| |

Received: 4 April 2019    Revised: 22 July 2019    Accepted: 26 July 2019

DOI: 10.1111/cns.13207

REVIEW ARTICLE

B Vitamins in the nervous system: Current knowledge of

the biochemical modes of action and synergies of thiamine,
pyridoxine, and cobalamin

Carlos Alberto Calderón‐Ospina1 | Mauricio Orlando Nava‐Mesa2

1
Center for Research in Genetics and
Genomics (CIGGUR), GENIUROS Research Abstract
Group, School of Medicine and Health Background: Neurotropic B vitamins play crucial roles as coenzymes and beyond in
Sciences, Universidad del Rosario, Bogotá,
Colombia the nervous system. Particularly vitamin B1 (thiamine), B6 (pyridoxine), and B12 (co-
2
Neuroscience Research Group balamin) contribute essentially to the maintenance of a healthy nervous system. Their
(NEUROS), School of Medicine and Health
importance is highlighted by many neurological diseases related to deficiencies in
Sciences, Universidad del Rosario, Bogotá,
Colombia one or more of these vitamins, but they can improve certain neurological conditions
even without a (proven) deficiency.
Correspondence
Mauricio Orlando Nava Mesa, Neuroscience Aim: This review focuses on the most important biochemical mechanisms, how they
Research Group (NEUROS), School of
are linked with neurological functions and what deficits arise from malfunctioning of
Medicine and Health Sciences, Universidad
del Rosario, Bogotá, Colombia. these pathways.
Emails: mauricio.nava@urosario.edu.co;
Discussion: We discussed the main role of B Vitamins on several functions in the
monavam@usal.es
peripheral and central nervous system (PNS and CNS) including cellular energetic
Funding information
processes, antioxidative and neuroprotective effects, and both myelin and neuro-
Merck Selbstmedikation GmbH, Darmstadt,
Germany, a legal entity of Procter & Gamble transmitter synthesis. We also provide an overview of possible biochemical synergies
Health
between thiamine, pyridoxine, and cobalamin and discuss by which major roles each
of them may contribute to the synergy and how these functions are inter‐related and
complement each other.
Conclusion: Taking into account the current knowledge on the neurotropic vitamins
B1, B6, and B12, we conclude that a biochemical synergy becomes apparent in many
different pathways in the nervous system, particularly in the PNS as exemplified by
their combined use in the treatment of peripheral neuropathy.

KEYWORDS
B vitamins, biochemical action mechanism, neuropathy, pyridoxine, thiamine, vitamin B12

1 |  BAC KG RO U N D though they are biochemically not related, referring to them as a group
makes sense because they often naturally occur in the same foods1
The eight B vitamins B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (panto- and share the feature of being water‐soluble. Mammals are not able
thenic acid), B6 (pyridoxine), B7 (biotin), B9 (folate), and B12 (cobalamin) to synthesize B vitamins on their own; therefore, they must take them
form a group of chemically very heterogeneous essential substances, up in sufficient quantities with the diet. Even though most of them are
which have a wide variety of functions in the human body.1-3 Even produced by plants, they can be ingested indirectly via animal‐derived

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2019 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

CNS Neurosci Ther. 2020;26:5–13. wileyonlinelibrary.com/journal/cns |  5

  
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6       CALDERÓN‐OSPINA and NAVA‐MESA

