicotinic acid mononucleotide is also produced through the “salvage pathway”, via the action ofacid
decarboxylated and converted to nicotinic acid mononucleotide by quinolinic (8)
phosphoribosyltransferase
nicotinic (QPRT). Nicotinic
acid phosphoribosyltransferase (NPRT).acid
Themononucleotide
subsequent action is of
also
(9) produced through the
nicotinamide/nicotinic
“salvage pathway”, via the action of (8)(NMNAT1-3)
acid-mononucleotide-adenylyltransferases nicotinic acid
andphosphoribosyltransferase
(10) NAD synthetase (NADSYN1) (NPRT).leadsThe
subsequent
to the generationaction
of NAD,of which
(9) nicotinamide/nicotinic
is then (11) phosphorylated acid-mononucleotide-adenylyltransferases
to produce NADP. NAD can also derive
(NMNAT1-3) and (10) NAD synthetase (NADSYN1) leads
directly from nicotinamide through the action of (12) nicotinamide to thephosphoribosyltransferase
generation of NAD, which is then
(NAMPT)
(11) phosphorylated to produce NADP. NAD can also derive directly from nicotinamide
and (13) nicotinamide/nicotinic acid-mononucleotide-adenylyltransferase (NMNAT1-3). Red frames: through the
action of (12) nicotinamide phosphoribosyltransferase (NAMPT) and (13) nicotinamide/nicotinic
dietary precursors of NAD(P). Ala: alanine; Gln: glutamine; Glu: glutamate; PLP pyridoxal phosphate;
acid-mononucleotide-adenylyltransferase
PRPP: 5-phosphoribosyl-1- pyrophosphate. (NMNAT1-3). Red frames: dietary precursors of NAD(P).
Ala: alanine; Gln: glutamine; Glu: glutamate; PLP pyridoxal phosphate; PRPP: 5-phosphoribosyl-1-
Tryptophan
pyrophosphate. 2,3 dioxygenase (TDO), catalyzing the first reaction, is the rate-limiting enzyme. Several
nutritional, hormonal and physio-pathological factors affect the efficiency of this anabolic pathway.
Deficiencies of vitamin B6 , riboflavin, iron and heme (all essential cofactors for specific enzymes), as well
as of vitamin B1 and Trp itself, slow the reaction rate [18,20]. Overall: (i) a protein-enriched diet
(particularly, consumption of foods with high concentrations of leucine, such as maize or sorghum)
decreases niacin biosynthesis; (ii) unsaturated fatty acid-enriched diet increases it, while saturated
fatty acids do not exert any effect; (iii) the transformation ratio is higher in diets containing starch with
respect to sucrose-rich diets; (iv) caloric restriction drastically suppresses biosynthesis [18,21–26].
Int. J. Mol. Sci. 2019, 20, 974 4 of 26

Among hormones, estrogens, glucorticoids and thyroxine are the best characterized modulators
of the KP. Estrogens enhance TDO activity; enzyme activity is triplicated in women who are pregnant
or are taking oral contraceptives [27,28]. Glucocorticoids stimulate de novo synthesis, by inducing
TDO via a mechanism potentiated by glucagon and inhibited by insulin and adrenaline [18,29,30].
The effects of thyroxine on TDO activity are still controversial, as some studies suggested a positive
action, while others did not observe any effect [31–34].
Due to individual differences, it has been estimated that, in human healthy individuals, Trp is
converted to niacin with an average conversion efficiency of 60:1 [35]. Therefore, niacin intakes are
expressed as niacin equivalents (NE; 1 mg NE = 1 mg niacin or 60 mg Trp): Recommended Dietary
Allowance for adults is 16 mg NE/day for men and 14 mg NE/day for women, with a Tolerable Upper
Intake Level of 35 mg/day, based on flushing as the critical adverse effect [36].

3. Vitamin Catabolism
The tight intracellular regulation of NAD is guaranteed not only at biosynthetic but also at
catabolic level; in the latter case, NAD can be either recycled or metabolized and eliminated via urine
Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 5 of 27
(Figure 3) [37–39].

Figure Schematic
3. 3.
Figure Schematicrepresentation
representationofofdistinct
distinct catabolic
catabolic pathways.
pathways. (1) (1)NAD
NADisishydrolyzed
hydrolyzedonto onto
nicotinamide mononucleotide via the action of specific pyrophosphatases
nicotinamide mononucleotide via the action of specific pyrophosphatases belonging to Nudix belonging to Nudix
(nucleoside
(nucleoside diphosphate
diphosphatelinked
linkedtotomoiety
moietyX)X)family.
family. (2)
(2) Nicotinamide mononucleotideisisthen
Nicotinamide mononucleotide then
dephosphorylated
dephosphorylated bybyIsn1
Isn1and
andSdt1
Sdt1cytosolic
cytosolicnucleotidases,
nucleotidases, which release
releasethe
thecorresponding
correspondingriboside
riboside
cleaved to to
cleaved nicotinamide
nicotinamidebybya apurinepurine nucleoside
nucleoside phosphorylase
phosphorylase (PNP) (PNP)(3). (3).Alternatively,
Alternatively,NAD NAD
becomes
becomes a substrate
a substrate ofofsirtuins
sirtuins(4),
(4),ADP-ribosyltransferases
ADP-ribosyltransferases (ARTC) (ARTC) (5) (5) and
anddiphtheria
diphtheriatoxin-like
toxin-like
ADP-ribosyltransferases
ADP-ribosyltransferases (ARTD)
(ARTD) (6).Nicotinamide
(6). Nicotinamide can can be either
either re-converted
re-convertedtotoNAD NADbybyspecific
specific
enzymes (7) (see also
enzymes (7) (see also Figure Figure 2) or methylated by nicotinamide-N-methyl transferase
or methylated by nicotinamide-N-methyl transferase (NNMT) (NNMT) to N1-to
1 methylnicotinamide (8)(8)that,
N -methylnicotinamide in turn,
that, (9) is(9)
in turn, oxidized
is oxidized 1 1
to N -methyl-4-pyridone-3-carboxamide
to N -methyl-4-pyridone-3-carboxamide (4-Py)
andand
(4-Py) N1 -methyl-2-pyridone-5-carboxamide
N1-methyl-2-pyridone-5-carboxamide (2-Py)(2-Py)
by aldehyde
by aldehydeoxidases. 2-OAADPr:
oxidases. O-acetyl-ADP
2-OAADPr: O-acetyl-
ADP ribose; NAMPT:
ribose; NAMPT: nicotinamide
nicotinamide phosphoribosyltransferase;
phosphoribosyltransferase; NMNAT: nicotinamide/nicotinic
NMNAT: acid-
nicotinamide/nicotinic
mononucleotide-adenylyltransferase; SAH:
acid-mononucleotide-adenylyltransferase; SAH: S-adenosylhomocysteine;
S-adenosylhomocysteine; SAM:
SAM: S-adenosyl-methionine.
S-adenosyl-methionine.

