Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1‐dependent adenosine monophosphate–activated kinase pathway

Wang, Pei; Xu, Tao; Guan, Yongjun; Tian, Wen; Viollet, Benoı̂t; Rui, Yao-Cheng; Zhai, Qiwei; Su, Ding‐Feng; Miao, Chao‐Yu

doi:10.1002/ana.22236

Cited by 256 publications

(286 citation statements)

References 32 publications

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“…A recent study reports that nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD biosynthesis, protects against ischemic stroke in rodents (53). Given that Nampt and Nmnat1 are in the NAD-synthesis pathway, they may share similar mechanistic pathways in protection against ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Verghese

Sasaki

Yang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxic-ischemic (H-I) injury to the developing brain is a significant cause of morbidity and mortality in humans. Other than hypothermia, there is no effective treatment to prevent or lessen the consequences of neonatal H-I. Increased expression of the NAD synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1 (Nmnat1) has been shown to be neuroprotective against axonal injury in the peripheral nervous system. To investigate the neuroprotective role of Nmnat1 against acute neurodegeneration in the developing CNS, we exposed wild-type mice and mice overexpressing Nmnat1 in the cytoplasm (cytNmnat1-Tg mice) to a well-characterized model of neonatal H-I brain injury. As early as 6 h after H-I, cytNmnat1-Tg mice had strikingly less injury detected by MRI. CytNmnat1-Tg mice had markedly less injury in hippocampus, cortex, and striatum than wild-type mice as assessed by loss of tissue volume 7 d days after H-I. The dramatic protection mediated by cytNmnat1 is not mediated through modulating caspase3-dependent cell death in cytNmnat1-Tg brains. CytNmnat1 protected neuronal cell bodies and processes against NMDA-induced excitotoxicity, whereas caspase inhibition or B-cell lymphoma-extra large (Bcl-XL) protein overexpression had no protective effects in cultured cortical neurons. These results suggest that cytNmnat1 protects against neonatal HI-induced CNS injury by inhibiting excitotoxicity-induced, caspase-independent injury to neuronal processes and cell bodies. As such, the Nmnat1 protective pathway could be a useful therapeutic target for acute and chronic neurodegenerative insults mediated by excitotoxicity.

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Section: Discussionmentioning

confidence: 99%

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Verghese

Sasaki

Yang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…It has been reported that increases in Nampt expression increase NAD þ levels and the NAD þ /NADH ratio. 6,14,15 Since our previous experiments identified PKCe as a regulator of mitochondrial Nampt, we now wanted to determine whether PKCe has a role in regulating mitochondrial levels of NAD þ , NADH, and the NAD þ /NADH ratio in the cortex.…”

Section: Protein Kinase C Epsilon Is a Major Regulator Of Amp-activatedmentioning

confidence: 99%

Protein Kinase C Epsilon Regulates Mitochondrial Pools of Nampt and NAD Following Resveratrol and Ischemic Preconditioning in the Rat Cortex

Morris-Blanco

Cohan

Neumann

et al. 2014

J Cereb Blood Flow Metab

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Preserving mitochondrial pools of nicotinamide adenine dinucleotide (NAD) or nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in NAD production, maintains mitochondrial function and confers neuroprotection after ischemic stress. However, the mechanisms involved in regulating mitochondrial-localized Nampt or NAD have not been defined. In this study, we investigated the roles of protein kinase C epsilon (PKCe) and AMP-activated protein kinase (AMPK) in regulating mitochondrial pools of Nampt and NAD after resveratrol or ischemic preconditioning (IPC) in the cortex and in primary neuronal-glial cortical cultures. Using the specific PKCe agonist ceRACK, we found that PKCe induced robust activation of AMPK in vitro and in vivo and that AMPK was required for PKCe-mediated ischemic neuroprotection. In purified mitochondrial fractions, PKCe enhanced Nampt levels in an AMPK-dependent manner and was required for increased mitochondrial Nampt after IPC or resveratrol treatment. Analysis of intrinsic NAD autofluorescence using two-photon microscopy revealed that PKCe modulated NAD in the mitochondrial fraction. Further assessments of mitochondrial NAD concentrations showed that PKCe has a key role in regulating the mitochondrial NAD þ / nicotinamide adenine dinucleotide reduced (NADH) ratio after IPC and resveratrol treatment in an AMPK-and Nampt-dependent manner. These findings indicate that PKCe is critical to increase or maintain mitochondrial Nampt and NAD after pathways of ischemic neuroprotection in the brain.

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“…Nicotinamide phosphoribosyltransferase therefore plays a key role in the regulation of energy metabolism and stress responses. Previous studies indicated that lentivirus-mediated NAMPT overexpression is neuroprotective against ischemic brain injury, 11 while genetic deletion of NAMPT exacerbates ischemic brain injury. 12 Specifically, Wang and colleagues reported that NAMPT upregulation is part of a natural stress response to ischemic injury and that it protects gray matter through sirtuin 1-dependent modulation of the adenosine monophosphate-activated kinase pathway.…”

Section: Introductionmentioning

confidence: 99%

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

Zheng

Xing

Chen

et al. 2014

J Cereb Blood Flow Metab

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Nicotinamide phosphoribosyltransferase (NAMPT) has been implicated in neuroprotection against ischemic brain injury, but the mechanism underlying its protective effect remains largely unknown. To further examine the protective effect of NAMPT against ischemic stroke and its potential mechanism of action, we generated a novel neuron-specific NAMPT transgenic mouse line. Transgenic mice and wild-type littermates were subjected to transient occlusion of the middle cerebral artery (MCAO) for 60 minutes. Neuron-specific NAMPT overexpression significantly reduced infarct volume by 65% (P ¼ 0.018) and improved long-term neurologic outcomes (Pr0.05) compared with littermates. Interestingly, neuronal overexpression of NAMPT increased the area of myelinated fibers in the striatum and corpus callosum, indicating that NAMPT protects against white matter injury. The mechanism of protection appeared to be through extracellular release of NAMPT. First, NAMPT was secreted into the extracellular medium by primary cortical neurons exposed to ischemia-like oxygen-glucose deprivation (OGD) in vitro. Second, conditioned medium from NAMPT-overexpressing neurons exposed to OGD protected cultured oligodendrocytes from OGD. Third, the protective effects of conditioned medium were abolished by antibody-mediated NAMPT depletion, strongly suggesting that the protective effect is mediated by the extracellular NAMPT released into in the medium. These data suggest a novel neuroprotective role for secreted NAMPT in the protection of white matter after ischemic injury.

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Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1‐dependent adenosine monophosphate–activated kinase pathway

Abstract: Our findings reveal that Nampt protects against ischemic stroke through rescuing neurons from death via the SIRT1-dependent AMPK pathway and indicate that Nampt is a new therapeutic target for stroke.

Cited by 256 publications

References 32 publications

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death

Protein Kinase C Epsilon Regulates Mitochondrial Pools of Nampt and NAD Following Resveratrol and Ischemic Preconditioning in the Rat Cortex

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

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