Drug Summary: Nicotinamide (also referred to as Vitamin B3) is believed to cause improvements in energy production due to its role as a precursor of NAD (nicotinamide adenosine dinucleotide), an important molecule involved in energy metabolism. Increasing nicotinamide concentrations increase the available NAD molecules that can take part in energy metabolism, thus increasing the amount of energy available in the cell. Nicotinamide has been shown to be effective at curing motor symptoms in a mouse model of HD.
Table of Contents
Nicotinamide and Energy Metabolism^
Nicotinamide is a vitamin that plays an important role in the synthesis of components necessary for the production of ATP. A more familiar term for nicotinamide is Vitamin B3. Vitamin B3 can be found in various meats, peanuts, and sunflower seeds. Nicotinamide is the biologically active form of niacin (also known as nicotinic acid). Both nicotinamide and nicotinic acid, as well as a variation on nicotinic acid, called inosital hexaniacinate, are available as supplements.
The human body receives its necessary quantities of nicotinamide from two sources: diet, as described above, and by synthesizing nictonamide in the body itself. Our body is able to convert tryptophan, an amino acid regularly found in the body, into niacin. Niacin is then converted to nicotinamide, which the body uses for various purposes. Figure J-2 shows a diagram depicting how nicotinamide is produced in the body.
Nicotinamide is sometimes preferred as a supplement because it lacks some of the side effects of niacin. Niacin, but not nicotinamide, has been used as a drug to lower blood cholesterol levels. Nicotinamide, on the other hand, has been found to be effective in arthritis and early-onset Type I diabetes. Nicotinamide is also currently being studied for its effects in improving energy deficits caused by mitochondrial dysfunctions.
Various diseases such as Huntington’s disease, Parkinson’s disease, and mitochondrial disorders are associated with impaired energy metabolism due to various mitochondrial dysfunctions. Nicotinamide is believed to cause improvements in energy production due to its role as a precursor of NAD (nicotinamide adenosine dinucleotide) which is an important molecule involved in energy metabolism. NAD acts as an electron carrier, meaning that it can accept and donate electrons to various enzymes involved in energy metabolism. Specifically, NAD is transformed into NADH when it accepts electrons in a number of reactions involved in glycolysis and the Kreb’s cycle (steps in energy metabolism). NADH then donates its electron to complex I of the electron transport chain. For each pair of electrons passed along the electron transport chain from NADH, a number of ATP molecules are formed. Increasing nicotinamide concentrations increase the available NAD molecules that can take part in energy metabolism, thus increasing the amount of energy available in the cell. Figure J-3 shows an image tracing the role of NAD in the cell.
Nicotinamide can also increase cellular energy by inhibiting the enzyme poly-ADP-ribose polymerase. Under normal conditions, damage to DNA activates poly-ADP-ribose polymerase. When poly-ADP-ribose polymerase is activated, it depletes the supply of NAD by transferring poly-ADP-ribose subunits from NAD to various DNA repair enzymes. The depletion of NAD leads to the depletion of ATP due to the decrease in the activity of both glycolysis and the Kreb’s Cycle. When nicotinamide inhibits the poly-ADP ribose polymerase, it essentially prevents the NAD molecules from becoming depleted.
Relationship between Nicotinamide and Nicotine^
Nicotinamide was one of the first vitamins ever discovered. Around the same time that it was discovered, scientists also found that nicotine, the addictive substance in tobacco products, can be harmful to humans. One of the ways by which nicotine causes deterimental effects in humans is that it has a similar structure to nicotinamide and can interfere with the absorption and incorporation of the vitamin. Figure J-4 shows the structures of nicotinamide and nicotine.
Nicotine competes with nicotinamide for the binding sites in the enzymes needed for the absorption of nicotinamide, thereby lowering the amounts of nicotinamide available to cells. Figure J-5 shows a diagram depicting the competition between nicotinamide and nicotine. This competition results in the depletion of NAD molecules that the cell needs to produce energy. This is one of the reasons why smoking can worsen the condition of people with mitochondrial dysfunction.
Research on Nicotinamide^
Beal, et al. (1994) examined whether Coenzyme Q10, nicotinamide, or riboflavin can block brain lesions produced by a compound that causes a dysfunction in the mitochondria. Coenzyme Q10, also known as ubiquinone, is an antioxidant and an essential component of the electron transport chain. (For more on Coenzyme Q10, click here.) Riboflavin is a precursor of another coenzyme needed by the electron transport chain. (For more on Riboflavin, click here.)
The researchers administered the mitochondrial toxin, malonate, to a group of male rats. Malonate acts as an inhibitor of complex II of the electron transport chain and has been known to disrupt oxidative phosphorylation, leading to lowered ATP concentrations. Administration of malonate has been known to cause lesions in brains due to the deficit in energy.