4. Severe Vitamin Deficiency

Severe niacin and/or Trp deficiency leads to a variety of clinical symptoms, including diarrhea,
dermatitis and dementia, collectively known as “pellagra” or “the three D disease” [69]; although this
disease has become rare in developed countries, it remains endemic in underdeveloped countries
Int. J. Mol. Sci. 2019, 20, 974 5 of 26

In the recycling pathways, NAD is metabolized to nicotinamide through the action of different
ADP-ribosyltransferases. Sirtuins (SIRT) are NAD-dependent deacetylases and mono-ADP-ribosyl
transferases belonging to the highly conserved family of silent information regulator-2 like
proteins [40–42]. During deacetylation, NAD is hydrolyzed and the ε-acetyl lysine residues of the
target protein is transferred onto the ADP-ribose moiety, thus forming O-acetyl-ADP ribose (Figure 3),
which is a ligand of calcium channels in the plasma membrane [43]. SIRTs deacetylate a broad spectrum
of proteins, thus modulating their activity, stability or localization. Depending on the targeted protein,
these enzymes affect several biological processes, including transcription, cell cycle progression,
genome stability, cell death and mitochondrial biogenesis [42,44,45]. ADP-ribosyltransferases (ARTC)
and diphtheria toxin-like ADP-ribosyltransferases (ARTD) catalyze mono- and poly-ADP-ribosylation,
respectively, of specific amino acids (arginine, cysteine, asparagine, histidine) of membrane proteins
(Figure 3), thus regulating innate immunity and cell-to-cell cross-talk, as well as cell cycle, cell death
and energy metabolism [46–48].
Finally, NAD(P) can be hydrolyzed to nicotinamide by two ADP-ribose cyclases, namely
CD38 and CD157, which also release cyclic ADP-ribose, an endogenous activator of ryanodine
receptor-mediated calcium release [49–52] and suggested to be involved in pathological diseases
such as cancer, neurodegeneration and autoimmune diseases [53–56].
If not recycled, nicotinamide is methylated, by the cytosolic nicotinamide N-methyltransferase
(NNMT) that uses S-adenosyl-methionine (SAM) as a methyl donor, and eliminated as oxidized
metabolites (Figure 3). Altered enzyme activity has been linked to several pathological conditions,
including neurodegenerative diseases, obesity, type 2 diabetes and cancer [57–64]. It should be recalled
that, beside nicotinamide by-products, also those deriving from conjugation of nicotinic acid to glycine
(nicotinuric acid) or from its methylation (1-methylnicotinic acid) can be found in urine [65–67].
Due to the multiplicity of NAD-dependent biological events, which lead to NAD degradation,
cells need to replenish their intracellular NAD(P) pools; inhibition of NAD biosynthesis, for example,
decreases intracellular NAD content within a few hours [68].

4. Severe Vitamin Deficiency

Severe niacin and/or Trp deficiency leads to a variety of clinical symptoms, including diarrhea,
dermatitis and dementia, collectively known as “pellagra” or “the three D disease” [69]; although this
disease has become rare in developed countries, it remains endemic in underdeveloped countries [70].
Pellagra is common in people who mostly eat maize [71], as well as in malnourished and alcoholic
men [26]; other risk factors leading to vitamin B3 deficiency are nervous anorexia [72], AIDS [73],
cancer [74] and chemotherapy [75], as well as malabsorptive disorders, such as Crohn’s disease [76].
Light sensitivity is high: dermatitis derives from deficits in poly(ADP-ribose) polymerase activity
that leads to impaired DNA repair. Patients can show psychiatric symptoms (i.e., depression, paranoid
behaviors, suicide and aggressive tendencies) that disappear when they take niacin [77,78]; some of
these symptoms are also related to deficit of serotonin that derives from Trp [78].

5. Pharmacological Effects of Niacin

When supplemented at physiological amounts, nicotinic acid (15–20 mg/day) and nicotinammide
(300 mg/day) are effective in treating traditional pellagra [77,78]; nonetheless, at higher concentrations,
they display separate additional pharmacological activities, ranging from anti-dyslipidemic to
anti-inflammatory action. The first evidence of lipid-altering effects of niacin dates back to 1955, when
Altschul and co-workers reported the ability of 3000 mg/day nicotinic acid (but not nicotinamide)
to reduce serum cholesterol in humans [79]. An every growing body of experimental data points to
beneficial effects of nicotinic acid as an anti-hyperlipidemic agent. It is now well established that
nicotinic acid efficaciously: (i) inhibits free fatty acid mobilization and lipolysis; (ii) reduces hepatic
triglyceride synthesis and very low density lipoprotein (VLDL) secretion; (iii) inhibits VLDL conversion
into low density lipoprotein (LDL); (iv) increases serum high-density-lipoprotein (HDL) levels;
Int. J. Mol. Sci. 2019, 20, 974 6 of 26

