BACKGROUND & AIMS: :The effect of rasagiline on learning and memory in Lister-Hooded rats was investigated in this study. Two cognitive tests were used: a 24-h temporal deficit novel object recognition test and a modified water maze task. Rasagiline (0.3 and 1 mg/kg) was administered subcutaneously 15 min before the cognitive tests. In a novel object recognition test, rasagiline treatment enhanced object recognition memory. A small effect was observed with 0.3 mg/kg rasagiline; at 1 mg/kg, rasagiline-treated animals spent twice as much time exploring the novel object. On the water maze test, the use of an on-demand platform allowed adjustment of the difficulty of this spatial learning task. This enabled the detection of a small positive effect of rasagiline (1 mg/kg) on spatial learning, which was not observed in earlier reports. For the first time, our study has showed the procognitive effect of rasagiline in young healthy rats. On the basis of these findings, a monoamine oxidase-B inhibitor would seem to be a potential symptomatic treatment for cognitive impairments affecting patients with neurodegenerative disorders.

背景与目标： : 本研究研究了雷沙吉兰对Lister-hooled大鼠学习和记忆的影响。使用了两种认知测试: 24小时时间缺陷新颖物体识别测试和改良的水迷宫任务。在认知测试前15分钟皮下施用雷沙吉兰 (0.3和1 mg/kg)。在一种新颖的物体识别测试中，雷沙吉兰处理增强了物体识别记忆。用0.3 mg/kg雷沙吉兰观察到很小的效果; 在1 mg/kg时，雷沙吉兰处理的动物花费了两倍的时间来探索新对象。在水迷宫测试中，使用按需平台可以调整此空间学习任务的难度。这使得可以检测到雷沙吉兰 (1 mg/kg) 对空间学习的微小积极作用，这在较早的报道中没有观察到。我们的研究首次显示了雷沙吉兰对年轻健康大鼠的前认知作用。基于这些发现，单胺氧化酶-B抑制剂似乎是影响神经退行性疾病患者的认知障碍的潜在对症治疗。

BACKGROUND & AIMS: :A neuroprotective therapy is the single most important unmet medical need in Parkinson's disease. Several promising agents in the laboratory have been tested in the clinic, but none has been established in clinical trials to have a disease modifying effect despite positive results because of potential confounding symptomatic or pharmacologic effects. The delayed start design was developed to try to avoid a symptomatic confound when testing a putative neuroprotective therapy. In this study design, patients are randomly assigned to study drug or placebo in the first phase of the study, and both groups receive the active drug in the second phase. If benefits seen at the end of phase I persist through the end of phase II, they cannot be readily explained by a symptomatic effect (as patients in both groups are receiving the same medication) and benefits in the early start group must relate to the early initiation of the treatment. Although the precise mechanism responsible for such an effect can be debated, positive results in a delayed start study indicate that patients who receive early treatment have a better outcome than those where the treatment is delayed. We are using the delayed start design to assess the potential disease modifying effects of rasagiline in a prospective double blind controlled trial (the ADAGIO study). We here describe the rationale for the study and baseline characteristics of the 1,176 patients who have been enrolled into the trial.

背景与目标： : 神经保护疗法是帕金森氏病中最重要的未满足的医疗需求。实验室中的几种有前途的药物已经在临床上进行了测试，但是在临床试验中，尽管由于潜在的混淆症状或药理作用而获得了积极的结果，但没有一个具有疾病缓解作用。开发了延迟启动设计，以避免在测试假定的神经保护疗法时出现症状混淆。在此研究设计中，患者在研究的第一阶段被随机分配到研究药物或安慰剂，两组在第二阶段均接受活性药物。如果在I期结束时看到的益处持续到II期结束时，则不能很容易地用症状效应来解释 (因为两组患者都接受相同的药物治疗)，并且早期开始组的益处必须与早期开始治疗有关。尽管可以讨论导致这种作用的确切机制，但延迟开始研究中的积极结果表明，接受早期治疗的患者比延迟治疗的患者有更好的结果。在一项前瞻性双盲对照试验 (ADAGIO研究) 中，我们正在使用延迟启动设计来评估雷沙吉兰的潜在疾病修饰作用。我们在这里描述研究的基本原理和已纳入试验的1,176患者的基线特征。

BACKGROUND & AIMS: :Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-β and amyloid-β protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways.