food like meat, dairy, and eggs. Only vitamin B12 is not produced by between thiamine deficiency and the development of fatal condi-
plants but by bacteria that colonize the foregut of ruminants or the tions such as beriberi, a syndrome compromising the PNS by poly-
colon of humans and thus can only be found in animal products like neuritis and/or cardiovascular symptoms, and the neuropsychiatric
liver, fish, eggs, or dairy products. However, the vitamin B12 produced Wernicke‐Korsakoff syndrome, characterized by encephalopathy
by bacteria in the colon of humans is not available for uptake because and psychosis, were already recognized in the early to mid‐20th
adsorption only takes place further up in the ileal mucosa through an century.3,20
2-4
intrinsic factor‐mediated mechanism. All B vitamins play crucial roles In general, thiamine is essential for many physiological functions
as coenzymes for enzymatic reactions in different biological systems.1,5 and is, among other roles, involved in glucose metabolism, the main-
Although those roles differ, they are closely inter‐related and comple- tenance of nerve membrane function, and the synthesis of myelin
2,6
ment each other. In order to fulfill the coenzymatic function, the bi- and several types of neurotransmitters (eg, acetylcholine, serotonin,
ologically active form of the respective vitamin (coenzyme) needs to and amino acids). 20-23
bind to a corresponding protein (enzyme), thereby activating its enzyme However, the most important function of thiamine is considered
function, so that the cellular processes can take place with the help of to be that it largely contributes to the cellular energy metabolism
the newly formed holoenzyme complex.2,3 Some of the B vitamins do and, as an essential cofactor in the conversion of carbohydrates,
not only contribute to important physiological functions in the whole helps providing energy to nerve cells. 24,25 This constant supply of
1
human body but also possess neurospecific functions. These com- energy is essential because nerve cells, especially in the brain, con-
monly called “neurotropic” B vitamins play special and essential roles sume a great amount of energy to maintain their functions and, for
both in the central nervous system (CNS) and the peripheral nervous example, prevent premature aging, but can hardly store high‐energy
system (PNS). It is well known that the diet and thus the supply of nutri- compounds themselves.7 To be more precise, one of the main activi-
7
ents strongly affect normal functioning of CNS and PNS. In particular, ties of thiamine is to enable biochemical steps in the energy‐creating
vitamin B1, B6, and B12 are essential for maintaining the health of the processes pentose phosphate pathway, glycolysis, and Krebs cycle
2,8
nervous system. Interaction between pyridoxine and cobalamin in (citric acid cycle). These processes supply the nerves with energy
the methionine cycle, as well as their participation in the citric acid cycle mainly in the form of adenosine triphosphate (ATP) or nicotinamide
with other B vitamins, including thiamine, suggests that these three adenine dinucleotide phosphate (NADPH), which in turn are essential
vitamins are linked from a biochemical point of view.2,9 Indeed, a sig- for numerous other cellular processes and reactions in nerves.20,23,26
nificant association between cognitive impairment and methionine‐ho- By means of that, vitamin B1 is also indirectly needed for the en-
