The Janus Face of Cyclooxygenase-2 in Ischemic Stroke

Iadecola, Costantino; Gorelick, Philip B.

doi:10.1161/01.str.0000153797.33611.d8

Cited by 69 publications

(57 citation statements)

References 39 publications

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“…Evidence points to a positive effect of NO on cyclooxygenase-2 [40] (COX2-prostaglandin H-synthase) activity and/or expression. COX2 is a component of the inflammatory cascade in the periphery [41,42].…”

Section: Introductionmentioning

confidence: 99%

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Bortolanza

Padovan-Neto

Cavalcanti-Kiwiatkoski

et al. 2015

Phil. Trans. R. Soc. B

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Inflammatory mechanisms are proposed to play a role in l -DOPA-induced dyskinesia. Cyclooxygenase-2 (COX2) contributes to inflammation pathways in the periphery and is constitutively expressed in the central nervous system. Considering that inhibition of nitric oxide (NO) formation attenuates l -DOPA-induced dyskinesia, this study aimed at investigating if a NO synthase (NOS) inhibitor would change COX2 brain expression in animals with l -DOPA-induced dyskinesia. To this aim, male Wistar rats received unilateral 6-hydroxydopamine microinjection into the medial forebrain bundle were treated daily with l -DOPA (21 days) combined with 7-nitroindazole or vehicle. All hemi-Parkinsonian rats receiving l -DOPA showed dyskinesia. They also presented increased neuronal COX2 immunoreactivity in the dopamine-depleted dorsal striatum that was directly correlated with dyskinesia severity. Striatal COX2 co-localized with choline-acetyltransferase, calbindin and DARPP-32 (dopamine-cAMP-regulated phosphoprotein-32), neuronal markers of GABAergic neurons. NOS inhibition prevented l -DOPA-induced dyskinesia and COX2 increased expression in the dorsal striatum. These results suggest that increased COX2 expression after l -DOPA long-term treatment in Parkinsonian-like rats could contribute to the development of dyskinesia.

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Section: Introductionmentioning

confidence: 99%

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Bortolanza

Padovan-Neto

Cavalcanti-Kiwiatkoski

et al. 2015

Phil. Trans. R. Soc. B

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“…The mechanisms underlying these complications have not been elucidated, but it has been suggested that COX-2 inhibitors downregulate PGI 2 (prostacyclin) and upregulate thromboxane A 2 resulting in a prothrombotic state (FitzGerald, 2003). Therefore, COX-2 activity is not uniformly deleterious and treatments based on inhibiting the COX-2 pathway have to focus on the mediators responsible for the deleterious effects of the enzyme sparing those mediating the beneficial actions (Iadecola and Gorelick, 2005;Rocca, 2006). Unfortunately, the COX-2 reaction products mediating the neurotoxicity of COX-2 have not been defined.…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-2 Does Not Contribute to Postischemic Production of Reactive Oxygen Species

Kunz

Anrather

Zhou

et al. 2006

J Cereb Blood Flow Metab

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We sought to determine whether reactive oxygen species (ROS) derived from cyclooxygenase-2 (COX-2) are involved in ischemic brain injury. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in C57BL/6 mice. The time course of neocortical ROS production was assessed in vivo using hydroethidine as a marker. The same brain sections were used for infarct volume measurements. Transient middle cerebral artery occlusion led to a biphasic increase in ROS production with peaks 2 and 72 h after reperfusion. The COX-2 inhibitor NS398 (10 mg/kg) attenuated the production of COX-2-derived prostaglandin E 2 and reduced brain injury, but did not affect ROS production at 2 and 72 h. Similarly, ROS production was not reduced in COX-2-null mice. In contrast, ROS production and brain injury were reduced in mice lacking the nox2 subunit of the superoxide-producing enzyme nicotinamide adenine dinucleotide phosphate (reduced form) oxidase. The data suggest that COX-2 is not a major source of oxygen radicals after cerebral ischemia and raise the possibility that other COX-2 reaction products, including prostanoids or nonoxygen-based radicals, mediate the COX-2-dependent component of the injury.

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“…Three cyclooxygenase isoforms (COX-1, COX-2, and COX-3) exist in brain tissue (67). COX-1 and COX-2 are both constitutively expressed in neural tissue (30,50).…”

Section: Cyclooxygenasementioning

confidence: 99%

Significance of Brain Tissue Oxygenation and the Arachidonic Acid Cascade in Stroke

Rink

Khanna

2011

Antioxidants & Redox Signaling

167

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The significance of the hypoxia component of stroke injury is highlighted by hypermetabolic brain tissue enriched with arachidonic acid (AA), a 22:6n-3 polyunsaturated fatty acid. In an ischemic stroke environment in which cerebral blood flow is arrested, oxygen-starved brain tissue initiates the rapid cleavage of AA from the membrane phospholipid bilayer. Once free, AA undergoes both enzyme-independent and enzyme-mediated oxidative metabolism, resulting in the formation of number of biologically active metabolites which themselves contribute to pathological stroke outcomes. This review is intended to examine two divergent roles of molecular dioxygen in brain tissue as (1) a substrate for life-sustaining homeostatic metabolism of glucose and (2) a substrate for pathogenic metabolism of AA under conditions of stroke. Recent developments in research concerning supplemental oxygen therapy as an intervention to correct the hypoxic component of stroke injury are discussed. Antioxid. Redox Signal. 14, 1889-1903. Brain Oxygen Consumption and Regulation

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The Janus Face of Cyclooxygenase-2 in Ischemic Stroke

Cited by 69 publications

References 39 publications

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced byl-DOPA?

Cyclooxygenase-2 Does Not Contribute to Postischemic Production of Reactive Oxygen Species

Significance of Brain Tissue Oxygenation and the Arachidonic Acid Cascade in Stroke

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