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Friday, January 17, 2025
The Influence of Nicotinamide on Health and Disease in the Central Nervous System
Did your competent? doctor start doing something with this way back in 2003? NO? So, you DON'T have a functioning stroke doctor, do you?
Nicotinamide, the amide form of vitamin B3
(niacin), has long been associated with neuronal development, survival,
and function in the central nervous system (CNS), being implicated in
both neuronal death and neuroprotection. Here, we summarise a body of
research investigating the role of nicotinamide in neuronal health
within the CNS, with a focus on studies that have shown a
neuroprotective effect. Nicotinamide appears to play a role in
protecting neurons from traumatic injury, ischaemia, and stroke, as well
as being implicated in 3 key neurodegenerative conditions: Alzheimer’s,
Parkinson’s, and Huntington’s diseases. A key factor is the
bioavailability of nicotinamide, with low concentrations leading to
neurological deficits and dementia and high levels potentially causing
neurotoxicity. Finally, nicotinamide’s potential mechanisms of action
are discussed, including the general maintenance of cellular energy
levels and the more specific inhibition of molecules such as the
nicotinamide adenine dinucleotide-dependent deacetylase, sirtuin 1
(SIRT1).
Introduction
There
is a growing body of evidence that diet and nutrition play a direct
role in maintaining neuronal health. In particular, dietary factors can
influence the onset and progression of Parkinson’s disease (PD), and
potentially its amelioration.1,2
The emerging pattern from this body of research is that there are clear
consequences to an imbalance in dietary factors on the production and
maintenance of mature neurons.
Our research
and that of others suggest that vitamins are essential both for the
formation of neurons and their survival. Here, we review nicotinamide
and associated active metabolites. We discuss nicotinamide’s role in the
maintenance of mature central nervous system (CNS) neurons; its
influence on neuronal health and survival during ageing, injury, and
disease; and its potential as a therapeutic for neurodegenerative
disease.
Vitamins and Their Role in Health
During
the last century, a new class of nutritional supplements was
identified. These ‘vitamins’ were defined as biologically active organic
compounds essential for normal health and growth, which cannot, or can
only partially, be synthesised by the human body. Grouped by their
biological and chemical activity, 13 classes of vitamins (Table 1)
are currently recognised, having diverse biochemical functions such as
regulation of cell and tissue growth, mineral metabolism, acting as
coenzymes in metabolism, and directing cell differentiation.3
Thus, vitamins are essential for the development and maintenance of the
body, with their deficiencies leading to conditions affecting multiple
systems, such as pellagra, scurvy, rickets, bleeding disorders, and
vulnerability to infections.4 If untreated, vitamin deficiencies can lead to significant ill health and potentially death.
Table 1. The thirteen recognised classes of vitamins and their roles.
Vitamin
Other names
Examples of physiological functions
Vitamin A
Retinol, retinoic acid, retinal, carotenoid
Growth, maintenance of skin, bone development, maintenance of myelin, maintenance of vision
Vitamin B1
Thiamine
Growth, appetite, digestion, nerve activity, energy production
Vitamin B2
Riboflavin
Growth and development of foetus, redox systems, and respiratory enzymes; maintenance of mucosal, epithelial, and eye tissues
Vitamin B3
Nicotinamide, niacinamide, nicotinic acid, niacin
Maintenance of NAD and NADP, coenzyme in lipid catabolism, oxidative deamination
Vitamin B5
Pantothenic acid
Lipid metabolism, protein metabolism, part of coenzyme A in carbohydrate metabolism
Vitamin B6
Pyridoxine, pyridoxol, adermine
Growth; protein, CHO, and lipid metabolism; coenzyme in amino acid metabolism
Vitamin B7
Biotin, protective factor X
Growth; maintenance of skin, hair, bone marrow, and sex glands; biosynthesis of aspartate and unsaturated fatty acids
Vitamin B9
Folic acid, folacin, folinic acid
Synthesis of nucleic acid, differentiation of embryonic nervous system
Vitamin B12
Cobalamin
Coenzyme in nucleic acid, protein, and lipid synthesis; maintenance of epithelial cells and nervous system
Vitamin C
Ascorbic acid
Absorption
of iron, antioxidant, growth, wound healing, formation of cartilage,
dentine, bone and teeth, maintenance of capillaries
Vitamin D
Vitamin D3, cholecalciferol, calcitriol
Normal
growth, Ca and P absorption, maintains and activates alkaline
phosphatase in bone, maintains serum calcium and phosphorus levels
Vitamin E
Tocopherol, Tokopharm, tocotrienols
Antioxidant,
growth maintenance, aids absorption of unsaturated fatty acids,
maintains muscular metabolism and integrity of vascular system and
central nervous system
Vitamin K
Prothrombin factor, menaquinones
Blood-clotting mechanisms, electron transport mechanisms, growth, prothrombin synthesis in liver
Nicotinamide, Nicotinamide Adenine Dinucleotide, and Neuronal Health
Nicotinamide, the water-soluble amide form of vitamin B3,
is a key component of the metabolic pathway involved in the production
of nicotinamide adenine dinucleotide (NAD+). One source of nicotinamide
is the diet, via intake of eggs, meat, fish, and mushrooms. A second
source of nicotinamide is the metabolism of endogenous tryptophan, an
essential amino acid. Nicotinamide can also be generated from niacin via
the formation of NAD+.
