The vitamin nicotinamide: translating nutrition into clinical care

Abstract

Nicotinamide, the amide form of vitamin B(3) (niacin), is changed to its mononucleotide compound with the enzyme nicotinic acide/nicotinamide adenylyltransferase, and participates in the cellular energy metabolism that directly impacts normal physiology. However, nicotinamide also influences oxidative stress and modulates multiple pathways tied to both cellular survival and death. During disorders that include immune system dysfunction, diabetes, and aging-related diseases, nicotinamide is a robust cytoprotectant that blocks cellular inflammatory cell activation, early apoptotic phosphatidylserine exposure, and late nuclear DNA degradation. Nicotinamide relies upon unique cellular pathways that involve forkhead transcription factors, sirtuins, protein kinase B (Akt), Bad, caspases, and poly (ADP-ribose) polymerase that may offer a fine line with determining cellular longevity, cell survival, and unwanted cancer progression. If one is cognizant of the these considerations, it becomes evident that nicotinamide holds great potential for multiple disease entities, but the development of new therapeutic strategies rests heavily upon the elucidation of the novel cellular pathways that nicotinamide closely governs.

Figure 1

Chemical structures of nicotinamide and nicotinic acid.

Figure 2

Nicotinamide prevents nuclear DNA fragmentation during oxidative stress with oxygen-glucose (OGD) deprivation. Representative images illustrate that nicotinamide (12.5 mM) with one hour pretreatment prior to OGD significantly blocked neuronal genomic DNA degradation assessed by terminal deoxynucleotidyl transferase nick end labeling (TUNEL) assay 24 hours after OGD.

Figure 3

Nicotinamide leads to increased cell survival in a specific concentration range. Increasing concentrations of nicotinamide (1-100 mmol/L) were administered one hour prior to oxygen-glucose (OGD) deprivation to primary hippocampal neurons and cell injury was assessed 24 hours later with the trypan blue dye exclusion assay. Optimal cellular protection for nicotinamide occurs in the concentration range of 5.0 - 25.0 mmol/L.

Figure 4

Nicotinamide prevents mitochondrial membrane depolarization during oxidative stress. Oxygen-glucose deprivation (OGD) produces a significant decrease in the red/green fluorescence intensity ratio of mitochondria using a cationic membrane potential indicator JC-1 within six hours when compared with untreated control cultures, demonstrating that OGD results in mitochondrial membrane depolarization. Pretreatment with nicotinamide one hour prior to OGD significantly increases the red/green fluorescence intensity of mitochondria, indicating that membrane potential is restored by nicotinamide.

Figure 5

Nicotinamide relies upon novel cellular pathways to impact cell survival, longevity, and immune system function. Nicotinamide controls apoptotic early phosphatidylserine exposure, DNA repair and degradation, cell longevity, and immune cell activation through multiple pathways that involve modulation of sirtuin activity, protein kinase B (Akt), poly (ADP-ribose) polymerase (PARP), forkhead transcription factors, mitochondrial membrane potential (ΔΨ_m), cytochrome c, (Cyto-c), and caspases 1,3, 8, and 9. These pathways can then regulate the onset of early apoptotic injury with phosphatidylserine exposure, late injury with nuclear DNA degradation, and inflammatory cell activation.