(v) triggers LDL conversion from small, dense particles to large, low density particles, (vi) reduces
serum lipoprotein concentrations; and (vii) increases apolipoprotein A1 [80,81].
To date, the underlying mechanisms are still speculative; in particular, nicotinic acid (at levels
higher than those achieved with diet) has been reported to bind to and activate GPR109A and GPR109B,
two G0 /Gi -coupled membrane receptors highly expressed in adipose tissue; nonetheless, these receptors
are absent, or present only at low levels, in the liver [82]. Therefore, it is conceivable that nicotinic acid
might exert its lowering-lipid effects through receptor-independent and -dependent mechanisms.
Due to the above mentioned positive effects, in 2008, nicotinic acid was commercially available
as Trevaclyn® , Tredaptive® or Pelzont® , at the dose of 1.0 g (in combination with laropipram,
an anti-flushing agent); this prescription product has been used to treat mixed dyslipidemic
and/or primary hypercholesterolemic adults receiving statins [83]. However, results from the
Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on
Global Health Outcomes (AIM-HIGH) trial [84], together with the Heart Protection Study 2-Treatment
of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial [85,86], reported no clinical
benefits (i.e., reduced risk of heart attack and stroke) from the long-lasting usage of niacin. A lack of
efficacy, together with the onset of recurrent serious side effects (gastrointestinal, musculoskeletal,
and skin-related), has led to drug withdrawal from the EU market.
In vitro and in vivo studies have also demonstrated that nicotinic acid (or activation of its
molecular targets) exerts significant anti-inflammatory, anti-oxidant and anti-apoptotic activities
in a variety of cells and tissues [87], thus being potentially beneficial for the management of several
pathological conditions, including type-2 diabetes [88,89], obesity [90,91], atherosclerosis [92], kidney
and lung injury [93–95], and hyperalgesia [96].
Also nicotinamide at high doses can exert specific pharmacological activities, particularly those
related to cancer management. Indeed, several experimental and clinical studies have shown the
ability of nicotinamide to sensitize tumors to radiation or chemotherapy [97–100]. Such an activity
depends on activation of poly(ADP-ribose)-dependent apoptosis cascade, as well as on inhibition of
myosin light chain kinase that, in turn, enhances microvascular flow, thus improving drug delivery
and tumor oxygenation [97–100].

6. Niacin in the Central Nervous System

Besides dermatitis and diarrhea, niacin/tryptophan deficit symptoms also include several nervous
system pathologies, such as dementia and depression, as well as other symptoms resembling those
observed in neurodegenerative diseases. This evidence, together with accumulating in vitro and
in vivo studies, has underlined the importance of niacin (particularly of nicotinamide) in growth and
maintenance of the central nervous system (CNS) [101,102].
Nicotinamide biosynthesis actively occurs in the mammalian brain, which contains nanomolar-low
micromolar concentrations of nicotinamide precursors derived from the KP [103–105]. Among them,
quinolinic acid (unevenly present in different brain regions and, unlike nicotinamide, unable to cross
the blood-brain barrier) displays evident neuroactivity [106]: it acts as a N-methyl-D-aspartate (NMDA)
receptor agonist, thus causing excitotoxic neuronal lesions and oxidative stress [107]. In addition,
quinolinic acid concentrations in the brain (particularly in the cortex) positively correlate with age, thus
contributing to neuron synapsis dropout occurring during aging [108]. Finally, neuroinflammation,
neurodegeneration and mood disturbs are accompanied by increased quinolinic acid levels in plasma
and/or cerebrospinal fluid [10,109,110].
Among KP enzymes, TDO activity is rather low in a healthy human healthy brain [111],
where it controls neurogenesis with implications in pre- and post-natal development, as well as in
anxiety-related behavior [112]. TDO activity is enhanced under pathological conditions: high activity,
indeed, has been found in neurodegenerative diseases and during tumor progression [113,114]. Also
indolamine-pyrrole 2-3 dioxygenase (IDO) is expressed in the brain and its activity is increased upon
pathological conditions, especially in depression, aging and neuroinflammatory diseases [115–117].
Int. J. Mol. Sci. 2019, 20, 974 7 of 26

Like other vitamins (ascorbic acid, calcitriol and retinoic acid) [118–122], nicotinamide
affects neurogenesis by accelerating differentiation of embryonic stem cells or neural progenitors
into post-mitotic neurons [123,124]. In vitro vitamin supplementation promotes progression of
undifferentiated stem cells to neural progenitors, which further mature into efficient GABAergic
neurons; the pro-inducing action is time-dependent as the effects are more pronounced when the
vitamin is early received early (day 0) [124]. Accordingly, decreased activity of NNMT (and, therefore,
low levels of its metabolic product, N1 -methylnicotinamide) is required for regulating pluripotency
in stem cells: accumulation of NNMT’s substrates SAM and nicotinamide, indeed, promotes naïve
to primed stem cell transition, by making SAM available for histone methylation and regulation of
epigenetic events that control the metabolic changes occurring in early human development [125].
Beside the pro-differentiating action, nicotinamide also promotes neuronal survival, especially
during oxidative stress conditions, and this effect is achieved via multiple mechanisms, including:
(i) prevention of cytochrome c release and caspase 3- and 9-like activities, (ii) inhibition of
caspase-3-mediated degradation of forkhead transcription factor (FOXO3a) and (iii) maintenance
of protein kinase B (Akt)-dependent phosphorylation of FOXO3a [126].
CNS vascular integrity also positively correlates with NAD levels in brain, where a fine-tuned
control of its metabolism occurs. As an example, heterozygous deletion of nicotinamide
phosphoribosyltransferase (NAMPT) in the brain exacerbates focal ischemic stroke-induced neuronal
death and brain damage [127], while its selective knock down in projection neurons of adult mice
leads to motor dysfunction, neurodegeneration and death [128].
Finally, alterations of NAD metabolism are key features of Wallerian degeneration, a process
occurring in crushed nerve fibers and leading to degeneration of the axon distal to the injury, representing
an early event of age-related neurodegenerative disorders, as well as of chemotherapy-induced peripheral
neuropathy [129]. By inducing intra-axonal Ca2+ increase through a pathway requiring the action of the
pro-axon death protein SARM1, accumulation of nicotinamide mononucleotide is, indeed, responsible
for loss of axonal integrity [130]. The pro-degenerative action of nicotinamide mononucleotide has
also been documented during vincristine-induced degeneration in dorsal root ganglion axons [131].
Accordingly, increased activity of nicotinamide/nicotinic acid-mononucleotide-adenylyltransferase
(NMNAT) 1–3 protects axons from degeneration, by either limiting nicotinamide mononucleotide
levels or activating SIRT1 [132,133].