Nicotinamide is
stored in only small quantities in the liver, with most being either
excreted or catabolised to provide other key metabolic products. It is
difficult to achieve adverse effects from excessive intake, even with
pharmacologically high doses, but overdose can cause hepatotoxicity in
rare cases.5
The
enzyme, nicotinamide phosphoribosyltransferase (NAMPT), catalyses the
synthesis of nicotinamide mononucleotide (NMN) from nicotinamide (Figure 1).
Its role in the metabolic pathway for the biosynthesis of NAD (oxidised
form NAD+; reduced form NADH) suggests its importance in cells that are
sensitive to decreases in NAD levels, such as neurons.6 NAD homeostasis has also been found to be altered with ageing7–10;
thus, by influencing levels of NAD+ within neurons, nicotinamide may
play a key role in neuronal maturation and neuroprotection.
Figure 1.
Simplified schematic representation of the key pathways for the
metabolism of nicotinamide, niacin, and tryptophan in the production of
NAD+.
The enzyme NMN adenylyltransferase (NMNAT) converts NMN to NAD+ (Figure 1). Three isozymes, NMNAT1, 2, and 3, are localised to the nucleus, cytoplasm, or mitochondria, respectively.11
An increase in NMNAT activity has been shown to lead to axonal
protection in cultured neurons undergoing Wallerian degeneration,
through a rise in nuclear NAD levels, leading to activation of the
NAD-dependent protein deacetylase sirtuin 1 (SIRT1),12,13 implicating nicotinamide indirectly in neuroprotection.
Nicotinamide, the amide form of vitamin B3
(niacin), has long been associated with neuronal development, survival,
and function in the central nervous system (CNS), being implicated in
both neuronal death and neuroprotection. Here, we summarise a body of
research investigating the role of nicotinamide in neuronal health
within the CNS, with a focus on studies that have shown a
neuroprotective effect. Nicotinamide appears to play a role in
protecting neurons from traumatic injury, ischaemia, and stroke, as well
as being implicated in 3 key neurodegenerative conditions: Alzheimer’s,
Parkinson’s, and Huntington’s diseases. A key factor is the
bioavailability of nicotinamide, with low concentrations leading to
neurological deficits and dementia and high levels potentially causing
neurotoxicity. Finally, nicotinamide’s potential mechanisms of action
are discussed, including the general maintenance of cellular energy
levels and the more specific inhibition of molecules such as the
nicotinamide adenine dinucleotide-dependent deacetylase, sirtuin 1
(SIRT1).
Introduction
There
is a growing body of evidence that diet and nutrition play a direct
role in maintaining neuronal health. In particular, dietary factors can
influence the onset and progression of Parkinson’s disease (PD), and
potentially its amelioration.1,2
The emerging pattern from this body of research is that there are clear
consequences to an imbalance in dietary factors on the production and
maintenance of mature neurons.