背景与目标： : 阿尔茨海默氏病 (AD) 是一种多因素综合征，在其进展过程中涉及一系列复杂的不同而相关的因素。因此，可以同时调节多个与疾病相关的靶标的新颖方法为有效治疗AD带来了巨大希望。这篇综述描述了具有多峰活性的新型杂化分子的发展，包括: i) M30，具有螯合和神经保护活性的脑渗透性选择性单胺氧化酶 (MAO)-A和-B抑制剂; ii) HLA20，具有神经保护活性的脑渗透性金属螯合剂; iii) HLA20A，乙酰胆碱酯酶 (AChE) 抑制剂，具有位点激活的螯合和神经保护活性; iv) M30D，AChE和mao-a和-B抑制剂，具有位点激活的螯合和神经保护活性; v) 神经保护氨基酸肽的类似物NAPVSIPQ。HLA20A和M30D充当亲螯合剂，可以通过伪抑制AChE来激活其各自的活性螯合剂HLA20和M30。我们首先讨论这些新型化合物的合理设计的知识和基于结构的策略。然后，我们回顾了我们最近对这些候选药物的研究，关于它们在体外和体内的广泛活性，重点是抗氧化剂螯合效力和AchE和MAO-A和-B抑制活性，以及神经保护/神经受体作用。最后，我们讨论了这些化合物与AD相关的多种分子作用机制，包括淀粉样 β 和淀粉样 β 蛋白前体表达/加工的调节; 诱导细胞周期停滞; 抑制神经元死亡标志物; 和神经营养因子的上调，以及蛋白激酶信号通路的激活。

BACKGROUND & AIMS: :The ADAGIO study demonstrated a symptomatic benefit for rasagiline in early Parkinson's disease (PD) and suggested a disease-modifying effect. Evidence indicates that mitochondrial dysfunction plays a role in the pathogenesis of PD and that this may be the site of effect for rasagiline. In this systematic review, evidence for the role of mitochondria in the pathogenesis of PD are reviewed in light of other proposed mechanisms of neuronal degeneration and the actions of rasagiline and its component parts, namely propargylamine and the metabolite, aminoindan. Evidence for the role of mitochondria in the pathogenesis and treatment of PD are reviewed in light of other proposed mechanisms of neuronal degeneration and clinical actions of rasagiline. Monoamine oxidase B (MAO-B) located in the outer mitochondrial membrane controls dopamine metabolism in early PD, and this is the likely location for the symptomatic action of rasagiline. Accumulating evidence indicates that mitochondrial impairment contributes to dopaminergic neuronal loss in PD, either directly or through other mechanisms such as oxidative stress or protein misfolding. Further rasagiline affects numerous mitochondrial mechanisms that prevent apoptotic cell death including prevention of opening of the mitochondrial transition pore, decreased release of cytochrome C, alterations in pro-antiapoptotic genes and proteins, and the nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Thus, the functional neuroprotective actions of rasagiline may not be dependent on MAO-B inhibition, but rather may involve actions of the propargylamine moiety and the aminoindan metabolite. An accumulating body of literature indicates a mitochondrial site of action for rasagiline and highlights the neuroprotective action of the drug, providing strong biological plausibility for disease-modifying effects of the drug such as those observed in ADAGIO.

