L-Arginine and Nitric Oxide in CNS Function and Neurodegenerative Diseases

Virarkar, Mayur; Alappat, Lini; Bradford, Peter G.; Awad, Atif B.

doi:10.1080/10408398.2011.573885

Cited by 76 publications

(42 citation statements)

References 144 publications

(145 reference statements)

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“…Nitric oxide, synthesized from L-arginine, affects brain functions by generating nitroxidative stress, and its elevation may play a causative role in the development of neurodegenerative diseases, including AD and PD (Virarkar et al, 2013). Many neurodegenerative diseases were associated with neurotransmitter levels, and glutamate is the most prevalent neurotransmitter in the brain.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Biomarkers and Neurodegeneration: A Pathway Enrichment Analysis of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

Kori

Aydın

Unal

et al. 2016

OMICS: A Journal of Integrative Biology

125

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Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) lack robust diagnostics and prognostic biomarkers. Metabolomics is a postgenomics field that offers fresh insights for biomarkers of common complex as well as rare diseases. Using data on metabolite-disease associations published in the previous decade (2006-2016) in PubMed, ScienceDirect, Scopus, and Web of Science, we identified 101 metabolites as putative biomarkers for these three neurodegenerative diseases. Notably, uric acid, choline, creatine, L-glutamine, alanine, creatinine, and N-acetyl-L-aspartate were the shared metabolite signatures among the three diseases. The disease-metabolite-pathway associations pointed out the importance of membrane transport (through ATP binding cassette transporters), particularly of arginine and proline amino acids in all three neurodegenerative diseases. When disease-specific and common metabolic pathways were queried by using the pathway enrichment analyses, we found that alanine, aspartate, glutamate, and purine metabolism might act as alternative pathways to overcome inadequate glucose supply and energy crisis in neurodegeneration. These observations underscore the importance of metabolite-based biomarker research in deciphering the elusive pathophysiology of neurodegenerative diseases. Future research investments in metabolomics of complex diseases might provide new insights on AD, PD, and ALS that continue to place a significant burden on global health.

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Section: Discussionmentioning

confidence: 99%

Metabolic Biomarkers and Neurodegeneration: A Pathway Enrichment Analysis of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

Kori

Aydın

Unal

et al. 2016

OMICS: A Journal of Integrative Biology

125

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“…Aberrant production of nitric oxide (NO) is implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, and other disorders of the central nervous system [1][2][3]. Three forms of nitric oxide synthases (NOSs) (i.e., nNOS, eNOS, and iNOS) are known to produce NO from a conditionally essential amino acid L-arginine [4].…”

Section: Introductionmentioning

confidence: 99%

Botanical Drug Puerarin Attenuates 6-Hydroxydopamine (6-OHDA)-Induced Neurotoxicity via Upregulating Mitochondrial Enzyme Arginase-2

et al. 2015

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Inhibition of nitric oxide synthases (NOSs) shows promise to halt the progression of neurodegenerative diseases. The present study was designed to explore whether botanical isoflavone puerarin could attenuate nitric oxide (NO)-mediated neurotoxicity via modulating the enzymes in the L-arginine-NO pathway. Neurotoxin 6-hydroxydopamine (6-OHDA) is well known to induce neurodegeneration via a NO-dependent mechanism. We first validated that puerarin protected rat dopamingeric PC12 cells against 6-OHDA-induced neurotoxicity in a concentration-dependent manner. We subsequently profiled the cellular responses to puerarin by a proteomic response fingerprinting approach. A total of 16 protein spots with >1.5-fold change of intensity were selected and identified by mass spectrometry. As one of puerarin-upregulated proteins, mitochondrial arginase-2 hydrolyzes L-arginine to L-ornithine, thereby competing with neuronal NOS for substrate L-arginine in mitochondria. Thus, we hypothesize that puerain may attenuate nitric oxide (NO)-mediated mitochondrial injury via increasing arginase-2 expression. Western blot and reverse transcription polymerase chain reaction (RT-PCR) analyses confirmed that puerarin increased arginase-2 expression in a concentration- and time-dependent manner. Accordingly, puerarin suppressed 6-OHDA-induced NO production and neurotoxicity in PC12 cells and primary rat midbrain neurons. Arginase inhibitor BEC diminished the effect of puerarin on 6-OHDA-induced NO production and neurotoxicity. The activation of arginase-2 by puerarin represents an endogenous mechanism for specific control of NO-mediated mitochondrial damage. Thus, puerarin is a useful lead for suppressing NO-mediated neurotoxicity in neurodegenerative diseases. Graphical Abstract Arginase-2 dependent mechanism underlying the neuroprotective activity of puerarin.