7. Alzheimer’s Disease
Alzheimer’s disease (AD) is a neurodegenerative disease affecting about 30 million people
worldwide, whose main hallmarks are the presence of amyloid β (Aβ) plaques and neurofibrillary
tangles [134].
Even if tryptophan/niacin deficiency leads to neurological symptoms that cause neurodegenerative
decline [135–137], a cause-effect relationship between niacin and AD pathogenesis has not been established
(Table 1).
Dietary niacin may protect against AD and age-related cognitive decline, as suggested by a
prospective population-based study: the Chicago Health and Aging Project (CHAP) study, considering
a geographically defined community of 6158 residents aged 65 years and older, found an inverse
association between AD and niacin intakes, after correction for several dietary (antioxidant nutrients,
fats, folate, and vitamins B6 , B12 , B1 and B2 ) and non-dietary (age, education, race, ApoEε4) risk factors
for dementia [135].
Int. J. Mol. Sci. 2019, 20, 974 8 of 26

Table 1. Main findings on the role of niacin in neurodegeneration.

Effector Main Findings Ref.

Niacin Inverse association between AD and dietary niacin intakes [135]
High brain levels restore mitochondrial function and antagonize
NAD+ [138,139]
cognitive decline
Nam/Nam Protect against Aβ-induced neurotoxicity via reduction of APP and
[140,141]
mononucleotide PSEN-1 expression and ROS levels
Alzheimer’s Reduces DNA damage, neuroinflammation and cell death of
disease Nam riboside [142]
hippocampal neurons
Supports the non-amyloidogenic pathway of AD
[143]
SIRT1 Lessens AD neuroinflammation, oxidative stress and
[144,145]
mitochondrial dysfunction
Protects against axon degeneration via reduction of nicotinamide
NMNAT1-3 [132,133]
mononucleotide levels and SIRT1 activation
Activity downregulated prior to neurodegeneration; restoration of
[146]
NMNAT2 activity is neuroprotective against tauopathy
[147]
Low gene expression in AD patients
Increased intake enhances striatal dopamine synthesis and restores
optimal NAD+ /NADH ratio [148]
Niacin High levels sequester transition metal ions [149,150]
Low doses impact macrophage polarization from M1 [151]
(pro-inflammatory) to M2 (anti-inflammatory) profile
NAD+ Decreased levels in PD patients [148]
Parkinson’s
disease Inhibits MPTP+ -induced oxidative stress and
NADPH [152]
glia-mediated neuroinflammation
High levels in the cerebrospinal fluid and midbrain dopamine neurons
of PD patients
High activity associated with low activity of mitochondrial complex 1; [153,154]
NNMT it counteracts the MPP+ -dependent toxicity on mitochondrial complex [154,155]
1 and activates neuronal autophagy [156]
Induces neurite branching, synaptophysin expression and
dopamine release
NAD Low levels correlate with disease progression in Drosophila HD model [157]
Protects against the toxicity of polyQ proteins in Drosophila HD models
Restores BDNF protein levels, increases acetylated PGC-1α, improves [158]
Huntington’s Nam motor deficits [159]
disease Prevents motor abnormality via PARP-1-dependent inhibition of [160–162]
neuronal death and oxidative stress
Rescues neurons from mutant huntingtin toxicity
SIRT1 [163,164]
Ameliorates pathological mechanisms underlying disease onset
AD: Alzheimer’s disease; APP: amyloid precursor protein; BDNF: brain-derived neurotrophic factor;
HD: Huntington’s disease; MPTP+ : N-methy-l-4-phenylpyridinium; Nam: nicotinamide; NMNAT:
nicotinamide/nicotinic acid-mononucleotide-adenylyltransferases; NNMT: Nicotinamide N-Methyltransferase;
PARP-1: poly(ADP-ribose) polymerase-1; PD: Parkinson’s disease; PGC-1α: peroxisome proliferator-activated
receptor gamma coactivator 1α; PSEN-1: presenilin-1; ROS: reactive oxygen species; SIRT1: sirtuin1.

Although the existing epidemiologic evidence remains limited and inconclusive, niacin (especially
nicotinamide) may be relevant for AD, especially keeping in mind that, by mediating key biological
processes (such as energy metabolism, mitochondrial functions, calcium homeostasis, survival
and cell death), NAD has lifespan-extending effects; this is particularly important in brain
functions, including neurotransmission, learning and memory. NAD+ depletion and mitochondrial
dysfunction, fundamental for synaptic plasticity, have usually been found in aging and AD
onset [138,165]; accordingly, in mice models of AD, increasing NAD+ brain concentrations can
restore mitochondrial function and antagonize cognitive decline [138,139]. Nicotinamide and/or
nicotinamide mononucleotide also counteract amyloid toxicity, by reducing expression of AD-related
genes (amyloid precursor protein and presenilin 1) and reactive oxygen species (ROS) generation,
and by improving neuron survival: both in vitro (organotypic hippocampal slice cultures) and
in vivo (AD model rats) studies have indeed underlined the protective effects of vitamin B3 against
Aβ-induced neurotoxicity [140,141]. Moreover, the vitamin is able to lessen phosphorylated-Tau
Int. J. Mol. Sci. 2019, 20, 974 9 of 26

pathology in a novel AD mouse model with introduced DNA repair deficiency: nicotinamide riboside
treatment significantly reduces DNA damage, neuroinflammation and cell death of hippocampal
neurons, thus suggesting a therapeutic potential of NAD+ supplementation for AD [142]. Accordingly,
the expression of Nmnat2, encoding for the enzyme catalyzing the conversion of nicotinamide to
NAD+ , is downregulated prior to neurodegeneration in a mouse model of dementia, and restoration
of enzymatic activity has been shown to be neuroprotective against tauopathy [146]. Low levels of
Nmnat2 have also been found in AD patients and its enzymatic activity is related to clearance of tau
protein [147].
Lastly, fluctuations in NAD+ availability can reduce AD pathology, also by modulating SIRT1
activity and slowing aging and age-associated diseases [166,167]. Several studies have underlined
the key role of SIRTs in AD prevention: in particular, deacetylase activity of SIRT1 has been
shown to support the non-amyloidogenic pathway of AD [143], and to counteract phenomena, like
neuroinflammation, oxidative stress and mitochondrial dysfunction, contributing to, and aggravating,
AD [144,145].

