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

Abstract

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. Antioxid. Redox Signal. 28, 691-710.

Uncovering the Potential Differentially Expressed miRNAs and mRNAs in Ischemic Stroke Based on Integrated Analysis in the Gene Expression Omnibus Database

“…SIRT4 is strongly expressed in astrocytes in the postnatal brain (specifically in the mitochondria) and reduced during development [44]. It is worth mentioning that SIRT4 associates with cerebral ischemia [45]. SERPINH1, expressed in vascular smooth muscle cells of the brain, is involved in atherosclerosis [46].…”

SIRT1 activation with neuroheal is neuroprotective but SIRT2 inhibition with AK7 is detrimental for disconnected motoneurons

“…We previously showed that SIRT1 activation was necessary for NH neuroprotection, although this drug composition targets multiple proteins 5 . SIRT1 has been shown to be important for neuroprotection in several models of neurodegenerative diseases (e.g., Alzheimer’s disease, Huntington’s disease) 29 – 31 and is crucial in cerebral ischemia and preconditioning 32 . We demonstrated herein that either NH-induced activation or overexpression of SIRT1 boost endogenous mechanisms of neuroprotection after injury, as it is the ATF6-GRP78 branch of UPR 5 .…”

Brain SIRT1 Mediates Metabolic Homeostasis and Neuroprotection

“…Sirtuins are homologs of yeast silent information regulator 2 (Sir2). Sir2 has attracted the attention of researchers given its involvement in longevity ( 1 ). The mammalian sirtuins (SIRT1-7) have different subcellular localizations.…”

“…In glycolysis, NAD + is reduced to NADH. In oxidative phosphorylation and cellular respiration, NADH is oxidized to NAD + by electron transport chain (ETC) ( 1 ). As such, NAD + concentrations fluctuate with cellular metabolic status and nutrient availability.…”