Our research
and that of others suggest that vitamins are essential both for the
formation of neurons and their survival. Here, we review nicotinamide
and associated active metabolites. We discuss nicotinamide’s role in the
maintenance of mature central nervous system (CNS) neurons; its
influence on neuronal health and survival during ageing, injury, and
disease; and its potential as a therapeutic for neurodegenerative
disease.
Vitamins and Their Role in Health
During
the last century, a new class of nutritional supplements was
identified. These ‘vitamins’ were defined as biologically active organic
compounds essential for normal health and growth, which cannot, or can
only partially, be synthesised by the human body. Grouped by their
biological and chemical activity, 13 classes of vitamins (Table 1)
are currently recognised, having diverse biochemical functions such as
regulation of cell and tissue growth, mineral metabolism, acting as
coenzymes in metabolism, and directing cell differentiation.3
Thus, vitamins are essential for the development and maintenance of the
body, with their deficiencies leading to conditions affecting multiple
systems, such as pellagra, scurvy, rickets, bleeding disorders, and
vulnerability to infections.4 If untreated, vitamin deficiencies can lead to significant ill health and potentially death.
Table 1. The thirteen recognised classes of vitamins and their roles.
Vitamin
Other names
Examples of physiological functions
Vitamin A
Retinol, retinoic acid, retinal, carotenoid
Growth, maintenance of skin, bone development, maintenance of myelin, maintenance of vision
Vitamin B1
Thiamine
Growth, appetite, digestion, nerve activity, energy production
Vitamin B2
Riboflavin
Growth and development of foetus, redox systems, and respiratory enzymes; maintenance of mucosal, epithelial, and eye tissues
Vitamin B3
Nicotinamide, niacinamide, nicotinic acid, niacin
Maintenance of NAD and NADP, coenzyme in lipid catabolism, oxidative deamination
Vitamin B5
Pantothenic acid
Lipid metabolism, protein metabolism, part of coenzyme A in carbohydrate metabolism
Vitamin B6
Pyridoxine, pyridoxol, adermine
Growth; protein, CHO, and lipid metabolism; coenzyme in amino acid metabolism
Vitamin B7
Biotin, protective factor X
Growth; maintenance of skin, hair, bone marrow, and sex glands; biosynthesis of aspartate and unsaturated fatty acids
Vitamin B9
Folic acid, folacin, folinic acid
Synthesis of nucleic acid, differentiation of embryonic nervous system
Vitamin B12
Cobalamin
Coenzyme in nucleic acid, protein, and lipid synthesis; maintenance of epithelial cells and nervous system
Vitamin C
Ascorbic acid
Absorption
of iron, antioxidant, growth, wound healing, formation of cartilage,
dentine, bone and teeth, maintenance of capillaries
Vitamin D
Vitamin D3, cholecalciferol, calcitriol
Normal
growth, Ca and P absorption, maintains and activates alkaline
phosphatase in bone, maintains serum calcium and phosphorus levels
Vitamin E
Tocopherol, Tokopharm, tocotrienols
Antioxidant,
growth maintenance, aids absorption of unsaturated fatty acids,
maintains muscular metabolism and integrity of vascular system and
central nervous system
Vitamin K
Prothrombin factor, menaquinones
Blood-clotting mechanisms, electron transport mechanisms, growth, prothrombin synthesis in liver
Nicotinamide, Nicotinamide Adenine Dinucleotide, and Neuronal Health
Nicotinamide, the water-soluble amide form of vitamin B3,
is a key component of the metabolic pathway involved in the production
of nicotinamide adenine dinucleotide (NAD+). One source of nicotinamide
is the diet, via intake of eggs, meat, fish, and mushrooms. A second
source of nicotinamide is the metabolism of endogenous tryptophan, an
essential amino acid. Nicotinamide can also be generated from niacin via
the formation of NAD+.
Nicotinamide is
stored in only small quantities in the liver, with most being either
excreted or catabolised to provide other key metabolic products. It is
difficult to achieve adverse effects from excessive intake, even with
pharmacologically high doses, but overdose can cause hepatotoxicity in
rare cases.5
The
enzyme, nicotinamide phosphoribosyltransferase (NAMPT), catalyses the
synthesis of nicotinamide mononucleotide (NMN) from nicotinamide (Figure 1).