mocysteine cycle dysfunction indicated by low levels of vitamins B6 and ergy‐consuming synthesis of nucleic acids, neurotransmitters, and
B12 has been found.9-11 Evidence suggests that a significant proportion myelin. 20,23-26 Therefore, thiamine even contributes to nerve con-
of the population suffers from deficiencies and insufficiencies of one or duction velocity because it participates in the maintenance of my-
more of these neurotropic B vitamins. The importance of B vitamins in elin sheaths. 23,25 Because the mentioned pathways not only produce
the context of nerve function is highlighted by the numerous neurolog- energy but also provide reducing power, thiamine is thought to also
ical diseases, such as Wernicke's encephalopathy, depression, beriberi, have an antioxidative—thereby protective—effect on nerve cells.3,20
seizures, subacute combined degeneration of the spinal cord, or periph- In addition to its coenzymatic functions, thiamine is also be-
eral neuropathy (PN), that are related to a deficiency in one or more lieved to be directly involved in nerve stimulation in a non‐coenzy-
of these neurotropic B vitamins.2,6,8,9,12,13 However, the significance matic way due to its interference with the structure and function of
of these vitamins is also emphasized by the fact that they can improve cellular membranes and its ability to regulate ion channels. 22,23,25,27
certain neurological conditions even if no (definite) deficiency can be Furthermore, through its antioxidative properties, sufficient
2,14,15
proven. Indeed, several reports indicate that the specific supple- amounts of thiamine may even prevent cell damage resulting from
mentation with the combination of vitamins B1, B6, and B12 interacts hyperglycemia. 25,28
synergistically to improve neuropathy, motor control, nociceptive, and At the molecular level, after being taken up by the cells by a usu-
neuropathic pain.16-19 The present review aims to compile the most im- ally active process, free thiamine is initially phosphorylated to form
portant biochemical pathways of the B vitamins, focusing on thiamine, biochemically active thiamine diphosphate (TDP), synonymously
pyridoxine, and cobalamin, and link them with neurological functions known as thiamine pyrophosphate (TPP). TPP acts as a coenzyme
and symptoms related to deficiencies. We also provide an overview of for thiamine‐using enzymes in three major pathways of glucose me-
possible biochemical synergies between these neurotropic vitamins tabolism; that is, for transketolase (TK) in the pentose phosphate
and discuss major roles by which they may contribute to this synergy. pathway, for pyruvate dehydrogenase (PDH) in the glycolysis, and
for alpha‐ketoglutarate dehydrogenase (AKD) in the Krebs cycle24-
26
(Figure 1). Each of these enzymes can only fulfill its purpose as a
2 |  B I O C H E M I C A L M O D E O F AC TI O N A N D
holoenzyme made up of several constituents. Therefore, the addi-
RO LE I N TH E N E RVO U S S YS TE M
tion of thiamine to the complex is crucial for the enzymes' function-
ality. The pentose phosphate pathway, which generates the sugar
2.1 | Vitamin B1 (thiamine)
molecule ribose‐5‐phosphate and the energy source NADPH, uses
Vitamin B1, also known as thiamine, has long been known to be the TPP‐activated TK in the cytosol to convert ribose‐5‐phosphate
associated with functions in the nervous system. The connections to glycerinaldehyde‐3‐phosphate. The substrates of the pentose
CALDERÓN‐OSPINA and NAVA‐MESA |
      7