8. Parkinson’s Disease
Parkinson’s disease (PD) is a progressive disorder characterized by degeneration of dopaminergic
neurons within the substantia nigra, whose main hallmarks are abnormal aggregation of the
α-synuclein protein, inhibition of mitochondrial respiratory complex 1, oxidative stress and
neuroinflammation. Because only 5–10% of PD cases can be ascribed to genetic predisposition, several
environmental factors may play a role in sporadic forms of PD [149]. Among them, vitamin B3 is a
promising preventive and therapeutic factor (Table 1), as it can alleviate certain types of early-onset
PD symptoms. NAD+ levels, indeed, fall in patients with PD and, conversely, increasing niacin intake
can increase dopamine synthesis in the striatum and restore optimal NAD+ /NADH ratio needed for
the activity of mitochondrial complex 1 [148]. High niacin levels can also sequester transition metal
ions (including iron) that usually accumulate together with the occurrence of aggregated misfolded
proteins [149,150]. Furthermore, optimal levels of vitamin B3 are needed for reducing oxidative stress
and neuroinflammation, also implicated in PD pathogenesis: low doses of niacin alter macrophage
polarization from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenothype, while exogenous
NADPH suppresses oxidative stress and glia-mediated neuroinflammation [151,152].
Neurons are the only cells of the brain expressing NNMT that seems to play an important role
in sustaining neuron homeostasis [153]. Despite numerous investigations, the exact cause-effect
relationship between NNMT and PD neuropathogenesis remains unclear. Some authors refer
to NNMT as a risk factor for PD, since its levels are elevated in the cerebrospinal fluid and
midbrain dopamine neurons of PD patients [153,154]. High NNMT activity is associated with
low activity of mitochondrial complex 1, thus providing a link with mitochondrial dysfunction
triggering neurodegeneration [154,155]. It is noteworthy that N1 -methylnicotinamide (the metabolite
generated by the action of NNMT) is structurally similar to N-methy-l-4-phenylpyridinium (MPP+ ),
a toxin damaging dopamine neurons [168]. Conversely, other studies have demonstrated that the
enzyme is able to (i) counteract the MPP+ -mediated toxicity on mitochondrial complex 1, (ii) activate
neuronal autophagy for balancing energy sources and cell homeostasis, and (iii) modulate neuron
morphology and differentiation, by inducing neurite branching, synaptophysin expression and
dopamine accumulation and release [156]. Likewise, NAD supplementation or inactivation of
NAD-consuming enzymes [like PARP-1, a poly(ADP-ribose) polymerase involved in DNA repair]
rescue mitochondrial defects and protect neurons against degeneration, in familial forms of PD
characterized by mutations in the pink1 gene; this finding suggests that neurotoxicity associated with
mitochondrial defects may be prevented by modulating NAD+ salvage metabolism in order to enhance
NAD availability [169].
Int. J. Mol. Sci. 2019, 20, 974 10 of 26

9. Huntington’s Disease
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized
by typical progressive motor disturbances (involuntary movements of face and body, abnormalities in
gait, posture and balance), psychiatric disorders (dementia) and other cognitive impairments [170].
HD is caused by a CAG expansion in the gene encoding for huntingtin (htt), located on chromosome 4;
normally, the htt gene contains up to 35 CAG repeats, while in HD it has more than 36 CAG repeats that
produce a mutant protein, with an abnormally long polyglutamine repeat (polyQ), responsible for the
selective striatal degeneration of medium-sized spiny neurons and cerebral cortex [170]. In neurons,
mutant htt protein aggregates, thus critically damaging cellular integrity by impairing proteostasis
network, mitochondrial function and energy balance, transcriptional regulation, synaptic function and
axonal transport [171].
From metabolomic studies, it has emerged that the metabolite (e.g., Trp, kynurenine, quinolinic
acid and 3-hydroxykynurenine) content and activity of KP enzymes are pathologically altered in
experimental HD models and human patients [109,110]. Moreover, in a Drosophila model of HD,
disease progression has been found to be associated with a reduction in NAD levels, suggesting
that dietetic or pharmacological supplementation of niacin (or its derivatives) may be useful in HD
patients [157]. Several studies, indeed, have put forward a beneficial effect of vitamin B3 in HD (Table 1):
for example, nicotinamide is protective against toxicity of polyQ proteins in Drosophila HD models [158],
while, in transgenic mouse models, it restores brain-derived neurotrophic factor (BDNF) protein levels,
increases acetylated peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α),
a master regulator of mitochondrial biogenesis, and improves motor deficits [159]. Nicotinamide
effects do not depend on inhibition of mutant htt aggregation, but rather on replenishment of NAD
levels required to restore energy balance dysregulation occurring in HD.
Further insights into the neuroprotective action of nicotinamide derive from a recent study
showing how nicotinamide dose-dependently prevents motor abnormality in 3-nitropropionic
acid-induced rat model of HD. Such an effect seems to be linked to prevention of oxidative stress
(i.e., decrease in malondialdehyde and nitrites, increase in glutathione), as well as to inhibition
of neuronal death in the striatum, most likely through a PARP-1-dependent mechanism [160].
Accordingly, PARP-1 is activated in response to 3-nitropropionic acid-induced neurotoxicity [161]
and PARP-1-triggered astrocyte death is prevented by nicotinamide [162]. Like PARP-1, SIRTs are
involved in HD neurodegeneration. In particular, SIRT1 is impaired, most likely because of the ability
of mutant htt to directly bind and inhibit it; subsequent hyperacetylation and inactivation of specific
genes lead to abrogation of the deacetylase pro-survival action [172]. Accordingly, increased SIRT1
activity rescues neurons from mutant htt toxicity and ameliorates pathological mechanisms underlying
HD onset [163,164].
All these findings are somewhat controversial, since other studies reported opposite effects.
By using the YAC128 transgenic model (expressing the full-length human mutant htt gene), Naia and
co-workers [173] compared the effects of nicotinamide (a SIRT1 inhibitor) and resveratrol (a SIRT1
activator), both in vitro and in vivo. Both compounds were able to modify histone H3 acetylation and
counteract mitochondrial dysfunction in striatal and cortical neurons isolated from YAC128 embryos;
nonetheless, only resveratrol ameliorated energy homeostasis and mitochondrial function, as well as
motor coordination, in in vivo HD models. Counterintuitively, in vivo nicotinamide supplementation
(especially at high concentrations) did not cause any improvement in motor behavior and, furthermore,
it worsened motor performance in wild-type control mice. The harmful action has further been
documented in other neurodegenerative pathologies: in lactacystin-lesioned rats (an in vivo model
of PD), one-month nicotinamide supplementation leads to SIRT1 inhibition and over-expression of
neurotrophic and anti-apoptotic factors, nonetheless it exacerbated degeneration of dopaminergic
neurons [174].
Int. J. Mol. Sci. 2019, 20, 974 11 of 26