背景与目标： : ADAGIO研究证明了雷沙吉兰在早期帕金森氏病 (PD) 中的症状益处，并暗示了疾病的改善作用。有证据表明，线粒体功能障碍在PD的发病机理中起作用，这可能是雷沙吉兰的作用部位。在本系统综述中，根据其他拟议的神经元变性机制以及雷沙吉兰及其组成部分 (即丙胺和代谢物氨基吲哚) 的作用，综述了线粒体在PD发病机理中的作用的证据。根据其他拟议的神经元变性机制和雷沙吉兰的临床作用，综述了线粒体在PD发病机理和治疗中的作用的证据。位于线粒体外膜的单胺氧化酶B (mao-b) 控制PD早期的多巴胺代谢，这是雷沙吉兰的症状作用的可能位置。越来越多的证据表明，线粒体损伤直接或通过其他机制 (例如氧化应激或蛋白质错误折叠) 导致PD中的多巴胺能神经元丢失。雷沙吉兰进一步影响许多防止凋亡细胞死亡的线粒体机制，包括防止线粒体过渡孔的打开，细胞色素C的释放减少，促凋亡基因和蛋白质的改变以及3-磷酸甘油醛脱氢酶 (GAPDH) 的核易位。因此，雷沙吉兰的功能性神经保护作用可能不依赖于mao-b抑制，而是可能涉及炔丙胺部分和氨基吲哚代谢物的作用。大量文献表明雷沙吉兰的线粒体作用位点，并强调了该药物的神经保护作用，为该药物的疾病缓解作用 (例如在ADAGIO中观察到的作用) 提供了强大的生物学合理性。

BACKGROUND & AIMS: UNLABELLED:In recent years, monoamine oxidase B (MAO-B) inhibitors have become widely used in the treatment of early-stage Parkinson's disease. (11)C-l-deprenyl PET has been used by others to characterize MAO-B ligands in terms of their in vivo potency toward MAO-B and duration of action. In this study, we used (11)C-l-deprenyl PET to demonstrate the specific binding characteristics of the new irreversible selective MAO-B inhibitor rasagiline in 3 healthy volunteers. METHODS:The healthy volunteers received 1 mg of rasagiline daily for 10 d. Dynamic (11)C-l-deprenyl PET brain scans were acquired before the first treatment (scan 1) and immediately (scan 2), 2-3 wk (scan 3), and 4-6 wk (scan 4) after the final treatment. RESULTS:On scan 1, all subjects showed the highest l-deprenyl uptake in the thalamus and basal ganglia, with fairly high activity also in the cortex and cerebellum and much lower activity in the white matter. The areas of high uptake were absent from scan 2, on which activity throughout the brain was comparable to that in white matter, presumably because of blocking of MAO-B binding sites by rasagiline. Gradual recovery toward the baseline state was observed in the weeks after termination of treatment (scans 3 and 4). CONCLUSION:(11)C-l-deprenyl PET showed binding of rasagiline to MAO-B, confirming blocking of MAO-B sites after 10 d of treatment with 1 mg of rasagiline per day, with immediate post-rasagiline treatment tracer uptake and metabolism in the basal ganglia compatible only with nonspecific binding. Subsequent gradual recovery was also seen, with return to near-baseline uptake. This finding is compatible with the known rate of de novo synthesis of MAO-B, confirming the irreversible binding of rasagiline.

背景与目标：

BACKGROUND & AIMS: :The inhibitors of monoamine oxidase B (MAO B) are effectively used as therapeutic drugs for neuropsychiatric and neurodegenerative diseases. However, their mechanism of action is not clear, since the neuroprotective effect of MAO B inhibitors is associated with the blockage of glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-death cascade, rather than the inhibition of MAO B. Here, we provide evidence that GAPDH potentiates the ethanol-induced activity of MAO B and brain cell toxicity. The levels of nuclear GAPDH and MAO B activity are significantly increased in brain-derived cell lines upon 75 mM ethanol-induced cell death. Over-expression of GAPDH in cells enhances ethanol-induced cell death, and also increases the ethanol-induced activation of MAO B. In contrast, the MAO B inhibitors rasagiline and selegiline (0.25 nM) and the rasagiline metabolite, 1-R-aminoindan (1 muM) decreases the ethanol-induced MAO B, prevents nuclear translocation of GAPDH and reduces cell death. In addition, GAPDH interacts with transforming growth factor-beta-inducible early gene (TIEG2), a transcriptional activator for MAO B, and this interaction is increased in the nucleus by ethanol but reduced by MAO B inhibitors and 1-R-aminoindan. Furthermore, silencing TIEG2 using RNAi significantly reduces GAPDH-induced MAO B upregulation and neurotoxicity. In summary, ethanol-induced cell death, attenuated by MAO B inhibitors, may result from disrupting the movement of GAPDH with the transcriptional activator into the nucleus and secondly inhibit MAO B gene expression. Thus, the neuroprotective effects of rasagiline or 1-R-aminoindan on ethanol-induced cell death mediated by a novel GAPDH-MAO B pathway may provide a new insight in the treatment of neurobiological diseases including alcohol-use disorders.

