Nirogi Ramakrishna, Grandhi Venkata Ramalingayya, Medapati Rajeshbabu, Ganuga Narender, Abraham Renny, Thentu Jagadeesh Babu, Palacharla Veera Raghava Chowdary, Petlu Surendra, Srirangavaram Maheshwari, Subramanian Ramkumar, Ravella Srinivasa Rao, Gagginapally Shankar Reddy, Benade Vijay, Jayarajan Pradeep, Mohammed Abdul Rasheed
Suven Life Sciences, Serene Chambers Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana, 500034, India.
Suven Life Sciences, Serene Chambers Road-5, Avenue-7, Banjara Hills, Hyderabad, Telangana, 500034, India.
Eur J Pharmacol. 2023 May 15;947:175625. doi: 10.1016/j.ejphar.2023.175625. Epub 2023 Mar 28.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder which affects cognitive functions with negative impact on day to day activities and an ultimate loss of independent living. Current standard of care (SOC) for AD, viz. donepezil, rivastigmine, galantamine, memantine etc. either alone or in combination show modest efficacy without changing the course of the disease. On prolonged treatment, side effects are more common with an eventual loss of efficacy. Aducanumab, a monoclonal antibody is a disease modifying therapeutic agent targeting the toxic amyloid beta (Aβ) proteins for its clearance. However, it is found to have only modest efficacy in AD patients and its approval by FDA is controversial. Alternate, effective and safe therapeutics are need of the hour, as AD cases are expected to be doubled by 2050. Recently, 5-HT receptors have been envisioned as target for alleviating AD associated cognitive impairment with potential disease modifying ability impacting disease progression. Usmarapride is a 5-HT receptor partial agonist, being developed for the possible treatment of AD with symptomatic and disease modifying potential. Usmarapride demonstrated promising effects in ameliorating cognitive deficits in diverse animal models of episodic, working, social, and emotional memories. Usmarapride produced elevation in cortical acetylcholine levels in rats. Furthermore, usmarapride increased levels of soluble amyloid precursor protein alpha, a potential mechanism to reverse toxic Aβ peptide pathology. Usmarapride also potentiated the pharmacological effects of donepezil in animal models. To conclude, usmarapride may be a promising intervention for alleviating the cognitive dysfunction in AD patients with disease modifying potential.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，会影响认知功能，对日常活动产生负面影响，并最终导致无法独立生活。目前AD的标准治疗方法（SOC），即多奈哌齐、卡巴拉汀、加兰他敏、美金刚等，单独使用或联合使用时疗效都较为有限，无法改变疾病进程。长期治疗后，副作用更为常见，最终还会失去疗效。阿杜卡单抗是一种单克隆抗体，是一种疾病修饰治疗药物，旨在清除有毒的淀粉样β（Aβ）蛋白。然而，它在AD患者中的疗效仅为中等，其被美国食品药品监督管理局（FDA）批准也存在争议。由于预计到2050年AD病例将翻倍，因此急需替代的、有效且安全的治疗方法。最近，5-羟色胺（5-HT）受体被视为缓解AD相关认知障碍的靶点，具有潜在的疾病修饰能力，可影响疾病进展。乌司马必利是一种5-HT受体部分激动剂，正在开发用于可能治疗AD，具有缓解症状和疾病修饰的潜力。乌司马必利在改善情景记忆、工作记忆、社交记忆和情感记忆的多种动物模型中的认知缺陷方面显示出有前景的效果。乌司马必利使大鼠皮质乙酰胆碱水平升高。此外，乌司马必利增加了可溶性淀粉样前体蛋白α的水平，这是一种逆转有毒Aβ肽病理的潜在机制。乌司马必利还增强了多奈哌齐在动物模型中的药理作用。总之，乌司马必利可能是一种有前景的干预措施，可缓解AD患者的认知功能障碍，并具有疾病修饰潜力。