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“…In vertebrates, NO regulates learning, memory, feeding, sleeping, sensory and motor functions by acting as an inhibitor or enhancer of neurotransmitter release (Calabrese et al, 2007;Garthwaite, 2008;Virarkar et al, 2013). For example, NO enhances acetylcholine release in the basal forebrain and ventral striatum and inhibits histamine release in the anterior hypothalamus (reviewed in Prast and Philippu, 2001;Philippu and Prast, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…In the vertebrate hippocampus and cerebral cortex, NO plays a dual role in the regulation of glutamate release, acting as an inhibitor at low concentrations and a stimulator at high concentrations (Sequeira et al, 1997). In addition, NO has neurotoxic effects that are associated with neurodegenerative disorders, such as Alzheimer's, Parkinson's and Huntington's diseases (Calabrese et al, 2007;Lorenc-Koci and Czarnecka, 2013;Virarkar et al, 2013). For comprehensive reviews of NO actions in vertebrates, see Hirst and Robson (Hirst and Robson, 2011) and Russwurm et al (Russwurm et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide production and sequestration in the sinus gland of the green shore crab, Carcinus maneas

Pitts

Mykles

2014

Journal of Experimental Biology

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Molting in decapod crustaceans is regulated by molt-inhibiting hormone (MIH), a neuropeptide produced in the X-organ (XO)/sinus gland (SG) complex of the eyestalk ganglia (ESG). Pulsatile release of MIH from the SG suppresses ecdysteroidogenesis by the molting gland or Y-organ (YO). The hypothesis is that nitric oxide (NO), a neuromodulator that controls neurotransmitter release at presynaptic membranes, depresses the frequency and/or amount of MIH pulses to induce molting. NO synthase (NOS) mRNA was present in Carcinus maenas ESG and other tissues and NOS protein was present in the SG. A copper based ligand (CuFL), which reacts with NO to form a highly fluorescent product (NO-FL), was used to image NO in the ESG and SG and quantify the effects of NO scavenger (cPTIO), NOS inhibitor (L-NAME), and sodium azide (NaN 3 ) on NO production in the SG. Pre-incubation with cPTIO prior to CuFL loading decreased NO-FL fluorescence ~30%; including L-NAME had no additional effect. Incubating SG with L-NAME during preincubation and loading decreased NO-FL fluorescence ~40%, indicating that over half of the NO release was not directly dependent on NOS activity. Azide, which reacts with NO-binding metal groups in proteins, reduced NO-FL fluorescence to near background levels without extensive cell death. Spectral shift analysis showed that azide displaced NO from a soluble protein in SG extract. These data suggest that the SG contains NO-binding protein(s) that sequester NO and releases it over a prolonged period. This NO release may modulate neuropeptide secretion from the axon termini in the SG.

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L-Arginine and Nitric Oxide in CNS Function and Neurodegenerative Diseases

Cited by 76 publications

References 144 publications

Metabolic Biomarkers and Neurodegeneration: A Pathway Enrichment Analysis of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

Metabolic Biomarkers and Neurodegeneration: A Pathway Enrichment Analysis of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

Botanical Drug Puerarin Attenuates 6-Hydroxydopamine (6-OHDA)-Induced Neurotoxicity via Upregulating Mitochondrial Enzyme Arginase-2

Nitric oxide production and sequestration in the sinus gland of the green shore crab, Carcinus maneas

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