NICM Health Research Institute, Western Sydney University, 158-160 Hawkesbury Rd, Westmead, NSW, 2145, Australia.
Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, NSW, 2560, Australia.
J Neural Transm (Vienna). 2022 Jun;129(5-6):755-771. doi: 10.1007/s00702-022-02480-x. Epub 2022 Mar 16.
Prof. Dr. Peter Riederer, the former Head of the Neurochemistry Department of the Psychiatry and Psychotherapy Clinic at the University of Würzburg (Germany), has been one of the pioneers of research into oxidative stress in Parkinson's and Alzheimer's disease (AD). This review will outline how his scientific contribution to the field has opened a new direction for AD treatment beyond "plaques and tangles". In the 1990s, Prof. Riederer was one of the first scientists who proposed oxidative stress and neuroinflammation as one of the major contributors to Alzheimer's disease, despite the overwhelming support for the "amyloid-only" hypothesis at the time, which postulated that the sole and only cause of AD is β-amyloid. His group also highlighted the role of advanced glycation end products, sugar and dicarbonyl-derived protein modifications, which crosslink proteins into insoluble aggregates and potent pro-inflammatory activators of microglia. For the treatment of chronic neuroinflammation, he and his group suggested that the most appropriate drug class would be cytokine-suppressive anti-inflammatory drugs (CSAIDs) which have a broader anti-inflammatory action range than conventional non-steroidal anti-inflammatory drugs. One of the most potent CSAIDs is curcumin, but it suffers from a variety of pharmacokinetic disadvantages including low bioavailability, which might have tainted many human clinical trials. Although a variety of oral formulations with increased bioavailability have been developed, curcumin's absorption after oral delivery is too low to reach therapeutic concentrations in the micromolar range in the systemic circulation and the brain. This review will conclude with evidence that rectally applied suppositories might be the best alternatives to oral medications, as this route will be able to evade first-pass metabolism in the liver and achieve high concentrations of curcumin in plasma and tissues, including the brain.
彼得·里德勒教授（Prof. Dr. Peter Riederer）曾任德国维尔茨堡大学精神病学和心理治疗诊所神经化学系主任，是帕金森病和阿尔茨海默病（AD）氧化应激研究的先驱之一。这篇综述将概述他在该领域的科学贡献如何为 AD 治疗开辟了超越“斑块和缠结”的新方向。在 20 世纪 90 年代，里德勒教授是最早提出氧化应激和神经炎症是导致阿尔茨海默病的主要因素之一的科学家之一，尽管当时压倒性地支持“淀粉样蛋白唯一”假说，该假说认为 AD 的唯一原因是β-淀粉样蛋白。他的研究小组还强调了晚期糖基化终产物、糖和二羰基衍生的蛋白质修饰的作用，这些产物将蛋白质交联成不溶性聚集体，并成为小胶质细胞的强效促炎激活剂。对于慢性神经炎症的治疗，他和他的研究小组建议最适合的药物类别是细胞因子抑制性抗炎药物（CSAIDs），它们的抗炎作用范围比传统的非甾体抗炎药更广。最有效的 CSAIDs 之一是姜黄素，但它存在多种药代动力学缺点，包括生物利用度低，这可能使许多人体临床试验受到影响。尽管已经开发出了多种具有更高生物利用度的口服制剂，但姜黄素经口服给药后的吸收太低，无法在全身循环和大脑中达到治疗浓度范围内的微摩尔级。这篇综述将以证据为结论，即直肠应用栓剂可能是口服药物的最佳替代品，因为这种途径能够避免肝脏的首过代谢，并在血浆和组织（包括大脑）中达到姜黄素的高浓度。
