NAD+ plays crucial roles in a variety of biological processes including energy metabolism, aging, and calcium homeostasis. Multiple studies have also shown that NAD+ administration can profoundly decrease oxidative cell death and ischemic brain injury. A number of recent studies have further indicated that NAD+ administration can decrease ischemic brain damage, traumatic brain damage and synchrotron radiation X-ray-induced tissue injury by such mechanisms as inhibiting inflammation, decreasing autophagy, and reducing DNA damage. Our latest study that applies nano-particles as a NAD+ carrier has also provided first direct evidence demonstrating a key role of NAD+ depletion in oxidative stress-induced ATP depletion. Poly(ADP-ribose) polymerase-1 (PARP-1) and sirtuins are key NAD+-consuming enzymes that mediate multiple biological processes. Recent studies have provided new information regarding PARP-1 and sirtuins in cell death, ischemic brain damage and synchrotron radiation X-ray-induced tissue damage. These findings have collectively supported the hypothesis that NAD+ metabolism, PARP-1 and sirtuins play fundamental roles in oxidative stress-induced cell death, ischemic brain injury, and radiation injury. The findings have also supported “the Central Regulatory Network Hypothesis”, which proposes that a fundamental network that consists of ATP, NAD+ and Ca2+ as its key components is the essential network regulating various biological processes. 1. Introduction Increasing evidence has indicated that NAD+ plays important roles not only in energy metabolism and mitochondrial functions but also in aging, gene expression, calcium homeostasis, and immune functions [1–3]. Because cell death plays pivotal roles in multiple biological processes and major diseases, it is of critical importance to generalize the information regarding the roles of NAD+ and NAD+-dependent enzymes, such as PARP-1, sirtuins, and CD38, in cell death. Brain ischemia is one of the major causes of death and disability around the world [4]. A number of studies have also suggested that NAD+ metabolism and NAD+-dependent enzymes may play significant roles in ischemic brain damage [1, 2, 5]. For examples, administration of either NAD+ [6] or PARP inhibitors [7] has been shown to profoundly decrease ischemic brain damage. In recent years, the information regarding the roles of NAD+, PARP-1, and sirtuins in various biological functions has been rapidly increasing [8–14]. A number of recent studies have also suggested novel mechanisms underlying the roles of NAD+, PARP-1, and sirtuins in cell
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