Trends in Pharmacological Sciences
Nicotinamide: necessary nutrient emerges as a novel cytoprotectant for the brain
Section snippets
Nicotinamide and apoptosis
Apoptosis, also termed programmed cell death, is thought to make a major contribution to cellular injury and brain dysfunction during a variety of neurological disorders such as ischemic stroke 14, 15, dementia [16] and Parkinson's disease [17]. Exposure of membrane phosphatidylserine (PS) and DNA fragmentation are two, functionally independent processes that lead to apoptosis. One pathway involves the externalization of membrane PS residues, which marks injured cells for phagocytosis and
Nicotinamide, protein kinase B, mitochondrial membrane potential and cytochrome c
Cytoprotection by nicotinamide in the CNS occurs at a series of distinct levels. Initially, nicotinamide might be dependent on the activation of protein kinase B (also known as Akt). Activation of Akt by phosphorylation plays a principal role in the control of apoptosis. A significant downstream substrate of Akt activation includes the forkhead transcription factor (FKHRL1) [24]. Phosphorylation of FKHRL1 leads to its association with 14-3-3 protein and retention in the cytoplasm. Thus, FKHRL1
Nicotinamide and cysteine protease activity
Caspase activation is responsible for cellular morphological alteration during apoptosis, including DNA fragmentation, chromatin condensation and externalization of membrane PS residues. Subsequent to depolarization of the mitochondrial membrane and release of cytochrome c, caspase activation is induced. Insults such as anoxia and NO can directly stimulate caspase-1 and caspase-3-like activities, which precipitate DNA fragmentation and membrane PS exposure 3, 4, 30. Caspase-8 is the upstream
Nicotinamide, poly(ADP-ribose) polymerase (PARP) and cellular energy
PARP is a nuclear protein that binds to DNA-strand breaks and cleaves NAD+ into nicotinamide and ADP-ribose [32]. During cell injury involving DNA-strand breaks, PARP is required for DNA repair. The ADP-ribose is subsequently polymerized onto nuclear proteins, including histones and transcription factors, at DNA-strand breaks [33]. However, excessive activity of PARP might be detrimental to cellular function. Augmented activation of PARP leads to a rapid depletion of NAD+, its sole substrate,
Nicotinamide-independent pathways: pH and MAP kinases
In the nervous system, toxic insults such as hypoxia can result in the disturbance of intracellular pH [36] and a biphasic, transient, intracellular acidification that directly precipitates cellular degeneration can occur within 15–30 min [4]. Although nicotinamide might protect against apoptosis through multiple cellular pathways, it does not appear to regulate intracellular acidification. Nicotinamide does not directly prevent the induction of intracellular acidification [4] and cannot
Concluding remarks
With its initial roots as a nutritive agent, nicotinamide continues to advance as a ‘broad spectrum’ cytoprotectant that impacts on both neuronal and vascular physiology (Table 1). The protection offered by nicotinamide through the maintenance of DNA integrity and the preservation of membrane PS asymmetry prevents acute cellular injury, secondary thrombosis, clot formation and inflammation. Cytoprotection occurs through a series of distinct pathways that involve the activation of Akt,
Acknowledgments
This research was supported by the following grants (K.M.): American Heart Association (National), Janssen Neuroscience Award, Johnson and Johnson Focused Investigator Award, LEARN Foundation, MI Life Sciences Challenge Award, and NIH NIEHS (P30 ES06639).
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