Neuroprotection by the stable nitroxide Tempol during reperfusion in a rat model of transient focal ischemia

Rak, Ramin; Chao, Daniel L.; Pluta, Ryszard; Mitchell, James B.; Oldfield, Edward H.; Watson, Joe C.

doi:10.3171/jns.2000.92.4.0646

Cited by 99 publications

(67 citation statements)

References 22 publications

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“…), and the carbonate radical (CO 3 .À ) (Augusto et al, 2008). Tempol readily crosses the BBB (Zhelev et al, 2009), and has previously been shown to provide neuroprotection as a free radical scavenger in several models of brain injury and ischemia (Kwon et al, 2003;Deng-Bryant et al, 2008;Rak et al, 2000;Cuzzocrea et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress Increases Blood–Brain Barrier Permeability and Induces Alterations in Occludin during Hypoxia–Reoxygenation

Lochhead

McCaffrey

Quigley

et al. 2010

J Cereb Blood Flow Metab

278

185

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The blood-brain barrier (BBB) has a critical role in central nervous system homeostasis. Intercellular tight junction (TJ) protein complexes of the brain microvasculature limit paracellular diffusion of substances from the blood into the brain. Hypoxia and reoxygenation (HR) is a central component to numerous disease states and pathologic conditions. We have previously shown that HR can influence the permeability of the BBB as well as the critical TJ protein occludin. During HR, free radicals are produced, which may lead to oxidative stress. Using the free radical scavenger tempol (200 mg/kg, intraperitoneal), we show that oxidative stress produced during HR (6% O 2 for 1 h, followed by room air for 20 min) mediates an increase in BBB permeability in vivo using in situ brain perfusion. We also show that these changes are associated with alterations in the structure and localization of occludin. Our data indicate that oxidative stress is associated with movement of occludin away from the TJ. Furthermore, subcellular fractionation of cerebral microvessels reveals alterations in occludin oligomeric assemblies in TJ associated with plasma membrane lipid rafts. Our data suggest that pharmacological inhibition of disease states with an HR component may help preserve BBB functional integrity.

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Section: Introductionmentioning

confidence: 99%

Oxidative Stress Increases Blood–Brain Barrier Permeability and Induces Alterations in Occludin during Hypoxia–Reoxygenation

Lochhead

McCaffrey

Quigley

et al. 2010

J Cereb Blood Flow Metab

278

185

View full text Add to dashboard Cite

show abstract

“…Intraperitoneal administration of Tempol before and after reperfusion resulted in a significant decrease in IHC staining and a decrease in lipid peroxidation as demonstrated by a decrease in cerebral malondialdehyde levels. In another study, the middle cerebral artery of rats was occluded then Tempol was administered during the first 20 minutes of reperfusion [70]. Tempol treatment resulted in a significant, dose-dependent decrease in infarct size as measured by digital imaging of brain slices which were collected and fixed after four hours of reperfusion ( Figure 11).…”

Section: Ischemia-reperfusion Injury and Inflammationmentioning

confidence: 99%

The chemistry and biology of nitroxide compounds

Soule

Hyodo

Matsumoto

et al. 2007

Free Radical Biology and Medicine

467

387

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Cyclic nitroxides are a diverse range of stable free radicals that have unique antioxidant properties. Because of their ability to interact with free radicals, they have been used for many years as biophysical tools. During the past 15-20 years, however, many interesting biochemical interactions have been discovered and harnessed for therapeutic applications. Biologically relevant effects of nitroxides have been described including their ability to degrade superoxide and peroxide, inhibit Fenton reactions and undergo radical-radical recombination. Cellular studies defined the activity of nitroxides in vitro. By modifying oxidative stress and altering the redox status of tissues, nitroxides have been found to interact with and alter many metabolic processes. These interactions can be exploited for therapeutic and research use including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. While much remains to be done, many applications have been well studied and some are presently being tested in clinical trials. The therapeutic and research uses of nitroxide compounds are reviewed here with a focus on the progress from initial development to modern trials.

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“…According to this author the lower dose of tempol in this experiment could explain the reason why the effects were not impressive in this study. Scavenger activity of tempol was also described with use of lower doses than in this experiment (Rak et al 2000). Thus, more investigations would be needed to determine the appropriate dosage of tempol required in inducing protective effects in ischemia/reperfusion models.…”

Section: Discussionmentioning

confidence: 77%

Modulations of behavioral consequences of minor cortical ischemic lesion by application of free radicals scavengers

Deykun¹,

Pometlová²,

Schutová³

et al. 2011

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Abstract. Functional and morphological consequences of ischemic lesions are partially related to the production of reactive oxygen species (ROS). The aim of the study was to create a unilateral photothrombic lesion with minimal morphological changes and minor sensorimotor and cognitive deficits and also to test whether the application of ROS scavengers after the end of induction of ischemia had improved the functional outcome.Adult Wistar male rats were randomly divided into five groups: naive control, sham operated animals, animals with induced ischemia, and two groups of animals with induced ischemia and subsequent ROS scavenger application -melatonin or tempol. The group subjected to ischemia showed a significant decline in performance in sensorimotor tests and the Morris water maze (MWM) test, compared to control animals. Tempol (50 mg/kg, i.p.) did not improve sensorimotor function and did not change spatial learning. Melatonin (100 mg/kg, i.p.), on the contrary, resulted in a significant improvement in animals' performances. All the ischemia subjected animals had increased speed of swimming in the MWM test, compared to the control group.Our findings showed that subsequent application of ROS scavengers improve ischemia outcomes, with melatonin being more potent. Conversely, neither melatonin, nor tempol decreased swimming speed cased by ischemia.

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Neuroprotection by the stable nitroxide Tempol during reperfusion in a rat model of transient focal ischemia

Abstract: Tempol provides significant neuroprotection after reperfusion in a rat model of transient focal ischemia. These results support the importance of ROS in reperfusion injury and encourage further study of this molecule as a therapeutic agent following thrombolysis.

Cited by 99 publications

References 22 publications

Oxidative Stress Increases Blood–Brain Barrier Permeability and Induces Alterations in Occludin during Hypoxia–Reoxygenation

Oxidative Stress Increases Blood–Brain Barrier Permeability and Induces Alterations in Occludin during Hypoxia–Reoxygenation

The chemistry and biology of nitroxide compounds

Modulations of behavioral consequences of minor cortical ischemic lesion by application of free radicals scavengers

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Neuroprotection by the stable nitroxide Tempol during reperfusion in a rat model of transient focal ischemia

Abstract: Tempol provides significant neuroprotection after reperfusion in a rat model of transient focal ischemia. These results support the importance of ROS in reperfusion injury and encourage further study of this molecule as a therapeutic agent following thrombolysis.

Cited by 99 publications

References 22 publications

Oxidative Stress Increases Blood–Brain Barrier Permeability and Induces Alterations in Occludin during Hypoxia–Reoxygenation

Oxidative Stress Increases Blood–Brain Barrier Permeability and Induces Alterations in Occludin during Hypoxia–Reoxygenation

The chemistry and biology of nitroxide compounds

Modulations of behavioral consequences of minor cortical ischemic lesion by application of free radicals scavengers

Contact Info

Product

Resources

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Modulations of behavioral consequences of minor cortical ischemic lesion by application of free radicals scavengers