Anti-hypertensive drugs that prevent Alzheimer's disease beta-amyloid pathology a

预防阿尔茨海默病β-淀粉样蛋白病理学的抗高血压药物

• 批准号: 7494089
• 负责人: Giulio Maria Pasinetti
• 金额: $ 22.68万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494089
• 关键词: Adrenergic Antagonists; Adverse effects; Age; Age-Months; Alzheimer disease prevention; Alzheimer' s Disease; Amiloride; Amyloid; Angiotensins; Antihypertensive Agents; Apis; Appendix; Attenuated; Biochemical; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Blood Circulation; Blood Pressure; Brain; Calcium Channel Blockers; Cells; Chemicals; Class; Classification; Clinical; Cognition; Cognitive; Collaborations; Conditioned Culture Media; Controlled Study; Deterioration; Development; Diuretics; Dose; Drug Kinetics; Embryo; Exhibits; Experimental Designs; Future; Gender; Generations; Goals; Hippocampus (Brain); Hydrazine; Hydrazines; Hypertension; Hypotension; Impaired cognition; In Vitro; Incidence; Institution; Investigation; Lead; Letters; Libraries; Losartan; Memory; Modeling; Molecular; Molecular Weight; Monitor; Mouse Strains; Mus; Neurons; Nicardipine; Outcome Study; Penetration; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Plasma; Potassium; Preclinical Drug Evaluation; Prevention therapy; Preventive; Principal Investigator; Property; Prophylactic treatment; Propranolol; Pyrimidine; Pyrimidines; Pyrimidinones; Range; Relative (related person); Research Personnel; Role; Scheme; Screening procedure; Series; Surveys; Tg2576; Therapeutic; Therapeutic Studies; Toxic effect; Toxicology; Treatment Efficacy; Treatment Protocols; United States Food and Drug Administration; Vasodilator Agents; Week; Wild Type Mouse; Work; amyloid peptide; attenuation; base; beta amyloid pathology; carvedilol; clinically relevant; design; dosage; extracellular; high throughput screening; hypertension treatment; improved; in vivo; indexing; mouse model; neuropathology; novel; pre-clinical; preclinical study; prescription document; prescription procedure; prevent; receptor; response; valsartan; young adult

DESCRIPTION (provided by applicant): Recent evidence suggests that treatment with certain antihypertensive drugs may decrease the incidence of Alzheimer's disease (AD), while other work has failed to support this finding. We hypothesized that the apparent inconsistency could be due, in part, to unknown pharmacological features exerted by subsets of antihypertensive drugs. Based on this consideration, we initiated a high throughput screening of 55 antihypertensive drugs, which encompass almost all of the prescribed antihypertensive drugs representing all the clinically relevant antihypertensive pharmacological classes available. Excitingly, we identified 7 clinically prescribed antihypertensive drugs that significantly reduce the accumulation of total AD-type ¿-amyloid (A¿) in vitro and, as recently found, also in vivo in response to treatment with propranolol-HCI, nicardipine-HCI, losartan in Tg2576 mice, even when these drugs were delivered in a short term dosing regimen at concentrations ~2-3 folds lower than the recommended dose for hypertension in the absence of hypotensive side effects. Moreover, consistent, in part with a central role of high-molecular-weight (HMW)- soluble oligomeric A¿ species in the development of AD-type cognitive impairment, we found that coincidental with attenuation of memory deterioration, long-term valsartan, another antihypertensive drug with A¿ lowering properties identified in our high-throughput drug screening, significantly reduces ApMo/Api-42 and HMW soluble A¿ oligomeric content in the brain and plasma when delivered at subclinical doses. Finally, in molecular topological studies assessing the structural basis of Ap-lowering activity amongst the originally 55 antihypertensive-A¿ lowering agents screened, allowed us to identify 32 novel molecules that we plan to further characterize as novel Ap-lowering lead compounds. Collectively, the proposed studies in this revised U01 application will allow to continue the preclinical characterization of a select group of seven antihypertensive-A¿ lowering drugs in vivo for the treatment of AD (Aims 1-2) while in molecular topological studies we will continue the refinement of 32 refined A¿ lowering lead compounds as novel AP lowering agents for the treatment of AD.

描述（由适用提供）：最近的证据表明，某些降压药的治疗可能会减少阿尔茨海默氏病（AD）的事件，而其他工作未能支持这一发现。我们假设明显的不一致可能部分归因于降压药子集施加的未知药物特征。基于这一考虑，我们开始对55种降压药进行高吞吐量筛查，该药物涵盖了几乎所有处方的降压药，代表了所有可用的临床相关的抗高血压药物。令人兴奋的是，我们确定了7种临床处方的抗高血压药物，可显着降低体外总体型 - 淀粉样淀粉样淀粉样淀粉样淀粉样蛋白（a。），并且最近发现，在体内响应于propranolol-hci治疗，nicardipine-hci，nicardipine-hci，losartan in tg2576鼠标，即使在TG2576鼠标中均已pressim arded arted arted arted！在没有降压性副作用的情况下，折叠低于建议的高血压剂量。此外，一致，部分与高分子重量（HMW）的核心作用 - 可溶性的寡聚物种在发展AD型认知障碍中的发展中，我们发现，与长期的瓦尔萨坦（Valsartan）相一致的降低记忆力降低，与我们在valsartan的长期降低，与我们的较低的药物相关的较低的药物，并确定了较低的药物，以较低的药物为单位，并在较低的药物中得到了强大的群体，以下是较高的药物。在以亚临床剂量递送时，大脑和血浆中的固体固体含量。最后，在分子拓扑研究中，评估了原始的55种降压剂 - 筛选的降低剂之间降低AP的活性的结构基础，这使我们能够识别出32个新型分子，我们计划进一步将其作为新型AP降低铅化合物。总的来说，在此修订后的U01应用中提出的研究将允许继续对七个降压药的精选组进行临床前表征，以治疗AD（AIMS 1-2），而在分子拓扑研究中，我们将继续进行32种降低的AP降低铅化合物，作为用于AD的新型AP降低剂量。