Neuronal NAMPT is Released after Cerebral Ischemia and Protects against White Matter Injury

Zheng, Jing; Xing, Juan; Chen, Xinzhi; Stetler, R. Anne; Weng, Zhen; Gan, Yu; Zhang, Feng; Gao, Yanqin; Chen, Jun; Leak, Rehana K.; Cao, Guodong

doi:10.1038/jcbfm.2014.119

Cited by 54 publications

(42 citation statements)

References 27 publications

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“…Regional cerebral blood flow was reduced similarly by 93.5 % and 92.4 % in AQP4 +/+ and AQP4 −/− mice during occlusion, and was restored at 15 min after reperfusion to 44.9 % and 47.1 % of baseline values before occlusion. These results are typical of reported MCAO studies in mice [9, 29]. …”

Section: Resultssupporting

confidence: 90%

Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia

Yao

Derugin

Manley

et al. 2015

Neuroscience Letters

103

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Aquaporin-4 (AQP4) is a water channel expressed in astrocyte end-feet lining the blood-brain barrier. AQP4 deletion in mice is associated with improved outcomes in global cerebral ischemia produced by transient carotid artery occlusion, and focal cerebral ischemia produced by permanent middle cerebral artery occlusion (MCAO). Here, we investigated the consequences of 1-hour transient MCAO produced by intraluminal suture blockade followed by 23 hours of reperfusion. In nine AQP4+/+ and nine AQP4−/− mice, infarct volume was significantly reduced by an average of 39 ± 4 % at 24 hours in AQP4−/− mice, cerebral hemispheric edema was reduced by 23 ± 3 %, and Evans blue extravasation was reduced by 31 ± 2 % (mean ± SEM). Diffusion-weighted magnetic resonance imaging showed greatest reduction in apparent diffusion coefficient around the occlusion site after reperfusion, with remarkably lesser reduction in AQP4−/− mice. The reduced infarct volume in AQP4−/− mice following transient MCAO supports the potential utility of therapeutic AQP4 inhibition in stroke.

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Section: Resultssupporting

confidence: 90%

Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia

Yao

Derugin

Manley

et al. 2015

Neuroscience Letters

103

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“…Similar observations were made in a mouse model [18,83]. Both eNAMPT and iNAMPT protein expression was detectable with two different NAMPT antibodies in WT C57BL/6 mice.…”

Section: Roles Of Nampt In Brain Ischemiasupporting

confidence: 83%

“…We then provided evidence that the protective effects are mediated by eNAMPT. Conditioned medium from NAMPT-overexpressing neurons exposed to OGD protected cultured oligodendrocytes from OGD and these effects were abolished with neutralizing antibodies [18]. Thus, we concluded that NAMPT may not function simply in a restricted intracellular manner during stroke recovery but that it protects both gray matter and WM from stroke injury through extracellular actions.…”

Section: Roles Of Nampt In Brain Ischemiamentioning

confidence: 95%

The Role of Nicotinamide Phosphoribosyltransferase in Cerebral Ischemia

Chen

Zhao²,

Song³

et al. 2015

CTMC

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Recombinant tissue plasminogen activator is the only drug approved for the clinical treatment of acute ischemic stroke. Thus, 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 nicotinamidephosphoribosyl-transferase (NAMPT) is an attractive candidate to improve post-stroke recovery. As a multifunctional protein, NAMPT 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, 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 improved our understanding of NAMPT. This review focuses on the multifaceted and complex roles of NAMPT under normal and ischemic conditions.

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“…89 Whether eNAMPT exhibits pro-inflammatory or antiinflammatory activity is still the subject of debate. 21,[58][59][60]90,91 However, several studies have reported pro-inflammatory effects of eNAMPT on different cell types, which include induction of inducible nitric oxide synthase, 92 activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2), 66 nuclear factor NF-κB activation 92,93 and production of cytokines such as TNF-α, IL-6, IL-1β, 93,94 transforming growth factor β 95 and monocyte chemoattractant protein 1. 96 Production of inflammatory cytokines and NAMPT expression in adipocytes, thus, seem to be regulated by a positive feedback activation loop.…”

Section: Pathophysiological Role Of Namptmentioning

confidence: 99%

Physiological and pathophysiological roles of NAMPT and NAD metabolism

et al. 2015

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Nicotinamide phosphoribosyltransferase (NAMPT) is a regulator of the intracellular nicotinamide adenine dinucleotide (NAD) pool. NAD is an essential coenzyme involved in cellular redox reactions and is a substrate for NAD-dependent enzymes. In various metabolic disorders and during ageing, levels of NAD are decreased. Through its NAD-biosynthetic activity, NAMPT influences the activity of NAD-dependent enzymes, thereby regulating cellular metabolism. In addition to its enzymatic function, extracellular NAMPT (eNAMPT) has cytokine-like activity. Abnormal levels of eNAMPT are associated with various metabolic disorders. NAMPT is able to modulate processes involved in the pathogenesis of obesity and related disorders such as nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) by influencing the oxidative stress response, apoptosis, lipid and glucose metabolism, inflammation and insulin resistance. NAMPT also has a crucial role in cancer cell metabolism, is often overexpressed in tumour tissues and is an experimental target for antitumour therapies. In this Review, we discuss current understanding of the functions of NAMPT and highlight progress made in identifying the physiological role of NAMPT and its relevance in various human diseases and conditions, such as obesity, NAFLD, T2DM, cancer and ageing.

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Neuronal NAMPT is Released after Cerebral Ischemia and Protects against White Matter Injury

Cited by 54 publications

References 27 publications

Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia

Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia

The Role of Nicotinamide Phosphoribosyltransferase in Cerebral Ischemia

Physiological and pathophysiological roles of NAMPT and NAD metabolism

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