Synthesis and Evaluation as a Blood–Brain Barrier-Permeable Probe of 7-&lt;i&gt;N&lt;/i&gt;-(PROXYL-3-yl-methyl)theophylline

Emoto, Miho C.; Sasaki, Kota; Maeda, Koya; Fujii, Hirotada; Sato, Shingo

doi:10.1248/cpb.c18-00333

Cited by 9 publications

(5 citation statements)

References 26 publications

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“…Furthermore, pharmacological applications of nitroxides have limitations, for example, long term exposure and high doses of TEMPOL have been shown to impact iron transport [ 78 ]. Nonetheless, nitroxides are able to cross the blood–brain-barrier and accumulate in brain tissue, and strategies to enhance nitroxide entry to the brain are available [ 79 , 80 ], including incorporation into nanoparticle delivery vehicles [ 81 ].…”

Section: Discussionmentioning

confidence: 99%

The Cyclic Nitroxide TEMPOL Ameliorates Oxidative Stress but Not Inflammation in a Cell Model of Parkinson’s Disease

et al. 2022

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The cyclic nitroxide TEMPOL exerts anti-oxidative and anti-inflammatory effects, and thus may provide therapeutic benefit in Parkinson’s disease (PD), in which mitochondrial dysfunction, oxidative damage and inflammation have been implicated as pathophysiological mechanisms underlying the selective loss of dopaminergic neurons. Markers of oxidative stress and inflammation were investigated in a cell model of differentiated human neuroblastoma (SH-SY5Y) cells treated with the neurotoxin, 6-hydroxydopamine (6-OHDA). Treatment with TEMPOL ameliorated 6-OHDA-mediated cytotoxicity and attenuated biomarkers of oxidative stress including: mitochondrial superoxide anion free radical production, lipid peroxidation, induction of heme oxygenase 1 (HO-1) protein expression and NFκB activation. Treatment with TEMPOL abated decreased gene expression of DRD2S and DRD2L induced by 6-OHDA indicating that TEMPOL may prevent mitochondrial dysfunction and activation of pathways that result in receptor desensitization. 6-OHDA insult decreased gene expression of the antioxidant, SOD-1, and this diminution was also mitigated by TEMPOL. Activation of NFκB increased pro-inflammatory IFNy and decreased IL-6, however, TEMPOL had no effect on these inflammation mediators. Overall, this data suggests that cyclic nitroxides may preserve dopaminergic neuronal cell viability by attenuating oxidative stress and mitochondrial dysfunction, but are unable to affect inflammatory mediators that propagate cellular damage and neurodegeneration in PD.

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Section: Discussionmentioning

confidence: 99%

The Cyclic Nitroxide TEMPOL Ameliorates Oxidative Stress but Not Inflammation in a Cell Model of Parkinson’s Disease

et al. 2022

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“…Investigations of in situ or in vivo drug delivery using nitroxyl-labeled drugs have long been conducted in the field of EPRI ( 39 , 40 , 45 ). In MRI, Zhelev et al ( 196 ) successfully visualized that i.v.-injected TEMPO-labeled nitrosourea (SLENU), which is an anticancer drug labeled by a nitroxyl radical, could penetrate through BBB and distribute into whole brain.…”

Section: Development Of Redox Sensing Into Redox Imagingmentioning

confidence: 99%

Nitroxyl Radical as a Theranostic Contrast Agent in Magnetic Resonance Redox Imaging

Matsumoto

Nakanishi

Zhelev

et al. 2022

Antioxidants & Redox Signaling

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Significance: In vivo assessment of paramagnetic and diamagnetic conversions of nitroxyl radicals based on cyclic redox mechanism can be an index of tissue redox status. The redox mechanism of nitroxyl radicals, which enables their use as a normal tissue-selective radioprotector, is seen as being attractive on planning radiation therapy. Recent Advances: In vivo redox imaging using nitroxyl radicals as redox-sensitive contrast agents has been developed to assess tissue redox status. Chemical and biological behaviors depending on chemical structures of nitroxyl radical compounds have been understood in detail. Polymer types of nitroxyl radical contrast agents and/or nitroxyl radical-labeled drugs were designed for approaching theranostics. Critical Issues: Nitroxyl radicals as magnetic resonance imaging (MRI) contrast agents have several advantages compared with those used in electron paramagnetic resonance (EPR) imaging, while support by EPR spectroscopy is important to understand information from MRI. Redox-sensitive paramagnetic contrast agents having a medicinal benefit, that is, nitroxyl-labeled drug, have been developed and proposed. Future Directions: A development of suitable nitroxyl contrast agent for translational theranostic applications with high reaction specificity and low normal tissue toxicity is under progress. Nitroxyl radicals as redoxsensitive magnetic resonance contrast agents can be a useful tool to detect an abnormal tissue redox status such as disordered oxidative stress. Antioxid. Redox Signal. 00, 000-000.

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“…Estimated resolution of the image after 12 iterations reached a maximum of 0.25 mm. While nitroxide radical probes have been used for a variety of EPR imaging applications for many years, typically these images and related data, while highly useful, were of limited quality and with mm resolution at best [24][25][26][27][28][29][30][31][32][33][34][35]. Image resolution and image quality were limited by the spectral linewidths with hyperfine structure as well as the limited number of projections possible with conventional slow scan EPR and the limited image matrix size.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Fast Scan EPR for High-Resolution Imaging Using Nitroxide Radical Probes at 1.2 GHz

2021

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Nitroxide probes have been commonly used for biomedical EPR imaging applications; however, image quality has been limited by the number of image projections, as well as the probe linewidth and hyperfine structure. In the current study, we evaluate the use of fast millisecond scan EPR projection acquisition along with a novel reconstruction algorithm optimized for 3D spatial EPR image reconstruction from a high number of noisy projections. This reconstruction method utilizes the raw image projection data and zero gradient spectrum to account for EPR line shape and hyperfine structure of any given paramagnetic probe without the need for deconvolution that is poorly suited for high noise data. Using fast scan EPR imaging with this reconstruction method, we image non-deuterated, deuterated and 15 N substituted nitroxide probes in experimental phantoms of complex geometries. We evaluate the image resolution that can be obtained and the imaging time required. With 16,384 projections acquired over 1 min, and a field gradient of 8 G/cm, with a 250 3 voxel 3D matrix, spatial resolutions of up to 100 µm are theoretically possible for a cubical volume of 25 × 25 × 25 mm 3 . In experiments with a variety of phantoms with mM nitroxide radical probes, resolutions of 600-250 µm were obtained with 1-10 min acquisitions, respectively. The presently obtainable signal sensitivity and noise levels of these acquisitions limited the obtainable resolution. With longer time acquisitions or further improvements in sensitivity and noise reduction, image resolutions approaching 100 µm should be possible.

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Synthesis and Evaluation as a Blood–Brain Barrier-Permeable Probe of 7-<i>N</i>-(PROXYL-3-yl-methyl)theophylline

Cited by 9 publications

References 26 publications

The Cyclic Nitroxide TEMPOL Ameliorates Oxidative Stress but Not Inflammation in a Cell Model of Parkinson’s Disease

The Cyclic Nitroxide TEMPOL Ameliorates Oxidative Stress but Not Inflammation in a Cell Model of Parkinson’s Disease

Nitroxyl Radical as a Theranostic Contrast Agent in Magnetic Resonance Redox Imaging

Evaluation of Fast Scan EPR for High-Resolution Imaging Using Nitroxide Radical Probes at 1.2 GHz

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