Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease
Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease
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DOI：
10.1124/jpet.108.137455
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发表时间：
2008-07-01
影响因子：
3.5
通讯作者：
Frautschy, Sally A.
中科院分区：
文献类型：
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作者：
Begum, Aynun N.;Jones, Mychica R.;Frautschy, Sally A.
姜黄素可以减少炎症和神经变性，但其化学不稳定性和代谢引起了人们的关注，包括更稳定的代谢物四氢姜黄素（TC）是否可能介导疗效。我们研究了姜黄素和TC的抗氧化、抗炎或抗淀粉样变性作用，无论是长期给药给龄Tg2576 APPsw小鼠，还是急性给药给脂多糖（LPS）注射野生型小鼠。尽管与姜黄素灌胃相比，TC后血浆药物水平显著升高，但大脑中母体化合物的水平相似，与lps刺激的诱导型一氧化氮合酶、硝基酪氨酸、F2异前列腺素和羰基的减少有关。在急性（LPS）和慢性炎症（Tg2576）中，TC和姜黄素相似地降低了白细胞介素-1 β。尽管有这些相似之处，只有姜黄素能有效减少淀粉样斑块负担、不溶性β -淀粉样肽（A β）和羰基。TC对斑块或不溶性A β没有影响，但都降低了tris缓冲的盐溶性A β和磷酸c- jun nh2末端激酶（JNK）。姜黄素而不是TC阻止A β聚集。在长期喂食母体化合物的小鼠脑和血浆中检测到TC代谢物。这些数据表明，姜黄素中的二烯酮桥对于减少阿尔茨海默病模型中的斑块沉积和蛋白质氧化是必要的，而TC中没有。然而，TC确实减少了神经炎症和可溶性A β，这可能是由于限制了jnk介导的转录。由于其良好的安全性以及多种慢性退行性疾病中错误折叠蛋白、氧化损伤和炎症的参与，这些有关姜黄素剂量与疗效所需的血液和组织水平相关的数据应该有助于多个成功的临床前模型的翻译工作。
Curcumin can reduce inflammation and neurodegeneration, but its chemical instability and metabolism raise concerns, including whether the more stable metabolite tetrahydrocurcumin (TC) may mediate efficacy. We examined the antioxidant, anti-inflammatory, or anti-amyloidogenic effects of dietary curcumin and TC, either administered chronically to aged Tg2576 APPsw mice or acutely to lipopolysaccharide (LPS)-injected wild-type mice. Despite dramatically higher drug plasma levels after TC compared with curcumin gavage, resulting brain levels of parent compounds were similar, correlating with reduction in LPS-stimulated inducible nitric-oxide synthase, nitrotyrosine, F2 isoprostanes, and carbonyls. In both the acute (LPS) and chronic inflammation (Tg2576), TC and curcumin similarly reduced interleukin-1 beta. Despite these similarities, only curcumin was effective in reducing amyloid plaque burden, insoluble beta-amyloid peptide (A beta), and carbonyls. TC had no impact on plaques or insoluble A beta, but both reduced Tris-buffered saline-soluble A beta and phospho-c-Jun NH2-terminal kinase (JNK). Curcumin but not TC prevented A beta aggregation. The TC metabolite was detected in brain and plasma from mice chronically fed the parent compound. These data indicate that the dienone bridge present in curcumin, but not in TC, is necessary to reduce plaque deposition and protein oxidation in an Alzheimer's model. Nevertheless, TC did reduce neuroinflammation and soluble A beta, effects that may be attributable to limiting JNK-mediated transcription. Because of its favorable safety profile and the involvement of misfolded proteins, oxidative damage, and inflammation in multiple chronic degenerative diseases, these data relating curcumin dosing to the blood and tissue levels required for efficacy should help translation efforts from multiple successful preclinical models.