Free radical scavengers and spin traps – therapeutic implications for ischemic stroke

Doeppner, Thorsten R.; Hermann, Dirk M.

doi:10.1016/j.bpa.2010.10.003

Cited by 17 publications

(6 citation statements)

References 91 publications

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“…Although many free-radical scavengers are utilized clinically, only a few of them (such as NXY-059, 21-aminosteroid tirilazad, and edaravone [3-methyl-1-phenyl-2-pyrazolin-5-one; see figure 1]) have been used in the conduct of clinical trials in ischemic stroke. [6] Among those, edaravone is widely utilized in clinical trials to protect tissues from ischemia reperfusion injury after acute ischemic stroke. [7–9]…”

Section: Introductionmentioning

confidence: 99%

Phase I Clinical Study of Edaravone in Healthy Chinese Volunteers

Wang

et al. 2012

Drugs R D

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ObjectiveThe objective of this study was to investigate the safety and pharmacokinetics of edaravone administered by single or successive intravenous infusions in healthy Chinese volunteers.MethodsA total of 30 subjects (15 males and 15 females) were recruited and randomly assigned to three groups receiving edaravone doses of 20, 30, and 60 mg. All subjects received a single dose of edaravone during a 30-minute period, and only the 30 mg dose group continued to receive the same dose successively by intravenous infusion twice daily for the next 5 days. Plasma concentrations of edaravone were monitored by high-performance liquid chromatography at the following times: 15, 30, 45, 60, 75, 105, 165, 225, 300, 390, 480, 600, and 720 minutes after edaravone administration.ResultsThe area under the plasma concentration-time curve during a dosage interval (AUCτ) values of the single dose in the 20, 30, and 60 mg dose groups were 3.64±1.37, 5.17 ± 0.93, and 11.25 ± 3.42 mg · h/L, respectively, while in the group receiving repeated dosing of 30 mg, the mean AUCτ value was 5.06 ± 0.89mg · h/L. The corresponding maximum plasma drug concentration (Cmax) values were 1599.0 ± 382.6, 2378.7 ± 316.7, and 4540.1 ± 901.1 ng/mL, respectively, in the single-dose groups, and 2479.1 ± 477.9 ng/mL in the 30 mg repeated-dose group. The mean AUCτ and Cmax ratios between the repeated-dose group and the single-dose groups were 0.98 and 1.04. All laboratory test abnormalities (including increased alanine transaminase and triacylglycerol levels, and decreased white blood cell counts and creatinine levels) were mild and tolerable. All abnormal blood biochemical indices returned to normal levels after 7 days.ConclusionEdaravone was safe and well tolerated in the volunteers and displayed linear increases in the Cmax and AUCτ values.

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Section: Introductionmentioning

confidence: 99%

Phase I Clinical Study of Edaravone in Healthy Chinese Volunteers

Wang

et al. 2012

Drugs R D

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“…It is noteworthy that ROS was regarded as a pivotal factor destabilizing the lysosomal membranes within lysosomes, where the acidic condition and the labile iron facilitated a Fenton-type reaction, particularly intralysosomal hydroxyl radicals HO• production [27]. More and more evidence have demonstrated that the cathepsins may play important roles in different diseases of the CNS, such as intracerebral hemorrhage (ICH), focal cerebral ischemia, and traumatic brain injury (TBI) [28][29][30].…”

Section: Discussionmentioning

confidence: 99%

The Neuroprotection of Lysosomotropic Agents in Experimental Subarachnoid Hemorrhage Probably Involving the Apoptosis Pathway Triggering by Cathepsins via Chelating Intralysosomal Iron