背景与目标： : 单胺氧化酶B (maob) 抑制剂被有效地用作神经精神和神经退行性疾病的治疗药物。然而，它们的作用机制尚不清楚，因为MAO B抑制剂的神经保护作用与glyceraldehyde-3-phosphate脱氢酶 (GAPDH)-死亡级联的阻断有关，而不是与MAO B的抑制有关。我们提供了GAPDH增强乙醇诱导的MAO B活性和脑细胞毒性的证据。在75 mM乙醇诱导的细胞死亡后，脑源性细胞系中的核GAPDH和MAO B活性水平显着增加。GAPDH在细胞中的过表达增强了乙醇诱导的细胞死亡，也增加了乙醇诱导的MAO B的活化。相反，MAO B抑制剂雷沙吉兰和司来吉兰 (0.25 nM) 和雷沙吉兰代谢物1-r-氨基吲哚 (1 muM) 降低了乙醇诱导的MAO B，防止GAPDH的核易位并减少细胞死亡。此外，GAPDH与转化生长因子-β 诱导的早期基因 (TIEG2) 相互作用，TIEG2是MAO B的转录激活因子，这种相互作用在细胞核中被乙醇增加，但被MAO B抑制剂和1-r-氨基吲哚减少。此外，使用RNAi沉默TIEG2可显着降低GAPDH诱导的MAO B上调和神经毒性。总之，乙醇诱导的细胞死亡，由MAO B抑制剂减弱，可能是由于用转录激活因子破坏GAPDH进入细胞核的运动，其次抑制MAO B基因表达。因此，雷沙吉兰或1-r-氨基吲哚对由新型GAPDH-MAO B途径介导的乙醇诱导的细胞死亡的神经保护作用可能为治疗包括酒精使用障碍在内的神经生物学疾病提供新的见解。

BACKGROUND & AIMS: :Rasagiline (Azilect(®)) is an oral, second-generation, selective, irreversible monoamine oxidase-B (MAO-B) inhibitor approved in the US for the treatment of Parkinson's disease. In randomized, controlled trials, oral rasagiline 1 mg once daily was superior to placebo in the symptomatic treatment of early Parkinson's disease, both as monotherapy or as an adjunct to dopamine agonists. Comparisons of early-start and delayed-start treatment suggested a disease-modifying effect for rasagiline, but the results were equivocal. Rasagiline 0.5 or 1 mg/day was also superior to placebo as adjunctive therapy to levodopa in Parkinson's disease patients with motor fluctuations. Rasagiline was generally well tolerated in clinical trials, displaying a placebo-like tolerability profile in several studies. Cost-utility studies predicted that rasagiline, either as monotherapy or adjunctive therapy, would be a cost-effective treatment option. Therefore, oral rasagiline is a valuable therapeutic option for use in all stages of Parkinson's disease.

背景与目标： : 雷沙吉兰 (Azilect (®)) 是一种口服，第二代，选择性，不可逆的单胺氧化酶-B (mao-b) 抑制剂，在美国被批准用于治疗帕金森氏病。在随机对照试验中，口服雷沙吉兰1 mg，每日一次，在对早期帕金森氏病的对症治疗方面优于安慰剂，无论是作为单药治疗还是作为多巴胺激动剂的辅助治疗。早期开始和延迟开始治疗的比较表明雷沙吉兰具有改善疾病的作用，但结果模棱两可。在运动波动的帕金森氏病患者中，雷沙吉兰0.5或1 mg/天也优于安慰剂作为左旋多巴的辅助治疗。雷沙吉兰在临床试验中通常耐受性良好，在多项研究中显示出类似安慰剂的耐受性。成本效用研究预测，雷沙吉兰作为单一疗法或辅助疗法，将是一种具有成本效益的治疗选择。因此，口服雷沙吉兰是用于帕金森氏病所有阶段的有价值的治疗选择。

BACKGROUND & AIMS: :Sprague-Dawley rats received a unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum and were treated daily for 6 weeks with increasing doses of monoamine oxidase type B inhibitor rasagiline [R(+)-N-propargyl-1-aminoindane] or saline (controls). Both doses of rasagiline markedly increased the survival of dopaminergic neurons in the lesioned substantia nigra, compared to controls (+97% and +119%, respectively). Treatment with the lower dose of rasagiline also abolished the motor stereotypies associated with nigrostriatal lesion. Our study supports the neuroprotective potential of chronic rasagiline administration in an experimental model of Parkinson's disease (PD).