F I G U R E 1   Biochemical mechanism of action of vitamin B1 (thiamine). Modified and simplified illustration based on. 24,26 TPP, thiamine
pyrophosphate; TK, transketolase; PDH, pyruvate dehydrogenase; AKD, alpha‐ketoglutarate dehydrogenase; CoA, coenzyme A; GABA,
gamma‐aminobutyric acid

phosphate pathway are then used for the synthesis of nucleic acids, and Korsakoff's psychosis (often referred to as Wernicke‐Korsakoff
complex sugar molecules, coenzymes, steroids, fatty acids, amino syndrome) can certainly be considered the most serious CNS mani-
acids, neurotransmitters, and glutathione. Through its operation, TK festations of thiamine deficiency. 20,30 In Wernicke's encephalopathy,
also connects the pentose pathway with the glycolysis. 24,26,29 for instance, thiamine deficiency is thought to trigger apoptotic cell
In contrast, the TPP‐activated enzymes PDH and AKD hold spe- death due to N‐methyl‐D‐aspartate (NMDA) toxicity and thereby in-
cial functions in glycolysis and the Krebs cycle, which in particular duce neurological symptoms.32 In the PNS, typical manifestations of
provide ATP for cell energy. Further, PDH induces the formation of thiamine deficiency include polyneuritis and paralysis, as occurs in
acetyl coenzyme A (CoA), a precursor of the neurotransmitter ace- dry beriberi.3,20 In the sensory system, it influences the tactile sen-
tylcholine, and helps producing myelin that is needed to enwrap the sation, causes pain, changes the temperature sensitivity, and leads to
axons of nerve cells.3,26 AKD in the Krebs cycle, on the other hand, the loss of vibratory sense. In the motor system, paralysis typically
helps maintaining the levels of neurotransmitters (ie, glutamate, begins in the tips of the lower extremities and spreads progressively.
26
GABA, and aspartate) and also supports protein synthesis. It involves increased muscle weakness, affected tendon reflexes, and
In the case of a vitamin B1 deficiency, activity levels of all three atrophy of the leg muscles. 21 Thiamine deficiency nowadays hardly
enzymes mentioned above are biochemically impaired; however, TK affects the general population in developed countries, but certain
activity may be most sensitive and AKD activity one of the earliest vulnerable populations are very often deficient or show suboptimal
changes. As vitamin B1 is essential for the production of energy (ATP levels. 22,24 For example, it is assumed that this applies to up to 80%
and NADPH) and a normal function of nerve cells, its deficiency can of alcoholics, 23 up to 98% of diabetics,33 and around one‐third of
30
cause neurons to die or become damaged. Thiamine deficiency dialysis patients with altered mental status.34
affects both the CNS and the PNS and can manifest clinically in Because vitamin B1 is largely involved in pathways that also create
multifaceted ways. In general, neurological symptoms of thiamine reducing power in cells, deficiency will cause cells to be exposed to
deficiency include confusion, psychomotor retardation, lack of in- oxidative stress, which can lead to cell damage and cell death and con-
sight, impaired retentive memory and cognitive function, confab- tribute to further symptoms and comorbidities.20,24-26
21,24
ulation, ataxia, and the loss of vibration and position sense. If In summary, these examples clearly show how important thia-
thiamine is not present in sufficient quantity for the CNS, sensitive mine is for the nervous system function due to its activating role
areas of the brain such as the thalamus and the mamillary bodies (part for neuronal excitability and metabolism as well as antioxidative
of the hypothalamus) suffer damage.31 Wernicke's encephalopathy effects.
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8       CALDERÓN‐OSPINA and NAVA‐MESA

