A cerebral metabolism imaging study on neuroprotection and neurotoxicity of nonsteroidal anti-inflammatory drugs
| Project/Area Number |
21591482
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Psychiatric science
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| Research Institution | University of Fukui |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
FUJIBAYASHI Yasuhisa 放射線医学総合研究所, 分子イメージングセンター, センター長 (50165411)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 脳スライス / NSAIDs / グルコース代謝 / ミトコンドリア機能 / ポジトロン / 神経毒性 / 神経保護 / Reye脳症 / アラキドン酸 |
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| Research Abstract |
Nonsteroidal anti-inflammatory drugs(NSAIDs) have recently attracted increasing attention due to their cytotoxic adverse reactions(such as Reye encephalopathy and gastrointestinal ulcer) and neuroprotective efficacy(against neurodegenerative disease, mood disorder, and other conditions), in addition to their general pharmacological actions(anti-inflammatory, analgesic, and antipyretic). In this study, we conducted an experiment involving the incorporation of[^<18> F] 2-fluoro-2-deoxy-D-glucose([^<18> F] FDG), a tracer of glucose metabolism, by applying a dynamic positron autoradiography technique(dPAT) in fresh brain slices obtained from rats, and quantitatively evaluated the effects of different types of NSAID on the local cerebral metabolic rate of glucose(CMRglc). The classic non-selective NSAIDs(salicylate and indomethacin) showed a concentration-dependent(100μM to 1 mM) increase of CMRglc in all cerebral regions studied, while the selective COX-2 inhibitors(celecoxib and rofecoxib
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) demonstrated an increase of CMRglc in a much lower concentration range(3 to 100μM) in all cerebral regions. For both types of NSAID, the increase of CMRglc was almost completely inhibited by BAPTA-AM, a chelate agent for intracellular calcium, suggesting the involvement of a COX selectivity-independent rise in the intracellular calcium level. Furthermore, we investigated the effects of different types of NSAID on mitochondrial function in the brain. As a result, the non-selective NSAIDs led to a significant decline in mitochondrial function at the concentrations nearly equivalent to those at which an increase in CMRglc was observed compared to the control group, while the selective COX-2 inhibitors led to no significant decline in mitochondrial function. In conclusion, disturbance of mitochondrial aerobic glucose metabolism(together with an increase in compensatory anaerobic glucose metabolism) may occur specifically with non-selective NSAIDs, but not selective COX-2 inhibitors, through a rise in the intracellular calcium level, suggesting the possibility that such variation in metabolic activities in the brain may be involved in the neurotoxicity and cytotoxic adverse reactions(Reye encephalopathy) due to NSAIDs. Further investigation of the mechanisms of neurotoxicity and neuroprotection of NSAIDs, providing clues for the development of new NSAIDs with more benefits and fewer adverse reactions, would be useful for healthcare and society, and is an extremely important issue. Less
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Report
(4 results)
Research Products
(3 results)