背景与目标： : Sprague-Dawley大鼠接受单侧向纹状体注射6-羟基多巴胺 (6-OHDA)，每天用增加剂量的单胺氧化酶b型抑制剂雷沙吉兰 [R ()-N-propargyl-1-aminoindane] 或生理盐水 (对照) 治疗6周。与对照组相比，两种剂量的雷沙吉兰均显着增加了病变黑质中多巴胺能神经元的存活 (分别为97% 和119%)。用较低剂量的雷沙吉兰治疗也消除了与黑质纹状体病变相关的运动刻板印象。我们的研究支持在帕金森氏病 (PD) 的实验模型中慢性雷沙吉兰给药的神经保护潜力。

BACKGROUND & AIMS: :Stress can affect the brain and lead to depression; however, the molecular pathogenesis is unclear. An association between stress and stress-induced hypersecretion of glucocorticoids occurs during stress. Dexamethasone (a synthetic glucocorticoid steroid) has been reported to induce apoptosis and increase the activity of monoamine oxidase (MAO) (Youdim et al. 1989). MAO is an enzyme for the degradation of aminergic neurotransmitters; dopamine, noradrenaline and serotonin and dietary amines and MAO inhibitors are classical antidepressant drugs. In this study, we have compared the ability of rasagiline (Azilect) and its main metabolite, R-aminoindan with selegiline (Deprenyl) in prevention of dexamethasone-induced brain cell death employing human neuroblastoma SH-SY5Y cells and glioblastoma 1242-MG cells. Dexamethasone reduced cell viability as measured by MTT test, but rasagiline, selegiline, and 1-R-aminoindan could significantly prevent dexamethasone-induced brain cell death. Among three drugs, rasagiline had the highest neuroprotective effect. Furthermore, the inhibitory effects of these drugs on MAO B catalytic activity and on apoptotic DNA damage (TUNEL staining) were examined. Rasagiline exhibited highest inhibition on MAO B enzymatic activity and prevention on DNA damage as compared to selegiline and 1-R-aminoindan. In summary, the greater neuroprotective effect of rasagiline may be associated with the combination of the parent drug and its metabolite 1-R-aminoindan.

背景与目标： : 压力会影响大脑并导致抑郁; 然而，分子发病机制尚不清楚。压力与压力引起的糖皮质激素分泌过多之间存在关联。据报道，地塞米松 (一种合成的糖皮质激素类固醇) 诱导细胞凋亡并增加单胺氧化酶 (MAO) 的活性 (Youdim等人1989)。MAO是一种用于降解胺能神经递质的酶; 多巴胺，去甲肾上腺素和5-羟色胺以及膳食胺和MAO抑制剂是经典的抗抑郁药。在这项研究中，我们比较了雷沙吉兰 (Azilect) 及其主要代谢物R-氨基吲哚与司来吉兰 (Deprenyl) 在使用人神经母细胞瘤SH-SY5Y细胞和胶质母细胞瘤1242 MG细胞预防地塞米松诱导的脑细胞死亡的能力。通过MTT测试，地塞米松降低了细胞活力，但是雷沙吉兰，司来吉兰和1-r-氨基吲哚可以显着防止地塞米松诱导的脑细胞死亡。在三种药物中，雷沙吉兰的神经保护作用最高。此外，还研究了这些药物对MAO B催化活性和凋亡DNA损伤 (TUNEL染色) 的抑制作用。与司来吉兰和1-r-氨基吲哚相比，雷沙吉兰对MAO B酶活性的抑制作用和对DNA损伤的预防作用最高。总之，雷沙吉兰更大的神经保护作用可能与母体药物及其代谢物1-r-氨基吲哚的组合有关。

