Expression of inducible nitric oxide synthase by neurones following exposure to endotoxin and cytokine

Minc-Golomb, Dahlia; Tsarfaty, Ilan; Schwartz, Joan P.

doi:10.1111/j.1476-5381.1994.tb13136.x

Cited by 154 publications

(68 citation statements)

References 9 publications

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“…The heightened expression of iNOS in the infected CNS, in all cases, is likely to be the reflection of the activation of both resident and invading cells, which may include neurons, vascular endothelial cells, glial cells, and monocytes. In vitro experiments by a number of groups have established that each of these cell types share the ability to express iNOS when stimulated by interferon y and endotoxin (12)(13)(14)(15)(16)(17)21). As clearly demonstrated by the EAE adoptivetransfer model, CD4+ T cells, which can traffic through most tissues, including the brain (34), are central to the activation of the more ubiquitous cells capable of producing NO.…”

Section: Resultsmentioning

confidence: 99%

“…Immune and inflammatory stimuli, such as interferon y and bacterial endotoxin, induce the expression of iNOS in diverse cell types, including endothelial cells, neurons, and cells of the macrophage/mononuclear lineage (12)(13)(14)(15)(16)(17)(18). NO and related free radicals produced primarily by macrophages have been implicated in the destruction of a variety of invading pathogens (3,19,20).…”

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confidence: 99%

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Local nitric oxide production in viral and autoimmune diseases of the central nervous system.

Hooper

Ohnishi

Kean

et al. 1995

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

168

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Because of the short half-life of NO, previous studies implicating NO in central nervous system pathology during infection had to rely on the demonstration of elevated levels of NO synthase mRNA or enzyme expression or NO metabolites such as nitrate and nitrite in the infected brain. To more definitively investigate the potential causative role of NO in lesions of the central nervous system in animals infected with neurotropic viruses or suffering from experimental allergic encephalitis, we have determined directly the levels of NO present in the central nervous system of such animals. Using spin trapping of NO and electron paramagnetic resonance spectroscopy, we confirm here that copious amounts of NO (up to 30-fold more than control) are elaborated in the brains of rats infected with rabies virus or borna disease virus, as well as in the spinal cords of rats that had received myelin basic protein-specific T cells.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Local nitric oxide production in viral and autoimmune diseases of the central nervous system.

Hooper

Ohnishi

Kean

et al. 1995

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

168

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“…Several investigators have reported that iNOS is expressed in both glia and neurons in response to cytokine exposure or other proinflammatory conditions (2,10,16). Similarly, iNOS is expressed in the cerebellum in adult rats (17).…”

Section: Discussionmentioning

confidence: 99%

Expression of nitric oxide synthase isoforms is reduced in late-gestation ovine fetal brainstem

Wood¹,

Chen²,

Keller‐Wood³

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Wood, Charles E., Gin-Fu Chen, and Maureen Keller-Wood. Expression of nitric oxide synthase isoforms is reduced in late-gestation ovine fetal brainstem. Am J Physiol Regul Integr Comp Physiol 289: R613-R619, 2005; doi:10.1152/ajpregu.00722.2004.-Fetal baroreflex responsiveness increases in late gestation. An important modulator of baroreflex activity is the generation of nitric oxide in the brainstem nuclei that integrate afferent and efferent reflex activity. The present study was designed to test the hypothesis that nitric oxide synthase (NOS) isoforms are expressed in the fetal brainstem and that the expression of one or more of these enzymes is reduced in late gestation. Brainstem tissue was rapidly collected from fetal sheep of known gestational ages (80, 100, 120, 130, 145 days gestation and 1 day and 1 wk postnatal). Neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) mRNA was measured using real-time PCR methodology specific for ovine NOS isoforms. The three enzymes were measured at the protein level using Western blot methodology. In tissue prepared for histology separately, the cellular pattern of immunostaining was identified in medullae from late-gestation fetal sheep. Fetal brainstem contained mRNA and protein of all three NOS isoforms, with nNOS the most abundant, followed by iNOS and eNOS, respectively. nNOS and iNOS mRNA abundances were highest at 80 days' gestation, with statistically significant decreases in abundance in more mature fetuses and postnatal animals. nNOS and eNOS protein abundance also decreased as a function of developmental age. nNOS and eNOS were expressed in neurons, iNOS was expressed in glia, and eNOS was expressed in vascular endothelial cells. We conclude that all three isoforms of NOS are constitutively expressed within the fetal brainstem, and the expression of all three forms is reduced with advancing gestation. We speculate that the reduced expression of NOS in this brain region plays a role in the increased fetal baroreflex activity in late gestation. medulla; messenger ribonucleic acid; immunohistochemistry; realtime reverse transcriptase-polymerase chain reaction IN ADDITION TO ITS ROLE as an endothelial cell-derived vascular smooth muscle relaxant, the role of nitric oxide as a neurotransmitter is well established (11). In the medullary nuclei of the adult animal, nitric oxide is synthesized by neurons that express the neuronal form of nitric oxide synthase (nNOS or NOSIII) (3, 23). One of the physiological roles of nNOS in medullary neurons is the local generation of NO that, in turn, acts as an inhibitory neurotransmitter with regard to baroreflex responsiveness (13). Numerous studies in this laboratory have helped to establish the importance of baroreceptor and chemoreceptor reflexes in the minute-to-minute control of blood pressure and umbilical-placental blood flow in the fetus in utero (24,27). Various studies have demonstrated that the reflex mechanisms governing cardiovascular function in the fetus mature as a function of fetal gestational age (18,19...

