| Propofol hemisuccinate protects neuronal cells from oxidative injury. | |
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MedLine Citation:
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PMID: 10582614 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Oxidative stress contributes to the neuronal death observed in neurodegenerative disorders and neurotrauma. Some antioxidants for CNS injuries, however, have yet to show mitigating effects in clinical trials, possibly due to the impermeability of antioxidants across the blood-brain barrier (BBB). Propofol (2,6-diisopropylphenol), the active ingredient of a commonly used anesthetic, acts as an antioxidant, but it is insoluble in water. Therefore, we synthesized its water-soluble prodrug, propofol hemisuccinate sodium salt (PHS), and tested for its protective efficacy in neuronal death caused by non-receptor-mediated, oxidative glutamate toxicity. Glutamate induces apoptotic death in rat cortical neurons and the mouse hippocampal cell line HT-22 by blocking cystine uptake and causing the depletion of intracellular glutathione, resulting in the accumulation of reactive oxygen species (ROS). PHS has minimal toxicity and protects both cortical neurons and HT-22 cells from glutamate. The mechanism of protection is attributable to the antioxidative property of PHS because PHS decreases the ROS accumulation caused by glutamate. Furthermore, PHS protects HT-22 cells from oxidative injury induced by homocysteic acid, buthionine sulfoximine, and hydrogen peroxide. For comparison, we also tested alpha-tocopherol succinate (TS) and methylprednisolone succinate (MPS) in the glutamate assay. Although TS is protective against glutamate at lower concentrations than PHS, TS is toxic to HT-22 cells. In contrast, MPS is nontoxic but also nonprotective against glutamate. Taken together, PHS, a water-soluble prodrug of propofol, is a candidate drug to treat CNS injuries owing to its antioxidative properties, low toxicity, and permeability across the BBB. |
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Authors:
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Y Sagara; S Hendler; S Khoh-Reiter; G Gillenwater; D Carlo; D Schubert; J Chang |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of neurochemistry Volume: 73 ISSN: 0022-3042 ISO Abbreviation: J. Neurochem. Publication Date: 1999 Dec |
Date Detail:
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Created Date: 1999-12-27 Completed Date: 1999-12-27 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 2985190R Medline TA: J Neurochem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 2524-30 Citation Subset: IM |
Affiliation:
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Salk Institute for Biological Studies, La Jolla 92037, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects Buthionine Sulfoximine / pharmacology Glutamic Acid / toxicity Hippocampus / cytology Homocysteine / analogs & derivatives, pharmacology Hydrogen Peroxide / pharmacology Methylprednisolone / pharmacology Mice Neurons / drug effects* Neuroprotective Agents / pharmacology* Neurotoxins / pharmacology Oxidative Stress Propofol / pharmacology* Rats Reactive Oxygen Species Tocopherols Vitamin E / analogs & derivatives, pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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5PO1NS28121/NS/NINDS NIH HHS; F32NS10032/NS/NINDS NIH HHS; R01NS09658/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Neuroprotective Agents; 0/Neurotoxins; 0/Reactive Oxygen Species; 1001-13-4/homocysteic acid; 1406-18-4/Vitamin E; 1406-66-2/Tocopherols; 2078-54-8/Propofol; 454-28-4/Homocysteine; 5072-26-4/Buthionine Sulfoximine; 56-86-0/Glutamic Acid; 7722-84-1/Hydrogen Peroxide; 83-43-2/Methylprednisolone |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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