F I G U R E 2   Biochemical mechanism of action of vitamin B6 (pyridoxine). A, Role of PLP on Dopamine and Serotonin Synthesis. B, Role
of PLP and Vit. B12 on one‐carbon unit metabolism and Hcy metabolism. Role of B Vitamins in the interlinked methionine and citric acid
cycles. Modified and simplified illustration based on.36,42,43 TH, tyrosine hydroxylase; AADC, aromatic L‐amino acid decarboxylase; PLP,
pyridoxal 5′‐phosphate; 5‐HTP, 5‐hydroxytryptophan; THF, tetrahydrofolate; SHMT, serine‐hydroxymethyltransferase; FAD, flavin adenine
dinucleotide; SAM, S‐adenosylmethionine; SAH, S‐adenosylhomocysteine; R, methyl group acceptor

which appears to be mainly linked with its ability to regulate the glu-
2.2 | Vitamin B6 (pyridoxine)
tamatergic system and thus GABA and glutamate levels. Since GABA
Vitamin B6 (pyridoxine) has been discovered in 1934 and has so serves as the major inhibitory neurotransmitter, it seems obvious
far been associated with over 140 coenzymatic functions.3,31,35 that GABA deficiency can lead to serious consequences, such as
Although its role goes far beyond, it is particularly well known for its seizures. Increased levels of the GABA precursor glutamate, an ex-
important function in the synthesis of neurotransmitters like dopa- citatory neurotransmitter, can be linked with seizures, whereas the
mine from L‐DOPA, serotonin from 5‐HTP, and gamma‐aminobutyric application of GABA or pyridoxine can end seizure activity.1,3,36 In
1,3,5,31,36,37
acid (GABA) from glutamate. According to its function for addition, pyridoxine administration even attenuates the excitotoxic-
the previously mentioned neurotransmitters (and others), pyridox- ity of the neurotoxin domoic acid.38 Beyond that, it has been shown
ine affects the adrenergic, the serotonergic, and the glutamatergic that vitamin B6 is essential during gestation and postnatal brain
system. Pyridoxine can also be attributed a neuroprotective role development, probably also through the regulation of GABA levels.
CALDERÓN‐OSPINA and NAVA‐MESA |
      9

