The Role of Nicotinamide Phosphoribosyltransferase in Cerebral Ischemia
2015
As recombinant tissue plasminogen activator is the only drug approved for the clinical treatment
of acute ischemic stroke, there is an urgent unmet need for novel stroke treatments. Endogenous
defense mechanisms against stroke may hold the key to new therapies for stroke. A large number of
studies suggest that nicotinamide phosphoribosyl-transferase (NAMPT) is an attractive candidate to improve
post-stroke recovery. NAMPT is a multifunctional protein and plays important roles in immunity, metabolism, aging,
inflammation, and stress responses. NAMPT exists in both the intracellular and extracellular space. As a rate-limiting enzyme,
the intracellular form (iNAMPT) catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide
(NAD) from nicotinamide. iNAMPT closely regulates energy metabolism, enhancing the proliferation of endothelial cells,
inhibiting apoptosis, regulating vascular tone, and stimulating autophagy in disease conditions such as stroke. Extracellular
NAMPT (eNAMPT) is also known as visfatin (visceral fat–derived adipokine) and has pleotropic effects. It is widely believed
that the diverse biological functions of eNAMPT are attributed to its NAMPT enzymatic activity. However, the effects
of eNAMPT on ischemic injury are still controversial. Some authors have argued that eNAMPT exacerbates ischemic
neuronal injury non-enzymatically by triggering the release of TNF-α from glial cells. In addition, NAMPT also participates
in several pathophysiological processes such as hypertension, atherosclerosis, and ischemic heart disease. Thus, it remains
unclear under what conditions NAMPT is beneficial or destructive. Recent work using in vitro and in vivo genetic/
pharmacologic manipulations, including our own studies, has greatly improved our understanding of NAMPT. This
review focuses on the multifaceted and complex roles of NAMPT under both normal and ischemic conditions.
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