BACKGROUND & AIMS: INTRODUCTION:Rasagiline (Azilect, AGN 1135) is a selective irreversible inhibitor of monoamine oxidase B (MAO-B). MAO-B regulates the brain concentrations of important neurotransmitters that are related to movement, emotion, and cognition. Oral rasagiline, as monotherapy or as adjunctive therapy to levodopa, was effective in the symptomatic treatment of adult patients with Parkinson's disease participating in double-blind, placebo-controlled, international studies. AREAS COVERED:This article reviews the reported adverse effects of rasagiline. A MEDLINE search was performed for all articles from 1990 to present, which reported any adverse effects from rasagiline or related references. We conducted an analysis of the adverse effects of rasagiline based on the reported clinical studies. Furthermore, we compared the incidence of adverse events in clinical trials for rasagiline and placebo. EXPERT OPINION:Among the most frequently reported adverse effects for rasagiline as monotherapy are headache, dizziness, and insomnia. Depression, dizziness, somnolence, and other sleep disorders are reported when used in combination therapy. Our analysis demonstrates that the most frequently reported adverse effects in trials did not occur more often with rasagiline than placebo. In conclusion, rasagiline is a well-tolerated MAO-B inhibitor that may help to achieve the desired level of clinical benefit in Parkinson's disease.

背景与目标：

BACKGROUND & AIMS: :Our studies have provided new insights into the biological mechanism of neuroprotection of the anti-Parkinson drug, rasagiline [N-propargyl-(1R)-aminoindan], involving the association of Bcl-2 family proteins with protein kinase C (PKC) pathway. In a model of serum withdrawal-induced apoptosis of rat pheochromocytoma PC12 cells, rasagiline and its propargyl moiety, N-propargylamine, decreased cell death via multiple neuroprotective pathways that include the stimulation of PKC phosphorylation; upregulation of PKCepsilon mRNA; induction of Bcl-X(L), Bcl-w, and brain-derived neurotrophic factor (BDNF) mRNAs; and downregulation of PKCgamma, Bad, and Bax mRNAs. Moreover, these drugs inhibited the cleavage and activation of pro-caspase-3 and poly(ADP-ribose) polymerase (PARP), while PKC inhibitor, GF109203X, reversed these actions. In addition, rasagiline decreased serum-free-induced levels of the important regulator of cell death, Bad, which was also blocked by GF109203X, indicating the involvement of PKC-dependent cell survival activity of rasagiline. Structure activity studies have established that N-propargylamine is essential for the novel neuroprotective and the neuronal cell survival activity of rasagiline since this moiety itself revealed similar protective effects and mechanisms of action. These results have led us to develop several multifunctional neuroprotective drugs containing the propargyl moiety and iron-chelating property for the treatment and/or prevention of neurodegenerative diseases.

背景与目标： : 我们的研究为抗帕金森药物雷沙吉兰 [N-炔丙基-(1R)-氨基吲哚] 的神经保护生物学机制提供了新的见解，涉及Bcl-2家族蛋白与蛋白激酶C (PKC) 途径的关联。在血清戒断诱导的大鼠嗜铬细胞瘤PC12细胞凋亡模型中，雷沙吉兰及其炔丙基部分N-炔丙胺通过多种神经保护途径减少细胞死亡，包括刺激PKC磷酸化; PKCepsilon mRNA的上调; Bcl-X(L)，Bcl-w，和脑源性神经营养因子 (BDNF) mrna; 以及PKCgamma，Bad和Bax mrna的下调。此外，这些药物抑制了pro-caspase-3和聚 (ADP-核糖) 聚合酶 (PARP) 的裂解和激活，而PKC抑制剂GF109203X逆转了这些作用。此外，雷沙吉兰降低了无血清诱导的细胞死亡的重要调节剂Bad的水平，这也被GF109203X阻断，表明雷沙吉兰参与了PKC依赖性细胞存活活性。结构活性研究已经确定，N-炔丙胺对于雷沙吉兰的新型神经保护和神经元细胞存活活性至关重要，因为该部分本身揭示了类似的保护作用和作用机制。这些结果使我们开发了几种含有炔丙基部分和铁螯合性质的多功能神经保护药物，用于治疗和/或预防神经退行性疾病。