Wang

Gao

et al. 2014

Mol Neurobiol

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α-Lipoic acid-plus (LAP), an amine derivative of α-lipoic acid (LA), could protect cells against oxidant challenges via chelating intralysosomal iron. However, the application of LAP in experimental subarachnoid hemorrhage (SAH) is still not well known. This study was designed to evaluate the potential neuroprotection of LAP on the early brain injury (EBI) and the underlying mechanisms in a rat model of SAH. The SAH models were induced in Sprague-Dawley rats. LA and LAP were oral administration and lasted for 72 h once a day. The brain tissue samples were obtained for assay at 72 h after SAH. In experiment 1, we found that lysosome amounts in neurons decreased significantly in SAH group, and LAP (100 mg/kg) could stabilize lysosomal membrane markedly based on lysosomal-associated membrane protein-1 (LAMP-1) expression in neurons by immunofluorescence. Hence, the LAP dosages of 100 and 150 mg/kg were applied in experiment 2. Firstly, Western blot analysis showed that the protein levels of cathepsin B/D, caspase-3, Bax, ferritin, and heme-oxygenase-1 (HO-1) markedly increased after SAH, which were further confirmed by double immunofluorescence staining and reversed by LA and LAP treatments. In addition, LA and LAP also reduced oxidative stress and iron deposition in brain tissue. Furthermore, LA and LAP significantly ameliorated brain edema, blood-brain barrier injury, cortical apoptosis, and neurological behavior impairment induced by SAH. Finally, it is noteworthy that LAP exerted more significant effects than LA on these parameters as described above. LAP probably exerted neuroprotective effects via targeting lysosomes and chelating intralysosomal iron in EBI post-SAH in rats.

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“…Oxidative stress occurs when the cellular homeostasis, normally involving a fine balance between free radical generation and their detoxification by cellular antioxidants, is disturbed. Earlier studies have pointed to oxidative stress as a major reason for neuronal cell death leading to neurodegenerative disorders like ischemia, PD, AD and HD (Axelsen et al, 2011;Caviness et al, 2011;Chen, 2011;Doeppner and Hermann, 2010). The anti-oxidant machinery of the cell (natural antioxidant molecules and enzymes) scavenges and reduces free radicals production, but sometimes it may not be sufficient to manage this stress, initiating extensive damage to biological macromolecules, proteins, nucleic acids and lipids, ultimately leading to tissue damage (Halliwell, 2012;Halliwell & Gutteridge, 1999).…”

Section: Discussionmentioning

confidence: 99%

Cytoprotective effect of methanolic extract of Nardostachys jatamansi against hydrogen peroxide induced oxidative damage in C6 glioma cells.

Dhuna

Dhuna²,

Bhatia³

et al. 2013

Acta Biochim Pol

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Oxidative stress has been implicated as an important factor in the process of neurodegeneration and hydrogen peroxide (H₂O₂) is one of the most important precursors of reactive oxygen species (ROS), responsible for many neurodegenerative diseases. This study used extracts from Nardostachys jatamansi rhizomes, known for nerve relaxing properties in Ayurvedic medicine, to ascertain their protective role in H₂O₂-induced oxidative stress in C6 glioma cells. The protective effect of methanolic, ethanolic and water extracts of N. jatamansi (NJ-MEx, NJ-EEx and NJ-WEx respectively) was determined by MTT assay. NJ-MEx significantly protected against H₂O₂ cytotoxicity when cells were pretreated for 24 h. The level of antioxidant enzymes, catalase, superoxide dismutase (Cu-ZnSOD), glutathione peroxidase (GPx), and a direct scavenger of free radicals, glutathione (GSH), significantly increased following pre-treatment with NJ-MEx. Lipid peroxidation (LPx) significantly decreased in NJ-MEx-pretreated cultures. The expression of a C6 differentiation marker, GFAP (glial fibrillary acidic protein), stress markers HSP70 (heat shock protein) and mortalin (also called glucose regulated protein 75, Grp75) significantly decreased when cells were pre-treated with NJ-MEx before being subjected to H₂O₂ treatment as shown by immunofluorescence, western blotting and RT-PCR results. The present study suggests that NJ-MEx could serve as a potential treatment and/or preventive measure against neurodegenerative diseases.

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Free radical scavengers and spin traps – therapeutic implications for ischemic stroke

Cited by 17 publications

References 91 publications

Phase I Clinical Study of Edaravone in Healthy Chinese Volunteers

Phase I Clinical Study of Edaravone in Healthy Chinese Volunteers

The Neuroprotection of Lysosomotropic Agents in Experimental Subarachnoid Hemorrhage Probably Involving the Apoptosis Pathway Triggering by Cathepsins via Chelating Intralysosomal Iron

Cytoprotective effect of methanolic extract of Nardostachys jatamansi against hydrogen peroxide induced oxidative damage in C6 glioma cells.

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