Sun GY, Horrocks LA, Farooqui AAThe roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases. J Neurochem 103:1-16

Department of Biochemistry, University of Missouri, Columbia, Missouri, USA.
Journal of Neurochemistry (Impact Factor: 4.28). 11/2007; 103(1):1-16. DOI: 10.1111/j.1471-4159.2007.04670.x
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Reactive oxygen species (ROS) are produced in mammalian cells through enzymic and non-enzymic mechanisms. Although some ROS production pathways are needed for specific physiological functions, excessive production is detrimental and is regarded as the basis of numerous neurodegenerative diseases. Among enzymes producing superoxide anions, NADPH oxidase is widespread in mammalian cells and is an important source of ROS in mediating physiological and pathological processes in the cardiovascular and the CNS. ROS production is linked to the alteration of intracellular calcium homeostasis, activation of Ca(2+)-dependent enzymes, alteration of cytoskeletal proteins, and degradation of membrane glycerophospholipids. There is evolving evidence that ROS produced by NADPH oxidase regulate neuronal functions and degrade membrane phospholipids through activation of phospholipases A(2) (PLA(2)). This review is intended to cover recent studies describing ROS generation from NADPH oxidase in the CNS and its downstream activation of PLA(2), namely, the group IV cytosolic cPLA(2) and the group II secretory sPLA(2). A major focus is to elaborate the dual role of NADPH oxidase and PLA(2) in mediating the oxidative and inflammatory responses in neurodegenerative diseases, including cerebral ischemia and Alzheimer's disease. Elucidation of the signaling pathways linking NADPH oxidase with the multiple forms of PLA(2) will be important in understanding the oxidative and degradative mechanisms that underline neuronal damage and glial activation and will facilitate development of therapeutic intervention for prevention and treatment of these and other neurodegenerative diseases.

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Available from: Grace Sun, Apr 10, 2014
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    • "Microglia derived inflammatory cytokines are capable of binding astrocytic cytokine receptors that are coupled to cytosolic phospholipase A2 (cPLA2), and secretory phospholipase A2 (sPLA2) [122]. Activation of these Ca2+-dependent enzymes results in the hydrolysis of membrane phospholipids, liberating arachidonic acid (AA) [123,124], itself a precursor of pro-inflammatory eicosanoids including prostaglandins and leukotrienes [125,126]. "
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    ABSTRACT: Alzheimer's disease (AD) has been reconceptualized as a dynamic pathophysiological process, where the accumulation of amyloid-beta (Abeta) is thought to trigger a cascade of neurodegenerative events resulting in cognitive impairment and, eventually, dementia. In addition to Abeta pathology, various lines of research have implicated neuroinflammation as an important participant in AD pathophysiology. Currently, neuroinflammation can be measured in vivo using positron emission tomography (PET) with ligands targeting diverse biological processes such as microglial activation, reactive astrocytes and phospholipase A2 activity. In terms of therapeutic strategies, despite a strong rationale and epidemiological studies suggesting that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the prevalence of AD, clinical trials conducted to date have proven inconclusive. In this respect, it has been hypothesized that NSAIDs may only prove protective if administered early on in the disease course, prior to the accumulation of significant AD pathology. In order to test various hypotheses pertaining to the exact role of neuroinflammation in AD, studies in asymptomatic carriers of mutations deterministic for early-onset familial AD may prove of use. In this respect, PET ligands for neuroinflammation may act as surrogate markers of disease progression, allowing for the development of more integrative models of AD, as well as for the measuring of target engagement in the context of clinical trials using NSAIDs. In this review, we address the biological basis of neuroinflammatory changes in AD, underscore therapeutic strategies using anti-inflammatory compounds, and shed light on the possibility of tracking neuroinflammation in vivo using PET imaging ligands.
    Journal of Neuroinflammation 07/2014; 11(1):120. DOI:10.1186/1742-2094-11-120 · 5.41 Impact Factor
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    • "These types of inflammatory reactions are stressors for neurons and will be adding to oxidative stress that neurons are subject to. All these in turn will be damaging to mitochondria and other cellular organelles which may lead to further inflammatory reactions in neurons and other cells in CNS (see review by Sun et al. [11]). A key molecule regulating the cellular antioxidant response is the basic region leucine-zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). "
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    ABSTRACT: Nrf2 (nuclear erythroid 2-related factor 2) is a basic region leucine-zipper transcription factor which binds to the antioxidant response element (ARE) and thereby regulates the expression of a large battery of genes involved in the cellular antioxidant and anti-inflammatory defence as well as mitochondrial protection. As oxidative stress, inflammation and mitochondrial dysfunctions have been identified as important pathomechanisms in amyotrophic lateral sclerosis (ALS), this signaling cascade has gained interest both with respect to ALS pathogenesis and therapy. Nrf2 and Keap1 expressions are reduced in motor neurons in postmortem ALS tissue. Nrf2-activating compounds have shown therapeutic efficacy in the ALS mouse model and other neurodegenerative disease models. Alterations in Nrf2 and Keap1 expression and dysregulation of the Nrf2/ARE signalling program could contribute to the chronic motor neuron degeneration in ALS and other neurodegenerative diseases. Therefore, Nrf2 emerges as a key neuroprotective molecule in neurodegenerative diseases. Our recent studies strongly support that the Nrf2/ARE signalling pathway is an important mediator of neuroprotection and therefore represents a promising target for development of novel therapies against ALS, Parkinson's disease (PD), Huntington's disease (HD), and Alzheimer's disease (AD).
    Neurology Research International 09/2012; 2012:878030. DOI:10.1155/2012/878030
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    • "et al., 2010). In addition, ROS activity is recognized as an inducer of the inflammatory response (Sun et al., 2007; Perricone et al., 2009). Consequently, it is possible that the mechanism elucidated here may also contribute to the induction of CNS inflammation in regions where this is more commonly seen in EAE and MS. "
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    ABSTRACT: Pathological changes occur in areas of CNS tissue remote from inflammatory lesions in multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). To determine if oxidative stress is a significant contributor to this non-inflammatory pathology, cortex tissues from mice with clinical signs of EAE were examined for evidence of inflammation and oxidative stress. Histology and gene expression analysis showed little evidence of immune/inflammatory cell invasion but reductions in natural antioxidant levels and increased protein oxidation that paralleled disease severity. Two-dimensional oxyblots and mass-spectrometry-based protein fingerprinting identified glutamine synthetase (GS) as a particular target of oxidation. Oxidation of GS was associated with reductions in enzyme activity and increased glutamate/glutamine levels. The possibility that this may cause neurodegeneration through glutamate excitotoxicity is supported by evidence of increasing cortical Ca(2+) levels in cortex extracts from animals with greater disease severity. These findings indicate that oxidative stress occurs in brain areas that are not actively undergoing inflammation in EAE and that this can lead to a neurodegenerative process due to the susceptibility of GS to oxidative inactivation.
    Neuroscience 06/2011; 185:97-105. DOI:10.1016/j.neuroscience.2011.04.041 · 3.36 Impact Factor
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