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“…3,4 Most brain cell types in culture can express inducible NO synthase after exposure to endotoxin and/or cytokines. [5][6][7][8][9] Thus, it appears that expression of inducible NO synthase and NO production in brain is an important element in the response of brain arterioles to endotoxin.…”

mentioning

confidence: 99%

Tumor Necrosis Factor-α–Induced Dilatation of Cerebral Arterioles

Brian

Faraci

1998

Stroke

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Background and Purpose-In brain, several cell types produce tumor necrosis factor-␣ (TNF␣) after injury or exposure to endotoxin. TNF␣ alone or in combination with endotoxin or other cytokines can cause expression of inducible nitric oxide (NO) synthase. We have previously demonstrated that endotoxin caused NO-dependent dilatation of cerebral arterioles in vivo. In the present study we examined the hypothesis that TNF␣ causes NO-mediated dilatation of cerebral arterioles in vivo. Methods-Cranial windows were implanted in anesthetized rats and used to measure the diameter of cerebral arterioles.Windows were flushed every 30 minutes for 4 hours with artificial cerebrospinal fluid (aCSF) (nϭ6); aCSF with TNF␣ (100 ng/mL; nϭ10); aCSF with TNF␣ and aminoguanidine (0.3 mmol/L; nϭ5), an inhibitor of inducible NO synthase; or aCSF with TNF␣ and dexamethasone (1 mol/L; nϭ6), which attenuates expression of inducible NO synthase. In some animals, brain from beneath the cranial window was examined by immunocytochemistry for inducible NO synthase expression. Results-Application of TNF␣ caused marked, progressive dilatation of cerebral arterioles, with a maximum increase in diameter of 46Ϯ9% (meanϮSEM) at 4 hours. Coapplication of either aminoguanidine or dexamethasone with TNF␣ prevented dilatation of cerebral arterioles compared with TNF␣ alone (4Ϯ2% and 1Ϯ1% dilatation at 4 hours, respectively; PϽ.05). Dexamethasone did not inhibit dilatation of cerebral arterioles in response to adenosine diphosphate. However, 2 hours of aminoguanidine treatment produced moderate inhibition of adenosine diphosphate-induced dilatation of cerebral arterioles. After treatment with TNF␣, immunocytochemistry for inducible NO synthase demonstrated expression in perivascular and arachnoid cells but not brain cells. There was no detectable expression of inducible NO synthase after treatment with aCSF. Conclusions-The present study indicates that TNF␣ causes cerebral vasodilatation and expression of inducible NO synthase in perivascular and arachnoid cells. Inhibition of TNF␣-induced dilatation by aminoguanidine and dexamethasone suggests that the vasodilatation was due predominantly to expression of inducible NO synthase. These findings support the concept that cerebral vasodilatation that occurs during pathophysiological conditions associated with increased TNF␣ production in brain is mediated by expression of inducible NO synthase. (Stroke. 1998;29:509-515.)

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Expression of inducible nitric oxide synthase by neurones following exposure to endotoxin and cytokine

Cited by 154 publications

References 9 publications

Local nitric oxide production in viral and autoimmune diseases of the central nervous system.

Local nitric oxide production in viral and autoimmune diseases of the central nervous system.

Expression of nitric oxide synthase isoforms is reduced in late-gestation ovine fetal brainstem

Tumor Necrosis Factor-α–Induced Dilatation of Cerebral Arterioles

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