BACKGROUND & AIMS: BACKGROUND/AIMS:Transdermal patch administration results in a locally high concentration of drug that induce local toxicity, including tumorogenicity. As a worst-case scenario for consequences of repeated application on neoplastic growth, the melanin-binding drug, rasagiline, was used in a transdermal formulation applied directly to a human-derived melanoma to determine the effects on tumor growth. MATERIALS AND METHODS:Rasagiline mesylate was administered either orally or transdermally to athymic mice implanted with human melanoma (SKMEL28) to determine the effects on tumor growth and survival. Over a 21-day period, animals were administered daily oral gavage (15 mg/kg) or one or two rasagiline mesylate transdermal patches every 3 days. After the last dose administration, blood samples were collected to confirm drug exposure. RESULTS:All animals from the untreated, vehicle and rasagiline groups survived to the end of the study; however, 7 out of the 10 cisplatin-treated animals died before the end of the study. Rasagiline mesylate dosed either via the oral or transdermal routes had comparable plasma exposure and, unexpectedly, significantly reduced absolute tumor volumes and tumor growth rates in the nude mouse SKMEL28 xenograft model. CONCLUSION:Transdermal delivery of melanin-binding rasagiline does not increase melanoma growth in the xenograft model. Because rasagiline decreases melanoma growth, it may be candidate for combination therapy for melanoma.

背景与目标：

BACKGROUND & AIMS: Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common neurodegenerative disorders, although there is no drug or therapeutic treatment to demonstrate disease-modifying effects. Previous work has proposed that neurodegeneration is linked to a lack of trophic support in those neurons and brain areas associated with PD and AD. Indeed, previous studies have found that neurotrophic factors (NTFs) support neuronal survival in various cellular and animal models of PD and AD. Thus, attention has begun to turn to the possibility of NTF neuroprotective-neurorescue therapies for these diseases, indicating that NTFs may be of significant clinical importance as exogenously supplied or endogenously induced elements that obliterate neuronal deficits and degeneration. We have recently reported that the anti-PD drug rasagiline, the anti-AD drug ladostigil, and their propargyl moiety, propargylamine, enhanced the expression levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, endogenous NTFs associated with activation of phosphatidylinositol 3-kinase, protein kinase, and mitogen-activated protein kinase cell signaling/survival pathways. These studies indicate that the induction of NTFs by rasagiline and ladostigil might suppress apoptosis and induce neurorescue in neurodegenerative disorders and may support the drugs' possible disease-modifying mechanism of action.

背景与目标： 帕金森氏病 (PD) 和阿尔茨海默氏病 (AD) 是最常见的神经退行性疾病，尽管没有药物或治疗方法可以证明疾病的改善作用。先前的工作已经提出，神经退行性变与那些与PD和AD相关的神经元和大脑区域缺乏营养支持有关。实际上，先前的研究发现，神经营养因子 (NTFs) 支持各种PD和AD细胞和动物模型中的神经元存活。因此，人们开始将注意力转向针对这些疾病的NTF神经保护神经应答疗法的可能性，这表明NTFs可能作为消除神经元缺陷和变性的外源供应或内源性诱导元素具有重要的临床意义。我们最近报道了抗PD药物雷沙吉兰，抗AD药物ladostigil及其炔丙基部分炔丙胺，增强了脑源性神经营养因子和胶质细胞系源性神经营养因子的表达水平，与磷脂酰肌醇3-激酶，蛋白激酶，和丝裂原活化蛋白激酶细胞信号传导/存活途径。这些研究表明，雷沙吉兰和ladosttigil诱导NTFs可能会抑制神经退行性疾病中的细胞凋亡并诱导神经应答，并可能支持该药物可能的疾病调节作用机制。