Its role in the metabolic pathway for the biosynthesis of NAD (oxidised
form NAD+; reduced form NADH) suggests its importance in cells that are
sensitive to decreases in NAD levels, such as neurons.6 NAD homeostasis has also been found to be altered with ageing7–10;
thus, by influencing levels of NAD+ within neurons, nicotinamide may
play a key role in neuronal maturation and neuroprotection.
Figure 1.
Simplified schematic representation of the key pathways for the
metabolism of nicotinamide, niacin, and tryptophan in the production of
NAD+.
The enzyme NMN adenylyltransferase (NMNAT) converts NMN to NAD+ (Figure 1). Three isozymes, NMNAT1, 2, and 3, are localised to the nucleus, cytoplasm, or mitochondria, respectively.11
An increase in NMNAT activity has been shown to lead to axonal
protection in cultured neurons undergoing Wallerian degeneration,
through a rise in nuclear NAD levels, leading to activation of the
NAD-dependent protein deacetylase sirtuin 1 (SIRT1),12,13 implicating nicotinamide indirectly in neuroprotection.
In humans, nicotinamide undergoes some level of degradation, primarily through N-methylation to N-methyl nicotinamide via activity of the enzyme nicotinamide N-methyltransferase
(NNMT). As mentioned above, the remaining metabolism of nicotinamide
produces the NAD coenzymes in both the oxidised and reduced forms (NAD+
and NADH) in addition to nicotinamide adenine nucleotide phosphate,
which is vital in mitochondrial respiration to produce adenosine
triphosphate (ATP), as well as being implicated in more than 200
enzymatic reactions including those conferring cell protective and
antioxidant roles (Figure 1).14–16
NAD+ can also be generated via tryptophan metabolism within the liver and kidneys17
and from dietary nicotinic acid and niacin. Tryptophan can be
metabolised into small amounts of nicotinic acid mononucleotide (NAMN)
that can then be converted to NAD+. However, 60 mg of tryptophan is
required to yield the equivalent amount of NAMN generated from 1 mg of
niacin.18 Therefore, tryptophan is not a necessary supplement to many Western, niacin-rich diets,19 although tryptophan alone can be enough to prevent niacin deficiency.17 Tryptophan metabolism is a 9-step process and the first part of this, known as the kynurenine pathway,17 is altered in a number of neurodegenerative diseases including PD, Huntington’s disease (HD), and Alzheimer’s disease (AD)20,21 as well as other neurological disorders.22 This disruption may increase the production of neurotoxins21–23
while also reducing NAD+ levels, leaving neurons more susceptible to
damage. Thus, the finely balanced relationship between nicotinamide and
NAD+ may greatly influence neuronal health. undergoes some level of degradation, primarily through N-methylation to N-methyl nicotinamide via activity of the enzyme nicotinamide N-methyltransferase
(NNMT). As mentioned above, the remaining metabolism of nicotinamide
produces the NAD coenzymes in both the oxidised and reduced forms (NAD+
and NADH) in addition to nicotinamide adenine nucleotide phosphate,
which is vital in mitochondrial respiration to produce adenosine
triphosphate (ATP), as well as being implicated in more than 200
enzymatic reactions including those conferring cell protective and
antioxidant roles (Figure 1).14–16
NAD+ can also be generated via tryptophan metabolism within the liver and kidneys17
and from dietary nicotinic acid and niacin. Tryptophan can be
metabolised into small amounts of nicotinic acid mononucleotide (NAMN)
that can then be converted to NAD+. However, 60 mg of tryptophan is
required to yield the equivalent amount of NAMN generated from 1 mg of
niacin.18 Therefore, tryptophan is not a necessary supplement to many Western, niacin-rich diets,19 although tryptophan alone can be enough to prevent niacin deficiency.17 Tryptophan metabolism is a 9-step process and the first part of this, known as the kynurenine pathway,17 is altered in a number of neurodegenerative diseases including PD, Huntington’s disease (HD), and Alzheimer’s disease (AD)20,21 as well as other neurological disorders.22 This disruption may increase the production of neurotoxins21–23
while also reducing NAD+ levels, leaving neurons more susceptible to
damage. Thus, the finely balanced relationship between nicotinamide and
NAD+ may greatly influence neuronal health.
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