Therefore, these data underscore the need of full understanding the pathogenetic mechanisms
of neurodegeneration, before suggesting any therapeutic challenge to slow down the progression
of symptoms.

10. Other Neurological Diseases

Besides neurodegeneration, the impact of vitamin B3 on CNS has also been investigated in other
neuropathological conditions, among which (i) ischemic and traumatic injuries, (ii) headache and
(iii) psychiatric disorders (Table 2).

Table 2. Main findings on the role of niacin in other neurological diseases.

Effector Main Findings Ref.

Diminishes TBI-dependent behavioral deficits and improves
Niacin [175–180]
functional recovery
Reduces neurologic deficits, hippocampal apoptosis, axonal
injury and microglial activation in corpus callosum and
Nam [181]
oxidative stress; restores NAD(P) content; represses MAPK
signaling and caspase 3 cleavage
Ameliorates hippocampal injury and improves neurological
Nam mononucleotide outcome, by decreasing poly-ADP-ribosylated proteins and [182]
NAD+ catabolism
Ischemic and
traumatic injuries Nam/PARP-1 Pre-treatment improves ATP content and neuronal recovery
[183]
antagonists during re-oxygenation
Increases local cerebral blood flow; promotes angiogenesis via
Niaspan
angpt/Tie2, Akt and eNOS pathways; promotes arteriogenesis [184,185]
(niacin)
via TACE and Notch signaling; ameliorates functional deficits
Attenuate cortical cell injury, via an increase in Akt
Niacin plus selenium [186]
phosphorylation and expression of Nrf2; reduce oxidative stress.
Increase function recovery; reduce lesion cavitation and tissue
Nam plus progesterone [187,188]
loss; modulate expression of inflammatory and immune genes
Decreased activity exacerbates post-ischemic brain damage
[189,190]
Heterozygous gene deletion aggravates brain damage following
NAMPT [190]
photothrombosis-induced focal ischemia
[191]
Gene over-expression reduces infarct size
Restores mitochondrial energy metabolism
Niacin Ameliorates blood flow and oxygenation in contracted [192,193]
skeletal muscle
Headaches
Dilates intracranial vessels and contracts extracranial vessels;
Nicotinic acid increases skin biosynthesis of prostaglandin D2; rises plasma [194–196]
content of 9a,11b-prostaglandin F2
Niacin Low dietary intakes in neuropsychiatric patients [197]
Psychiatric disorders Positive correlation between vitamin levels and schizophrenia
[198]
Nam Chronic supplementation effective in maintaining a bipolar
[199]
type II patient stable and calm
Akt: protein kinase B; Angpt: angiopoietin1; eNOS: endothelial Nitric oxide synthase; MAPK: mitogen-activated
protein kinase; Nam: nicotinamide; NAMPT: nicotinamide phosphoribosyltransferase; Nrf2: Nuclear factor
(erythroid-derived 2)-like 2; PARP-1: poly(ADP-ribose) polymerase-1; TACE: tumor necrosis factor-alpha-converting
enzyme; TBI: traumatic brain injury.

10.1. Ischemic and Traumatic Injuries

When brain cells are deprived of oxygen for more than a few seconds, severe damage occurs,
culminating in cell death, through cerebral infarction or ischemic stroke. During reperfusion
following a transient ischemic episode, other significant harm (including oxidative stress, leukocyte
infiltration, mitochondrial dysfunction, platelet activation and aggregation, complement activation,
and blood-brain-barrier disruption) also occur, contributing to neurological dysfunction [200].
Re-oxygenation of neural tissue dramatically impairs NAD+ /NADH recycling, an event known as
NADH hyperoxidation [201]. Over the years, the potential neuroprotective and neurorestorative role
of vitamin B3 in ischemic brain injury has extensively been demonstrated in in vitro and in vivo
models. By using hippocampal slices, Shetty and co-workers [183] demonstrated that NADH
Int. J. Mol. Sci. 2019, 20, 974 12 of 26

