The NAD(+)-Dependent Family of Sirtuins in Cerebral Ischemia and Preconditioning

Significance: Sirtuins are an evolutionarily conserved family of NAD(+)-dependent lysine deacylases and ADP ribosylases. Their requirement for NAD(+) as a cosubstrate allows them to act as metabolic sensors that couple changes in the energy status of the cell to changes in cellular physiological processes. NAD(+) levels are affected by several NAD(+)-producing and NAD(+)-consuming pathways as well as by cellular respiration. Thus their intracellular levels are highly dynamic and are misregulated in a spectrum of metabolic disorders including cerebral ischemia. This, in turn, compromises several NAD(+)-dependent processes that may ultimately lead to cell death. Recent Advances: A number of efforts have been made to replenish NAD(+) in cerebral ischemic injuries as well as to understand the functions of one its important mediators, the sirtuin family of proteins through the use of pharmacological modulators or genetic manipulation approaches either before or after the insult. Critical Issues and Future Directions: The results of these studies have regarded the sirtuins as promising therapeutic targets for cerebral ischemia. Yet, additional efforts are needed to understand the role of some of the less characterized members and to address the sex-specific effects observed with some members. Sirtuins also exhibit cell-type-specific expression in the brain as well as distinct subcellular and regional localizations. As such, they are involved in diverse and sometimes opposing cellular processes that can either promote neuroprotection or further contribute to the injury; which also stresses the need for the development and use of sirtuin-specific pharmacological modulators.