Besides neurodegeneration, the impact of vitamin B
3 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).
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 B
3 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 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 B
3 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,
203,
204,
205,
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 B
3 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,
176,
177,
178,
179,
180].
Regardless the type of brain injury, greater beneficial effects have been observed when vitamin B
3 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 (B
2, B
12, D) and alpha lipoic acid, can be used as preventive compounds able to counteract headache migraine attacks [
209]. When orally, intramuscularly or intravenously administrated, vitamin B
3 (especially, nicotinic acid) has therapeutic effects in headache management [
210,
211,
212,
213,
214,
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 B
3 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].
Together, such findings suggest a potential antidepressant effect of vitamin B3 or its related products. In a patient with bipolar type II disorder, nicotinamide supplementation (1 g three times daily) for over 11 years has proven effective in maintaining the patient stable and calm [
199]. Although a single case report is weak and does not allow us to generalize the results, it may aid in the understanding the potential additional mechanisms accounting for mental disorders.