Time-related changes in constitutive and inducible nitric oxide synthases in the rat striatum in a model of Huntington's disease

Aguilera, Penélope; Chánez‐Cárdenas, María Elena; Floriano-Sánchez, Esaú; Barrera, Diana; Santamarı́a, Abel; Sánchez-González, Dolores Javier; Pérez-Severiano, Francisca; Pedraza‐Chaverrí, José; Maldonado, Perla D.

doi:10.1016/j.neuro.2007.07.010

Cited by 40 publications

(29 citation statements)

References 57 publications

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“…6a) and neurons (Fig. 6b) with and without QUIN (550 nM) exposure for 24 h. As previously described, iNOS was not expressed in human neurons (Aguilera et al 2007). Based on the ratio of iNOS and nNOS expression relative to GAPDH expression, iNOS and nNOS expression was significantly higher in QUIN-treated astrocytes (Fig.…”

Section: Detection Of Inos and Nnos Mrna Expression In Human Astrocytsupporting

confidence: 75%

“…Although iNOS mRNA (Fig. 6b) was not expressed in human neurons (Aguilera et al 2007) nNOS mRNA expression was significantly increased in QUIN-treated neurons compared to non-treated cells (Fig. 6b, d).…”

Section: Discussionmentioning

confidence: 90%

“…It has been previously shown that iNOS transcription is induced during inflammation in response to cytokine stimulation (Possel et al 2000) and several endotoxins, including QUIN (Rya et al 2004). Activation of nNOS also has several implications in neuroinflammation: (1) NMDA receptor-mediated excitotoxicity is reduced in response to NOS inhibition in cultured rat cortical neurons (Dawson et al 1991); (2) nNOS knockout mice report a significant reduction in death due to NMDA receptor-mediated excitotoxicity (Ayata et al 1997); (3) nNOS activity is increased following QUIN injection in the rat striatum (Aguilera et al 2007;PerezSeveriano et al 1998).…”

Section: Introductionmentioning

confidence: 99%

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Mechanism for Quinolinic Acid Cytotoxicity in Human Astrocytes and Neurons

et al. 2009

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There is growing evidence implicating the kynurenine pathway (KP) and particularly one of its metabolites, quinolinic acid (QUIN), as important contributors to neuroinflammation in several brain diseases. While QUIN has been shown to induce neuronal and astrocytic apoptosis, the exact mechanisms leading to cell death remain unclear. To determine the mechanism of QUIN-mediated excitotoxicity in human brain cells, we measured intracellular levels of nicotinamide adenine dinucleotide (NAD(+)) and poly(ADP-ribose) polymerase (PARP) and extracellular lactate dehydrogenase (LDH) activities in primary cultures of human neurons and astrocytes treated with QUIN. We found that QUIN acts as a substrate for NAD(+) synthesis at very low concentrations (<50 nM) in both neurons and astrocytes, but is cytotoxic at sub-physiological concentrations (>150 nM) in both the cell types. We have shown that the NMDA ion channel blockers, MK801 and memantine, and the nitric oxide synthase (NOS) inhibitor, L-NAME, significantly attenuate QUIN-mediated PARP activation, NAD(+) depletion, and LDH release in both neurons and astrocytes. An increased mRNA and protein expression of the inducible (iNOS) and neuronal (nNOS) forms of nitric oxide synthase was also observed following exposure of both cell types to QUIN. Taken together these results suggests that QUIN-induced cytotoxic effects on neurons and astrocytes are likely to be mediated by an over activation of an NMDA-like receptor with subsequent induction of NOS and excessive nitric oxide (NO(*))-mediated free radical damage. These results contribute significantly to our understanding of the pathophysiological mechanisms involved in QUIN neuro- and gliotoxicity and are relevant for the development of therapies for neuroinflammatory diseases.

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Section: Detection Of Inos and Nnos Mrna Expression In Human Astrocytsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Mechanism for Quinolinic Acid Cytotoxicity in Human Astrocytes and Neurons

et al. 2009

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“…In addition, three isoforms of NOS have participated in the progression of neurodegenerative diseases [Guix et al, 2005]. eNOS was responsible for the abnormalities in Huntington's disease [Aguilera et al, 2007] and AD [Sohn et al, 1999]. Our results presented that Cdk5 phosphorylates eNOS and down regulates its activity, indicating the phosphorylation of eNOS by Cdk5 may be implicated in pathogenesis of neurodegenerative disease.…”

Section: Discussionmentioning

confidence: 62%

CDK5 phosphorylates eNOS at Ser‐113 and regulates NO production

Lee

Wei

Huang

et al. 2010

J of Cellular Biochemistry

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Phosphorylation of endothelial nitric oxide synthase (eNOS) is key mechanism in response to various forms of cellular stimulation. Through protein nitration by peroxynitrite, eNOS is believed to be responsible for the major abnormalities in several important neurodegenerative diseases including Alzheimer's (AD) and Parkinson's diseases (PD). Recent studies provide important in vivo evidence that hyperactivation of Cdk5 by p25 plays an essential role in the cell death of neurons in experimental models of AD and PD. This study focuses on the functional regulation of eNOS by Cdk5/p35 complex in a phosphorylation dependent manner. Our results showed that Cdk5 can phosphorylate eNOS both in vitro and in vivo. In vitro kinase assay together with the bioinformatic analysis and site direct mutagenesis revealed that Ser-113 is the major phosphorylation site for Cdk5. Most interestingly, the nitrite production was significantly reduced in eNOS and Cdk5/p35 co-transfected SH-SY5Y cells when compared with co-transfection of Cdk5/p35 and S113A. Together, our data suggest that Cdk5 can phosphorylate eNOS at the Ser-113 site and down-regulate eNOS-derived NO levels.

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“…In the striatum, NOS, the enzyme involved in the synthesis of NO, has been selectively found in a scattered population of interneurons (Vincent & Kimura, 1992). The level of neuronal NOS (nNOS) is increased in neurodegenerative diseases in which disorders of the basal ganglia have been described (Aguilera et al, 2007;Pérez-Severiano et al, 2002). Increased NO (via nNOS activity) can be harmful to surrounding cells in neurodegenerative processes mediated by glutamate.…”

Section: Nitric Oxide In the Nigrostriatal Systemmentioning

confidence: 99%