BACKGROUND & AIMS: :Rasagiline is a second-generation potent, irreversible and selective inhibitor of monoamine-oxidase type B (MAO-B), which has been evaluated for the treatment of Parkinson's disease. Rasagiline also possesses neuroprotective properties that are independent of its MAO inhibitory activity. Unlike selegiline, rasagiline has no amphetamine-like metabolites and its major metabolite, 1-(R)-aminoindan, has demonstrated favourable pharmacological activity in experimental studies. Rasagiline has shown significant beneficial effects as monotherapy in the treatment of early Parkinson's disease. Monotherapy with rasagiline 1 or 2 mg once daily significantly attenuated the worsening of symptoms, compared with placebo, in patients with early Parkinson's disease in a randomised, double-blind trial (n = 404). Furthermore, patients treated with rasagiline for 12 months had less functional decline than patients whose treatment was delayed for 6 months (n = 371). In patients with moderate-to-advanced disease receiving background therapy with levodopa and additional anti-parkinsonian medications (n = 1159), rasagiline 0.5 or 1 mg once daily reduced the daily 'off' time by 0.49-0.94 hours relative to that in placebo recipients in two randomised, double-blind trials. The efficacy of rasagiline 1 mg once daily was similar to entacapone 200 mg administered with each levodopa dose. Rasagiline was generally well tolerated in clinical trials as both monotherapy and when administered with other antiparkinsonian drugs. Adverse events with rasagiline were generally similar in frequency to those seen in placebo or entacapone recipients.

背景与目标： : 雷沙吉兰是b型单胺氧化酶 (mao-b) 的第二代有效，不可逆和选择性抑制剂，已被评估用于治疗帕金森氏病。雷沙吉兰还具有独立于其MAO抑制活性的神经保护特性。与司来吉兰不同，雷沙吉兰没有苯丙胺样代谢物，其主要代谢物1-(R)-氨基吲哚在实验研究中显示出良好的药理活性。雷沙吉兰作为单一疗法在治疗早期帕金森氏病方面显示出显着的有益效果。在一项随机，双盲试验中，与安慰剂相比，每日一次雷沙吉兰1或2 mg的单药治疗可显着减轻早期帕金森氏病患者的症状恶化 (n = 404)。此外，雷沙吉兰治疗12个月的患者比治疗延迟6个月的患者功能下降更少 (n = 371)。在接受左旋多巴和其他抗帕金森病药物背景治疗的中度至晚期疾病患者 (n = 1159) 中，雷沙吉兰每天0.5或1 mg，相对于安慰剂接受者，每日 “关闭” 时间减少了0.49-0.94小时在两个随机双盲试验中。雷沙吉兰1 mg每日一次的疗效与每次左旋多巴给药的恩他卡200 mg相似。雷沙吉兰在单药治疗和与其他抗帕金森病药物一起使用时，在临床试验中通常耐受性良好。雷沙吉兰的不良事件发生频率通常与安慰剂或恩他卡酮接受者相似。

BACKGROUND & AIMS: BACKGROUND:The LARGO study demonstrated that rasagiline 1 mg/day as adjunct to levodopa significantly reduces OFF time to the same magnitude as adjunct entacapone. This substudy of LARGO aimed to assess the effect of rasagiline and entacapone on the motor symptoms of PD during the practically defined OFF state. METHODS:LARGO was a randomized, double-blind, multicenter trial that assessed the efficacy and safety of rasagiline (1 mg/day), entacapone (200 mg with each levodopa dose), and placebo in 687 levodopa-treated PD patients with motor fluctuations. A substudy of LARGO measured UPDRS motor scores in the practically defined OFF state in 32 rasagiline, 36 entacapone, and 37 placebo patients. RESULTS:Treatment with rasagiline produced a significant improvement over placebo of 5.64 units in UPDRS motor OFF score (P = 0.013 vs. placebo). By contrast, the effect of adjunct entacapone was not significant (P = 0.14 vs. placebo). Whereas rasagiline also showed a trend in reducing the UPDRS-ADL OFF score (P = 0.058 vs. placebo), no such trend was noted for entacapone (P = 0.26 vs. placebo). Retrospective analysis, using the Bonferroni correction, of UPDRS motor subdomains further revealed that rasagiline, but not entacapone, significantly improved bradykinesia (P < 0.001) and showed trends for improvements in facial expression, speech, and axial impairment during OFF time. CONCLUSIONS:This study provides the first objectively measured evidence that adjunct rasagiline 1 mg/day is effective in reducing the severity of motor symptoms in the OFF state. This suggests a continuous effect of rasagiline 1 mg/day throughout the day and night and is consistent with its extended duration of therapeutic action.

背景与目标：