A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds

Lipton, Stuart A.; Choi, Yun-Beom; Pan, Zhuo‐Hua; Lei, Sizheng Z.; Chen, Huei‐Sheng Vincent; Sucher, Nikolaus J.; Loscalzo, Joseph; Singel, David J.; Stamler, Jonathan S.

doi:10.1038/364626a0

Cited by 2,357 publications

(1,364 citation statements)

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“…First, studies have suggested that changes in ambient redox milieu may switch the influence of NO from neurotoxicity to neuroprotection. 15 Secondly, the role of NO seems to depend on the time of NO release and the cellular location of the NOgenerating enzyme. Whereas previous studies on knockout mice in our laboratory indicate an involvement of nNOS in secondary damage after SCI, 16 less is known about the influence of eNOS.…”

Section: Discussionmentioning

confidence: 99%

Improved functional outcome after spinal cord injury in iNOS-deficient mice

2004

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Study design: Functional outcome was evaluated following experimental compression-type spinal cord injury (SCI) in wild-type mice and knockout mice, lacking the inducible nitric oxide synthase (iNOS) gene. Objectives: To evaluate the role of the nitric oxide generating enzyme iNOS in SCI. Methods: The experimental animals were subjected to an extradural compression of the thoracic spinal cord. Functional outcome was studied during the first 2 weeks post-injury using a scoring system for assessment of hind limb motor function. Results: Injury resulted in initial paraplegia followed by gradual improvement of motor function in most cases. Mice lacking the iNOS gene (iNOSÀ/À) clearly tended to have a better functional outcome than wild-type mice. The difference was significant on day 14 after injury. Conclusion: In accordance with a few earlier experimental studies, showing beneficial effects of pharmacological iNOS inhibition, the present report would indicate a destructive influence of iNOS following spinal cord trauma.

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Section: Discussionmentioning

confidence: 99%

Improved functional outcome after spinal cord injury in iNOS-deficient mice

2004

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“…41,42 The mechanisms of extracellular EAA accumulation after SCI may include both increasing release from vesicles, injured cells or blood and decreasing uptake by astrocytes and neurons. 41,43 Intrathecal administration of NMDA, at a dose with no e ects on uninjured animals, signi®cantly worsens recovery after SCI. 21 On the basis of these ®ndings, several investigators analyzed NMDA receptor antagonists for the treatment of experimental SCI or ischemia.…”

Section: Discussionmentioning

confidence: 99%

Effects of MK801 on evoked potentials, spinal cord blood flow and cord edema in acute spinal cord injury in rats

Tator

1999

Spinal Cord

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Objectives: To determine whether MK801, an NMDA receptor antagonist, blocks glutamate excitotoxicity directly or via other mechanisms such as improving blood supply at the injury site in a rat model of spinal cord injury (SCI). In the present study, the e ects of pre-and posttreatment with MK801 on axonal function, spinal cord blood¯ow (SCBF) and cord water content were studied after acute SCI in rats. Methods: Somatosensory evoked potentials (SSEPs) and cerebellar evoked potentials (CEPs) were used to quantify electrophysiological function, and the hydrogen clearance technique and wet-dry weight measurements were used to measure SCBF and cord water content, respectively. Twenty rats received a 21 g clip compression injury of the cord at T1, and were then randomly and blindly allocated to either MK801 or saline groups. Each rat received an intravenous infusion of drug or saline four times during the experiment (16 min/infusion) with the ®rst infusion (MK801 3 mg/kg) beginning 8 min pre-injury, and the other infusions (MK801 1.5 mg/kg) at 1 h intervals after injury. Control experiments on uninjured rats were performed in 10 rats using the same procedure as above except the clip compression injury of the cord was omitted. Results: In the MK801 groups with or without SCI, the amplitude of the evoked potential peaks, especially the SSEPs, was signi®cantly lower than in the saline group. There were no di erences in SCBF or cord water content between the MK801 and saline groups. Conclusion: Pre-and posttreatment with MK801 inhibits evoked potentials, but does not improve SCBF or cord edema after acute compression SCI in rats. For the ®rst time it has been shown that MK801 produced a blockade of glutamate excitatory transmission in a erent pathways after SCI. Further work is required to determine whether this inhibition is reversible and related to neuroprotection and functional recovery after SCI.

