Parnetti L, Senin U, Mecocci P
Perugia University, Italy.
Drugs. 1997 May;53(5):752-68. doi: 10.2165/00003495-199753050-00003.
Although at present there is no definitive treatment or cure for Alzheimer's disease, different pharmacological strategies are being actively investigated. At present, cholinergic therapy and nootropics and some neuronotrophic agents represent the available approaches to symptomatic treatment of Alzheimer's disease. The use of cholinesterase inhibitors (ChEI) constitutes the best cholinergic approach to increase acetylcholine levels. Available data suggest that about 15 to 40% of Alzheimer's disease patients show a varying degree of cognitive improvement while taking these medications; however, haematological complications (neutropenia or agranulocytosis), together with hepatotoxicity, need to be considered carefully. Recent data suggest that long term administration of nootropics may lead to a significant improvement of cognitive functions in Alzheimer's disease patients compared with untreated individuals, having excellent tolerability. Protocols for the intracerebroventricular administration of neuronotrophic substances are also ongoing. The most promising approaches for the future currently undergoing investigation involve attempts to slow the production of beta-amyloid and/or to inhibit beta-amyloid aggregation. Another rational therapeutic approach would be to inhibit the formation of paired helical filaments (PHF) by increasing and/or modulating the activities of protein phosphatases and kinases. Antioxidant therapy should disrupt or prevent the free radical/beta-amyloid recirculating cascade and the progressive neurodegeneration. Idebenone, a synthetic compound acting as an 'electron trapper' and free radical scavenger, has shown some efficacy in degenerative and vascular dementia; at present, other different molecules having antioxidative properties [lazaroids (21-aminosteroids), pyrrolopyrimidines, nitric oxide blockers, selegiline, some vitamins] are under investigation. Lowering absorption or brain tissue concentrations of aluminium also offers possible therapeutic opportunities for slowing the rate of clinical progression of the disease; in this sense, some evidence exists using the aluminium chelating agent deferoxamine (desferrioxamine). Inflammation also may play a significant pathogenetic role in Alzheimer's disease. As shown by several retrospective analyses, there is an inverse association of anti-inflammatory drug use with the frequency of Alzheimer's disease diagnosis. Consequently, clinical trials using both nonsteroidal and steroidal molecules have been proposed. These lines of pharmacological intervention represent an important premise for future therapeutic strategies capable of counteracting the pathogenesis of Alzheimer's disease.
虽然目前尚无针对阿尔茨海默病的确切治疗方法或治愈手段，但不同的药理学策略正在积极研究中。目前，胆碱能疗法、益智药和一些神经营养药物是阿尔茨海默病症状性治疗的可用方法。使用胆碱酯酶抑制剂（ChEI）是提高乙酰胆碱水平的最佳胆碱能方法。现有数据表明，约15%至40%的阿尔茨海默病患者在服用这些药物时会出现不同程度的认知改善；然而，血液学并发症（中性粒细胞减少或粒细胞缺乏症）以及肝毒性需要仔细考虑。最近的数据表明，与未治疗的个体相比，长期服用益智药可能会使阿尔茨海默病患者的认知功能得到显著改善，且耐受性良好。脑室内给予神经营养物质的方案也在进行中。目前正在研究的未来最有前景的方法包括试图减缓β-淀粉样蛋白的产生和/或抑制β-淀粉样蛋白的聚集。另一种合理的治疗方法是通过增加和/或调节蛋白磷酸酶和激酶的活性来抑制双螺旋细丝（PHF）的形成。抗氧化疗法应破坏或预防自由基/β-淀粉样蛋白循环级联反应和进行性神经退行性变。艾地苯醌是一种作为“电子捕获剂”和自由基清除剂的合成化合物，已在退行性和血管性痴呆中显示出一定疗效；目前，其他具有抗氧化特性的不同分子[拉扎罗类化合物（21-氨基类固醇）、吡咯并嘧啶、一氧化氮阻滞剂、司来吉兰、一些维生素]正在研究中。降低铝的吸收或脑组织浓度也为减缓疾病临床进展速度提供了可能的治疗机会；从这个意义上说，有证据表明使用铝螯合剂去铁胺（去铁敏）有效。炎症在阿尔茨海默病中也可能起重要的致病作用。几项回顾性分析表明，使用抗炎药物与阿尔茨海默病诊断频率呈负相关。因此，已提出使用非甾体和甾体分子的临床试验。这些药理学干预措施是未来能够对抗阿尔茨海默病发病机制的治疗策略的重要前提。