Rats exposed to vitamin B6 deficiency during this time showed sig- and thermal sensations (PNS effects).1,3,5,7,35,36 Treating these con-
nificantly lower GABA levels and permanently damaged brains.39 ditions with pyridoxine is clearly useful, even though the intake of
While only nonphosphorylated B6 vitamers can cross cell mem- extremely high doses over long periods can itself trigger sensory
branes, including the blood‐brain barrier,40 and can therefore be neuropathy.3,36 However, even in these circumstances, symptoms
taken up by cells, vitamin B6 is intracellularly phosphorylated to resolve after withdrawal and no permanent damage to the nervous
form the active interconvertible 5′‐phosphate esters pyridoxine 5′‐ system has so far been described.3 Like thiamine deficiency, vita-
phosphate (PNP), pyridoxal 5′‐phosphate (PLP; most important co- min B6 deficiency is also rare in the healthy general population in
enzyme variant), and pyridoxamine 5′‐phosphate (PMP).36 Beyond countries with high nutritional standards but frequently affects he-
its essential role in neurotransmitter production, PLP also acts as modialysis patients (over 80%),45 particularly if they are uremic. In
a coenzyme in one‐carbon unit generation and homocysteine me- addition, increased amounts of vitamin B6 are needed during preg-
tabolism, supports carbohydrate and fat synthesis as well as break- nancy to ensure fetal brain development,46 and pyridoxine supple-
down, and helps releasing food‐bound energy that is needed for the mentation may even reduce nausea during early pregnancy.47
3,31,36,41
metabolism of proteins and amino acids. Besides, PLP also In summary, pyridoxine strongly contributes to the proper func-
serves as a cofactor in sphingolipid synthesis and is thereby import- tioning of the nervous system by facilitating neurotransmitter and
ant for myelin formation.5,36,38 myelin synthesis, and also controlling glutamate excitability and neu-
With regard to neurotransmitter synthesis, PLP helps, for in- ronal metabolism.
stance, catalyzing the final production step of dopamine and sero-
tonin, that is, the enzymatic decarboxylation of L‐DOPA to dopamine
2.3 | Vitamin B12 (cobalamin)
and of 5‐HTP to serotonin (Figure 2A). In both pathways, successful
formation of the neurotransmitters depends on the action of aro- The discovery of vitamin B12 (cobalamin) can be attributed to a
matic L‐amino acid decarboxylase (AADC), which in turn essentially disease that already attracted attention long time ago and became
37,42,43
depends on PLP. known as pernicious anemia.3,48,49 Even though it first became fa-
In the one‐carbon unit metabolism, PLP‐activated serine‐hy- mous for its role in hematopoiesis, cobalamin also plays an essential
droxymethyltransferase (SHMT) catalyzes the process in which role as a coenzyme in many biochemical processes that maintain or
one‐carbon units are generated from serine and activated through restore the health of the nervous system. Thus, vitamin B12 is es-
association with tetrahydrofolate (THF). This pathway forms 5,10‐ pecially awarded a function in the DNA synthesis of myelin‐produc-
methylene‐THF for nucleic acid synthesis and the methyl donor 5‐ ing oligodendrocytes and the synthesis of myelin.48-51 The myelin
methyl‐THF, which is needed for protein synthesis and to methylate sheath surrounds the axons of many nerves and serves as an electri-
homocysteine (Hcy) to methionine in a process that also depends on cal insulation, thereby facilitating fast conduction velocity. Through
vitamin B12 and folate. A great proportion of the formed methionine this important contribution to myelin formation and remyelination, it
is converted to S‐adenosylmethionine (SAM), a universal donor of significantly supports the regeneration of nerves after an injury.8,50
methyl groups needed for the synthesis of DNA, RNA, hormones, In addition to this major role, cobalamin is involved in Hcy metabo-
neurotransmitters, membrane lipids, proteins, and others. Being an lism, nerve metabolism (transmethylation processes), fatty acid and
intermediate compound of the methionine metabolism, Hcy can be nucleic acid synthesis, energy production as well as cell maturation
disposed by two pathways. When methionine is in excess or cys- processes and even supports the maintenance of an intact gastro-
teine is required, it will be disposed via the intermediates cystathi- intestinal mucosa.48-53 Since the level of cobalamin also affects the
onine and cysteine to glutathione. In methionine deficiency, on the amount of reduced glutathione with antioxidant functions in the
other hand, it is remethylated to methionine in the above‐described erythrocytes and in the liver, the lower availability of reduced glu-
way36,44 (Figure 2B). tathione in cobalamin deficiency may expose cells to increased oxi-
The role of pyridoxine in the nervous system is clearly demon- dative stress.7
strated by its use in the treatment of pyridoxine dependency sei- The pathway from nutritional vitamin B12 intake to cellular us-
zures—an inborn abnormality in infants with seizures not responding ability of the coenzyme forms is complex and involves several steps
to common anticonvulsants.3,36 Due to its important function as a during which cobalamin (Cbl) is bound and transported through the
coenzyme in pathways responsible for the synthesis of neurotrans- intestine and the blood by different proteins such as haptocorrin, in-
mitters and myelin, vitamin B6 deficiency can severely impair the trinsic factor, and transcobalamin II. The holotranscobalamin complex
1,3,5,36
CNS and the PNS. Biochemically, in a partial deficiency of is finally absorbed by the target cell after binding to the transcobala-
vitamin B6, some enzymes may be more affected than others, re- min receptor.48,54 Cbl naturally occurs in several forms differing only
sulting in greater depletion of some neurotransmitters and thereby in their prosthetic groups, all of which are cleaved and metabolized to
imbalances between the levels of different neurotransmitters.38 the coenzyme variants methylcobalamin (MeCbl) and adenosylcobala-
Neurological symptoms of deficiency generally range from impaired min (AdoCbl) after uptake.49,51,53,55 It is important to understand that
cognitive function, convulsive seizures, depression, and even prema- all of these forms first have to be converted to the Cbl core structure
ture aging of neurons (CNS effects) to carpal tunnel syndrome and before they are later newly assembled into the active coenzymes in the
PN with symptoms like paresthesia, burning and painful dysesthesias, body. Therefore, direct intake of the coenzyme forms does not seem
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10       CALDERÓN‐OSPINA and NAVA‐MESA