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“…Besides a role in differentiation and synaptic plasticity, NO • has also been implicated in neuronal apoptosis, and consequently, in neurodegenerative diseases, specifically when NO • production is increased to toxic levels [49,64,77,123,202]. In particular, NO • has been linked to the phenomenon of excitotoxicity involving the over-stimulation of the NMDA receptor by glutamate, subsequently triggering a strong intracellular accumulation of Ca 2+ [141].…”

Section: Nitric Oxide and Mapk Signalingmentioning

confidence: 99%

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

Schroeter

Boyd

Spencer

et al. 2002

Neurobiology of Aging

302

176

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Oxidative and nitrosative stress is increasingly associated with the pathology of neurodegeneration and aging. The molecular mechanisms underlying oxidative/nitrosative stress-induced neuronal damage are emerging and appear to involve a mode of death in which mitogen-activated protein kinase (MAPK) signaling pathways are strongly implicated. Thus, attention is turning towards the modulation of intracellular signaling as a therapeutic approach against neurodegeneration. Both endogenous and dietary agents have been suggested as potent modulators of intracellular signal transduction, e.g. nitric oxide and flavonoids, respectively. This review addresses recent findings on the biological effects of flavonoids and nitric oxide in neurodegeneration and aims to elucidate the rationale for their prospective use as modulators of cellular signal transduction. © 2002 Elsevier Science Inc. All rights reserved.Keywords: Apoptosis; Oxidative stress; Neuron; Flavonoids; MAP kinase; JNK; ERK; Epicatechin; Nitric oxide; Mitochondria; Redox status; Polyphenols Abbreviations: AKT, serine/threonine kinase (also known as protein kinase B); AP-1, activator protein-1; Apaf-1, apoptosis protease activating factor-1; ASK1, apoptosis signal-regulating kinase-1; Bad, Bcl-2/BclX Lassociated death promoting protein; Bax, pro-apoptotic protein of the Bcl-2 family; Bcl-2, B-cell lymphoma 2: protein with anti-apoptotic properties; BclX L , long form of Bclx: anti-apoptotic protein of the Bcl-2 family; Caspase, cysteinyl aspartic acid-protease; c-Jun, mammalian equivalent of Jun: part of the AP-1 transcription complex; CREB, cAMP response element binding protein; DIABLO/smac, mitochondria-related pro-apoptotic protein: inhibits XIAP; ERK1/2, extracellular signal-related kinase; Fas, CD95: member of the TNF receptor family; GSHST, glutathione Stransferase; JNK, c-Jun amino-terminal kinase; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MEK1/2, ERK1/2-specific MAPKK; MKK4/7, JNK-specific MAPKK; MSK1, mitogen-and stress-activated kinase-1; NF-B, nuclear factor of immunoglobulin k locus in B-cells; ONOO − , peroxynitrite anion; p53, pro-apoptotic tumor suppressor gene product; PI3-kinase, phosphoinositol 3-kinase; Ras, small G-protein; RNS, reactive nitrogen species; ROS, reactive oxygen species; RSK, pp90 ribosomal S6 kinase; SAPK, stressactivated protein kinase; XIAP, X-linked inhibitor of apoptosis: inhibits the activation of caspase-9

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A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds

Cited by 2,357 publications

References 30 publications

Improved functional outcome after spinal cord injury in iNOS-deficient mice

Improved functional outcome after spinal cord injury in iNOS-deficient mice

Effects of MK801 on evoked potentials, spinal cord blood flow and cord edema in acute spinal cord injury in rats

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

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