hyperoxidation is correlated with diminished neuronal recovery that can be rescued by enhancing
NAD+ levels. Pre-treatment of brain tissue with nicotinamide (to enhance NAD+ availability) or
PARP-1 antagonists (to lessen NAD+ consumption), indeed, prevents mitochondrial dysfunction,
improves ATP content and stimulates neuronal recovery, during re-oxygenation [183]. Nicotinamide
seems to be efficacious also when provided after ischemia-reperfusion injury. For example, rats
receiving a single high dose or repeated low doses of vitamin B3 after cardiac arrest show reduced
neurologic deficits, hippocampal apoptosis, axonal injury and microglial activation in corpus
callosum [181]. Nicotinamide-dependent mechanisms underlying these effects include restoration of
NAD(P) content and decrease in oxidative stress, along with repression of mitogen-activated protein
kinase signaling and caspase 3 cleavage in brain tissue [181]. These data are in agreement with
previous reports showing how nicotinamide significantly reduces brain infarct size and improves
neurological deficits in different rat strains [202–206]. Interestingly, neurorestoring effects are also
present when niacin is provided several hours after ischemic damage: when administrated 24 h
after a middle cerebral artery occlusion, Niaspan (a FDA-approved prolonged release formulation of
niacin) increases local cerebral blood flow, promotes angiogenesis (via angiopoietin1/Tie2, Akt and
endothelial NOS pathways) and arteriogenesis (via tumor necrosis factor-alpha-converting enzyme
and Notch signaling), and ameliorates functional deficits [184,185].
NAMPT is critically involved in vitamin B3 effects. Proof of its key role include: (i) decreased
NAMPT activity significantly worsens post-ischemic brain damage [189,190]; (ii) heterozygous
Nampt deletion aggravates brain damage following photothrombosis-induced focal ischemia [190],
(iii) Nampt over-expression reduces infarct size [191]. Accordingly, when intraventricularly injected,
the NAMPT substrate nicotinamide mononucleotide reverts the detrimental effects of FK866 (a NAMPT
inhibitor) [189], ameliorates hippocampal injury and improves neurological outcome, by decreasing
poly-ADP-ribosylated proteins and NAD+ catabolism [182].
The evidence of niacin efficacy against ischemic insult strongly prompted researchers to investigate
its validity in other brain injuries, including traumatic brain injury (TBI). Rats receiving niacin following
a cortical contusion injury (an experimental model of TBI) show reduced behavioral deficits and
improved long-lasting functional recovery [175–180].
Regardless the type of brain injury, greater beneficial effects have been observed when vitamin B3
was administrated in combination with other “natural compounds”. Co-administration of nicotinamide
and progesterone not only increases function recovery, reduces lesion cavitation and tissue loss in
both injured cortex and reactive astrocytes, but also modulates expression of genes involved in
inflammatory and immune responses, including Ccr1 (chemokine (C-C motif) receptor 1), Clec4e
(C-type lectin domain family 4, member 3), Fn1 (fibronectin 1), Hmox1 (heme-oxygenase 1), Hspb1
(heat shock protein b1), Igf1 and 2 (insulin like growth factor 1 and 2), Il1β (interleukin 1 β), Il16 and 18
(interleukin 16 and 18), Mmp8 and 9 (matrix metallopeptidase 8 and 9), Niacr1 (niacin receptor 1) and
Ptgs2 (prostaglandin-endoperoxide synthase 2) [187,188]. In an in vitro model of ischemia-reperfusion
injury, combination of niacin and selenium (at clinically relevant doses) synergistically attenuates
cortical cell injury, by increasing Akt phosphorylation and expression of nuclear factor erythroid
2-related factor 2, stimulating glutathione redox cycle and reducing hydrogen peroxide levels [186].

10.2. Headache
Affecting more than fifty percent of adult population, headache represents one of the most
widespread causes of disability worldwide. Pathogenic mechanisms underlying migraine and
tension-type headache (the most common primary headache types) are mostly superimposable:
headache, indeed, is triggered by trigeminovascular complex activation that leads to intracranial
vessel vasoconstriction followed by extracranial vessel vasodilation and perivascular nociceptive nerve
activation. Pressure changes in cerebrospinal fluid and/or intracranial veins are also involved [207,208].
Some nutrients, such as magnesium, carnitine, coenzyme Q10, vitamins (B2 , B12 , D) and alpha
lipoic acid, can be used as preventive compounds able to counteract headache migraine attacks [209].
Int. J. Mol. Sci. 2019, 20, 974 13 of 26

When orally, intramuscularly or intravenously administrated, vitamin B3 (especially, nicotinic acid) has
therapeutic effects in headache management [210–215]. It has been proposed that niacin might exert
beneficial effects by acting at both central and peripheral levels; in particular, it efficaciously dilates
intracranial vessels and subsequently contracts extracranial vessels, favoring, in parallel, the release
of compounds leading to peripheral vasodilation and cutaneous flushing. Taking into account that
plasma content of serotonin inversely correlates with headache onset, niacin acts, at the central level,
by increasing Trp-dependent synthesis of serotonin, via feedback inhibition of the KP [194]. At the
peripheral level, pharmacological doses of nicotinic acid increase skin biosynthesis of prostaglandin
D2 [195] and the plasma content of its by-product 9a,11b-PGF2, in healthy volunteers [196].
It should also be mentioned that alterations of mitochondrial regulatory networks play a key role
in migraine pathophysiology [192,193]. Therefore, by enhancing substrate availability for complex
I and reducing lactate concentration, niacin might restore mitochondrial energy metabolism and
ameliorate blood flow and oxygenation in sore skeletal muscle, especially in tension-type headache.