F I G U R E 3   Biochemical mechanism of action of vitamin B12 (cobalamin). Modified and simplified illustration based on.48,54
HoloTC, holotranscobalamin; TC, transcobalamin; Cbl, cobalamin; MeCbl, methylcobalamin; MS, methionine synthase; SAH, S‐
adenosylhomocysteine; SAM, S‐adenosylmethionine; AdoCbl, adenosylcobalamine; MCM, methylmalonyl CoA mutase; CoA, coenzyme A

to be associated with advantages.55 Cbl forms in the mitochondria are available. SAM synthesis critically depends on vitamin B12 and has
changed in a complex enzymatical process into AdoCbl, which supports various important functions in the nervous system, including myelin
the enzyme methylmalonyl CoA mutase (MCM) and thereby helps cata- as well as neurotransmitter synthesis. Demyelination generally af-
lyzing the formation of succinyl CoA—an important intermediate of the fects both peripheral and central nerves but especially the long tracts
Krebs cycle—from methylmalonyl CoA (Figure 3). Methylmalonyl CoA of white matter in the posterior and lateral columns of the spinal cord,
emerges when odd‐chain fatty acids, cholesterol, and ketogenic amino which contain sensory fibers for the vibration and position sense.
acids are metabolized.3,54,56 In contrast to the processes in the mito- However, motor fibers can also become demyelinated.3 Affected
chondria, the equally complex enzymatical conversion of Cbl to MeCbl persons may suffer from symptoms such as symmetric dysesthesia,
only occurs in the cytosol. Here, the enzyme methionine synthase disturbance of position sense, spastic paraparesis or tetraparesis,
(MS) requires MeCbl as a cofactor to methylate the amino acid Hcy to paresthesias, numbness in limbs, and difficulties in activities of daily
methionine (Figure 3), which is needed to sustain adequate synthesis living like writing or buttoning.51,53,54,57 Vitamin B12 deficiency ap-
of proteins, DNA, and neurotransmitters.3,48,51,53-55 If Cbl is deficient pears to be particularly common in the elderly with estimates as high
in the cell, plasma concentrations of methylmalonic acid—a functional as 30‐40% and may often be due to malabsorption. In addition, veg-
marker of vitamin B12 deficiency—and Hcy will rise. Moreover, defi- etarians and particularly vegans often show suboptimal vitamin B12
ciency also leads, among other things, to defect in myelin synthesis levels but do not necessarily develop a clinical deficiency.3,49,51,57
and the incorporation of abnormal fatty acids into neuronal.48,49,51,53,54 Overall, it can also be summarized for vitamin B12 that it is es-
Because vitamin B12 is involved in so many essential pathways, sential for the nervous system, particularly with regard to myelin
its deficiency is a tremendous health problem. However, symptoms synthesis, nerve metabolism, and neuronal regeneration.
strongly differ in severity and can manifest as mild conditions or
life‐threatening disorders.57 Neurological deficiency disorders in-
clude but are not limited to subacute combined sclerosis of the spinal 3 | TH E RO LE O F N EU ROTRO PI C B
cord, polyneuritis, neuropathy, myelopathy, optic nerve atrophy, and V ITA M I N S I N D I FFE R E NT R EG I O N S O F TH E
impaired cognitive function and are mainly related to impaired neu- N E RVO U S S YS TE M
rotransmitter production, myelin lesions, or increased Hcy and meth-
ylmalonic acid levels.3,49,51,54,57-60 Neuronal demyelination is thought As outlined in this review, neurotropic B vitamins play impor-
to be mainly caused when the universal methyl donor SAM is less tant roles both in the CNS and the PNS. While the biochemical
CALDERÓN‐OSPINA and NAVA‐MESA |
      11