The measures used by the researchers to assess the efficacy of the various supplements were lesion size after malonate administration and ATP concentrations. The researchers discovered that rats treated with coenzyme Q10 alone or nicotinamide alone showed decreased lesion size, while treatment with riboflavin had no effect on lesion size. Mice treated with a combination of coenzyme Q10 and nicotinamide showed the greatest reduction in lesion size. Furthermore, the combination of coenzyme Q10 and nicotinamide increased ATP concentrations and prevented ATP depletion caused by malonate.
These results suggest that coenzyme Q10 and nicotinamide can block ATP depletions and may improve the efficiency of the electron transport chain. It is therefore possible that coenzyme Q10 and/or nicotinamide may be able to slow the progression of HD, given that inefficiency of the electron transport chain contributes to the progression of HD.
Schulz, et al. (1995) studied the potential neuroprotective effects of Coenzyme Q10 and nicotinamide on mouse models of Parkinson’s disease (PD). Impaired energy metabolism has been found to be associated with some of the symptoms of PD.
To mimic the symptoms seen in people with PD, the researchers administered MPTP, a poison that is toxic to nerve cells. Administration of MPTP disrupts the energy metabolism of cells that release the neurotransmitter dopamine. Specifically, MPTP administration results in an inhibition of complex I of the electron transport chain of dopamine-releasing nerve cells. The impairment in the electron transport chain results in decreased ATP and increased lactate levels in the brains of people with PD. The affected dopamine cells are also unable to release as much glutamate, resulting in decreased dopamine levels in people with PD.
Dopamine concentration in the brain of treated mice was used as a measure of the efficacy of coenzyme Q10 and/or nicotinamide.
The researchers divided the mice into two groups – one group was given water that contained MPTP while another group was given normal water. The mice were then treated with either coenzyme Q10 alone, nicotinamide alone, or a combination of coenzyme Q10 and nicotinamide. They found that in mild cases, the combination of coenzyme Q10 and nicotinamide significantly protected neurons, lowering the rate of dopamine depletion. However, treatment was ineffective in mice with more severe dopamine depletions. Nicotinamide alone produced significant neuroprotective effects and prevented dopamine depletion in mild cases, but coenzyme Q10 alone showed no significant effect.
Hathorn et al. (2011): Scientists studied nicotinamide in a mouse model of Huntington’s disease. They used R6/1 mice that had between 122 and 127 CAG repeats. Each mouse given a dose based on its weight; for every gram that a mouse weighed, it received 250 micrograms of nicotinamide a day. Mice began treatment when they were 8 weeks old, and treatment ended when they were 20 weeks old.
The mice were measured in two ways. First, the behavior of the mice was studied once every two weeks. Scientists found that HD mice treated with nicotinamide were much better at tasks that required motor skills than untreated HD mice. They also found that treated HD mice explored their cages just as much as mice that didn’t have the HD mutation – which is important because HD mice generally move around much less than healthy mice.
Scientists also studied the brains of the mice. They found that levels of BDNF, an important chemical in the brain that promotes neuron health, were restored to normal. There were also increased levels of PGC-1a, a chemical that is involved in energy metabolism in the cell. However, nicotinamide did not decrease protein aggregates, or prevent the late-stage weight loss that HD mice and patients with HD generally experience. The scientists suggested that nicotinamide could be a useful treatment when used in combination with other treatments that reduce protein aggregation and help fight weight loss.
For further reading^
- Beal, et al. “Coenzyme Q10, and Nicotinamide Block Striatal Lesions Produced by the Mitochondrial Toxin Malonate.” Annals of Neurology. 1994; 36(6): 882-88.
This article reports that nicotinamide treatment was able to improve the conditions of cells exposed to a mitochondrial toxin.
- Hathorn T, Snyder-Keller A, Messer A. Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol Dis. 2011 Jan;41(1):43-50. Epub 2010 Aug 22. This technical article describes the study in which HD mice are treated with nicotinamide.
- Schulz, et al. “Coenzyme Q10 and Nicotinamide and a Free Radical Spin Trap Protect against MPTP Neurotoxicity.” Experimental Neurology. 1995; 132: 279-283.
This article reported that nicotinamide treatment improved the condition of mouse models of Parkinson’s Disease.
- Hathorn T, Snyder-Keller A, Messer A. Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington’s disease. Neurobiol Dis. 2011 Jan;41(1):43-50. Epub 2010 Aug 22. This study found that nicotinamide helped relieve symptoms in a mouse model of HD, and is fairly technical
- Vitamin B-3: Niacin. Online.
This web page describes food sources, benefits, recommended daily allowances, as well as warnings and precautions with regards to supplementation.
-E. Tan, 9-22-01; Updated by P. Chang, 5-6-03, updated by M. Hedlin 7-20-11