10.3. Psychiatric Disorders

A large number of mental disorders have been shown to be influenced by dietary habits, leading
to the development of nutritional guidelines for prevention and/or treatment of psychological
disorders, including depression, anxiety, schizophrenia, bipolar disorders and psychological distress.
In particular, vitamin B3 dysmetabolism may be linked with some of these neuropsychiatric disorders,
although the literature reports conflicting data: as an example, an epidemiologic study conducted on
140 subjects (73 controls and 67 patients with schizophrenia) has revealed that affected individuals
show significantly lower dietary intakes of specific nutrients, including niacin [197], whereas a 1-year
case-control study performed on 101 controls and 128 cases of schizophrenia found a direct relationship
between the disease and nicotinamide levels [198].
The main etiological factors involved in mood disorders appear to be metabolites produced in the
KP, as a consequence of the shunt of Trp from serotonin synthesis to kynurenine formation [216].
Serotonergic neurotransmission, indeed, is compromised in the brain of depressed individuals,
as a result of activated KP. Since IDO activity is induced under inflammatory and oxidative
conditions, and KP is mostly active in astrocytes and microglia (also responsible for production
of pro-inflammatory mediators), it has been proposed that unbalanced KP leads to impaired
glial-neuronal network, thus priming the CNS against psychological stress [217]. In human postmortem
studies, high levels of kynurenic acid (deriving from transamination of kynurenine instead of
hydroxylation, see Figure 2) have been found in the prefrontal cortex of schizophrenic individuals;
this finding may have clinical relevance, as kynurenic acid is an antagonist of both NMDA and
nicotinic acetylcholine receptors, whose blockade is involved in cognitive deficits associated with the
disease [218]. Like schizophrenia, alterations in kynurenine precursor have also been observed in
bipolar disorder, although, in this case, nicotinamide levels represent a better prognostic factor; indeed,
higher nicotinamide levels are correlated with suicide as a cause of death in bipolar patients (1.3-fold
increase with respect to bipolar individuals who died from other causes) [219].
The immune-related imbalance of KP can also be responsible for dendritic atrophy and anhedonia
associated with major depressive disorder (MDD): comparison between controls (20 healthy subjects)
and patients (29 unmedicated individuals who met the Diagnostic and Statistical Manual of Mental
Disorders-IV criteria for MDD) revealed, in the MDD group, a lower neuroprotective index [ratio
between kynurenic acid (neuroprotective) and quinolinic acid (neurotoxic)], which was negatively
correlated with anhedonia and positively correlated with hippocampal and amygdala volume [220].
According to these data, tdo knock-out mice show, if compared to wild-type littermates, higher levels
of Trp and serotonin in the hippocampus and midbrain, which are connected to increased neurogenesis
and amelioration of anxiety-related behavior [221].
Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 14 of 27

midbrain, which
Int. J. Mol. Sci. are974connected to increased neurogenesis and amelioration of anxiety-related
2019, 20, 14 of 26
behavior [221].
Together, such findings suggest a potential antidepressant effect of vitamin B3 or its related
products. Together, such findings
In a patient suggest
with bipolar typeaIIpotential
disorder,antidepressant effect of vitamin(1B3g or
nicotinamide supplementation its related
three times
products. In a patient with bipolar type II disorder, nicotinamide supplementation
daily) for over 11 years has proven effective in maintaining the patient stable and calm [199]. (1 g three times
daily) foraover
Although 11 case
single yearsreport
has proven effective
is weak in maintaining
and does not allow usthetopatient stablethe
generalize andresults,
calm [199].
it mayAlthough
aid in
a single case report is weak and does not allow us to generalize
the understanding the potential additional mechanisms accounting for mental disorders. the results, it may aid in the
understanding the potential additional mechanisms accounting for mental disorders.
11. Conclusions
11. Conclusions
A growing body of evidence highlights the key role of vitamin B3 in neuronal health. What is
A growing body of evidence highlights the key role of vitamin B3 in neuronal health. What is
emerging is that niacin bioavailability is crucial for neuronsurvival and functions: indeed, vitamin
emerging is that niacin bioavailability is crucial for neuronsurvival and functions: indeed, vitamin
deficiency has been recognized as a pathogenic factor for neurological deficits and dementia, as well
deficiency has been recognized as a pathogenic factor for neurological deficits and dementia, as well
as for neuronal injury and psychiatric disorders.
as for neuronal injury and psychiatric disorders.
Several molecular mechanisms are influenced by vitamin B3 (Figure 4), often strictly linked each
Several molecular mechanisms are influenced by vitamin B3 (Figure 4), often strictly linked each
other, thus making it difficult to define the precise mechanisms of action of this dietary metabolite.
other, thus making it difficult to define the precise mechanisms of action of this dietary metabolite.
Although further research is needed, it may be speculated that optimal dietary intake of the vitamin
Although further research is needed, it may be speculated that optimal dietary intake of the vitamin
will support neuronal health and delay neurodegeneration.
will support neuronal health and delay neurodegeneration.

Main
Figure4.4.Main
Figure molecular
molecular mechanisms
mechanisms underlying
underlying beneficial
beneficial effects
effects of ofniacin
niacinininthe
theCNS
CNSunder
under
physio-pathological conditions. See text for further details. Akt: protein
physio-pathological conditions. See text for further details. Akt: protein kinase B; Angpt: kinase B; Angpt:
angiopoietin1;; eNOS:
angiopoietin1 eNOS: endothelial
endothelial nitric
nitricoxide
oxidesynthase;
synthase;MAPK:
MAPK: mitogen-activated
mitogen-activated protein kinase;
protein
PARP-1: poly(ADP-ribose) polymerase-1; SIRT1: sirtuin-1; TACE: tumor necrosis
kinase; PARP-1: poly(ADP-ribose) polymerase-1; SIRT1: sirtuin-1; TACE: tumor necrosis factor- factor-alpha-
converting enzyme.
alpha-converting enzyme.

This
Funding:This
Funding: researchreceived
research receivednonoexternal
externalfunding.
funding.
Conflicts of Interest: The authors declare no conflict of interest.
Conflicts of Interest: The authors declare no conflict of interest.
Int. J. Mol. Sci. 2019, 20, 974 15 of 26

Abbreviations
AD Alzheimer’s disease
Akt protein kinase B
ARTC ADP-ribosyltransferases
ARTD diphtheria toxin-like ADP-ribosyltransferases
CNS central nervous system
FOXO3a forkhead transcription factor
HD Huntington’s disease
HDL high density lipoprotein
hOAT-10 human organic anion transporter-10
Htt huntingtin
IDO indolamine-pyrrole 2-3 dioxygenase
KP kynurenine pathway
LDL low density lipoprotein
MDD major depressive disorder
MPP+ N-methy-l-4-phenylpyridinium
NAD(P) nicotinamide adenine dinucleotide (phosphate)
NAMPT nicotinamide phosphoribosyltransferase
NE niacin equivalents
NMDA N-methyl-D-aspartate
NNMT N-methyltransferase
PARP poly(ADP-ribose) polymerase
PD Parkinson’s disease
polyQ polyglutamine repeat
ROS reactive oxygen species
SAM S-adenosyl-methionine
SIRT sirtuin
SMCT1/SLC5A8 sodium-coupled monocarboxylate transporter
TBI traumatic brain injury
TDO tryptophan 2,3 dioxygenase
Trp tryptophan
VLDL very low density lipoprotein

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