mechanisms at the cellular level are identical in both systems, the neither of them can replace one of the others. Table 1 provides
1,3
phenotypic manifestations of deficiencies differ. an overview on the major implications in overlapping biochemi-
In the CNS (ie, the brain and the spinal cord), one of the most prom- cal pathways important for the nervous system, pointing to a
inent roles of neurotropic B vitamins (particularly vitamins B6 and B12 synergistic effect as a logical consequence of these overlaps.
as well as the herein not described B9) derives from their contribution Considering the fact that PN of different etiologies is believed
to the folate and Hcy metabolism. Deficiencies in these vitamins are to be a multifactorial process involving different factors like oxi-
associated with increased Hcy levels, which are assumed to have neu- dative stress and demyelination, 65-69 the hypothesis of synergy
rotoxic effects. By promoting oxidative stress and neurodegeneration, becomes even more likely. We postulate that the synergistic func-
increased Hcy may be a risk factor for dementia, cognitive decline, and tion of neurotropic B vitamins in the PNS may be primarily due to
Alzheimer's disease.2,9,12,53 In addition, dietary supplementation with B prominent functions of each vitamin. While we assume that vita-
Vitamins may have beneficial effects in other neurological conditions min B1 is mainly needed as an antioxidant in this context, vitamin
such as anxiety, stress‐related disorders, and multiple sclerosis.61,62 B6 may be primarily involved in a neuroprotective and vitamin B12
Also in the PNS, neurotropic B vitamins contribute to the main- in a myelin‐regenerating role. However, the idea of synergistic ef-
tenance of optimal nerve functioning. Deficiencies can result in the fects between B vitamins has already been discussed by other au-
development of disorders of the peripheral nerves, for example, pe- thors. 6,8 Nevertheless, clinical studies that support the hypothesis
ripheral neuropathies. Evidence suggests that these vitamins also are needed and should directly compare the combination of the
play a role in the regeneration of injured nerves, as shown in several neurotropic B vitamins B1, B6, and B12 with the individual vita-
63,64
animal studies (for examples see ). In addition, studies in humans mins in humans suffering from PN. In contrast, results from animal
have shown that treatment with neurotropic B vitamins effectively studies suggest the correctness of the hypothesis. Thus, evidence
relieved symptoms of neuropathy in different patient groups (for ex- for the practical synergistic action in the PNS was impressively
amples see19,64). Patients with such conditions may even benefit from demonstrated by Jolivalt et al, who showed that none of the indi-
pharmacological B vitamin doses if no clear diagnosis of deficiency vidual B vitamins (B1, B6, and B12) was as effective in alleviating
can be established or only suboptimal B vitamin levels (“marginal de- neuropathic pain and restoring nerve function in rats with experi-
ficiency”) are detected.2,14,15 This assumption is supported by a re- mentally induced diabetic neuropathy as the combination of the
cent prospective, non‐interventional study of Hakim et al, in which three when comparing high‐dose administration.70
patients with PN of different etiology were treated with high‐dose B
vitamins (B1, B6, and B12) for a period of 90 days without prior de-
termination of B vitamin levels; all groups benefited significantly from 5 | FI N A L R E M A R K S A N D CO N C LU S I O N
the treatment and felt progressive relief of different symptoms such
as pain, burning, paresthesia, and numbness.19 However, the benefit As highlighted here, the neurotropic vitamins B1, B6, and B12 have
of neurotropic B vitamins in patients with neuropathy should in the different neurospecific functions in the nervous system. They are all
future also be confirmed by randomized controlled trials. important for the maintenance of normal neurological functions due
to different biochemical modes of action, especially as coenzymes
but also beyond,1,3 and can effectively be used in combination for
4 | S Y N ERG I S T I C EFFEC T O F T H E the treatment of PN in humans.19,64 However, the exact mechanisms
CO M B I N AT I O N O F N EU ROT RO PI C of action of these B vitamins in PN are still not clarified in detail and
B V I TA M I N S B1 , B 6 , A N D B12 W I T H require further research.
EM PH A S I S O N T H E PN S In summary, vitamin B1 is particularly needed as a cofactor in
glucose metabolism and thereby indirectly supports the synthesis
It needs to be stressed that vitamin B1, B6, and B12 most likely of nucleic acids, neurotransmitters, myelin, etc by providing en-
hold synergistic biochemical roles in the nervous system, that is, ergy for these processes. In addition, it is assumed to contribute to

TA B L E 1   Overview on major biochemical mechanisms of action of vitamins B1, B6, and B12 for nerve function

Vitamin Processes Coenzyme for Implication in nervous system

B1 (thiamine) Glycolysis Pentose phosphate Pyruvate dehydrogenase Provide energy to nerve cells which are
pathway Krebs cycle (citric acid Transketolase needed for synthesis of nucleic acids,
cycle) Alpha‐ketoglutarate dehydrogenase neurotransmitters, and myelin
B6 (pyridoxine) One‐carbon unit metabolism Hcy Serine‐hydroxymethyltransferase Metabolism of amino acids, neurotransmit-
metabolism Dopamine and sero- Cystathionine‐beta‐synthase/lyase ters, and DNA/RNA
tonin synthesis Aromatic L‐amino acid decarboxylase
B12 (cobalamin) Hcy metabolism Methymalonyl Methionine synthase Metabolism of fatty acids, amino acids,
CoA pathway Methylmalonyl CoA mutase neurotransmitters, myelin, and DNA/RNA

Note: Overview not exhaustive. Content based on references.3,6,23,26,36,49,54,57

 |
12       CALDERÓN‐OSPINA and NAVA‐MESA

antioxidative mechanisms. 24,26 Vitamin B6, most importantly, func- 10. Palacios N, Scott T, Sahasrabudhe N, Gao X, Tucker KL. Lower
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vitamins B1, B6, and B12, we conclude that they form a biochem- fects of vitamin B on the immune/cytokine network and their in-
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