Wong-Guerra Maylin, Montano-Peguero Yanay, Ramírez-Sánchez Jeney, Jiménez-Martin Javier, Fonseca-Fonseca Luis Arturo, Hernández-Enseñat Daniela, Nonose Yasmine, Valdés Odalys, Mondelo-Rodriguez Abel, Ortiz-Miranda Yaquelin, Bergado Gretchen, Carmenate Tania, Soto Del Valle Roberto Menéndez, Pardo-Andreu Gilberto, Outeiro Tiago Fleming, Padrón-Yaquis Alejandro Saúl, Martimbianco de Assis Adriano, O Souza Diogo, Nuñez-Figueredo Yanier
Centro de Investigación y Desarrollo de Medicamentos (CIDEM), Ave 26, No.1605, e/Boyeros y Puentes Grandes, CP10600, La Habana, Cuba.
Department of Physiology, Otago School of Medical Sciences, University of Otago, P.O. Box 913, Dunedin, 9016, New Zealand.
Neurotoxicology. 2021 Dec;87:70-85. doi: 10.1016/j.neuro.2021.08.017. Epub 2021 Sep 2.
The number of people with dementia worldwide is estimated at 50 million by 2018 and continues to rise mainly due to increasing aging and population growth. Clinical impact of current interventions remains modest and all efforts aimed at the identification of new therapeutic approaches are therefore critical. Previously, we showed that JM-20, a dihydropyridine-benzodiazepine hybrid molecule, protected memory processes against scopolamine-induced cholinergic dysfunction. In order to gain further insight into the therapeutic potential of JM-20 on cognitive decline and Alzheimer's disease (AD) pathology, here we evaluated its neuroprotective effects after chronic aluminum chloride (AlCl) administration to rats and assessed possible alterations in several types of episodic memory and associated pathological mechanisms. Oral administration of aluminum to rodents recapitulates several neuropathological alterations and cognitive impairment, being considered a convenient tool for testing the efficacy of new therapies for dementia. We used behavioral tasks to test spatial, emotional- associative and novel object recognition memory, as well as molecular, enzymatic and histological assays to evaluate selected biochemical parameters. Our study revealed that JM-20 prevented memory decline alongside the inhibition of AlCl -induced oxidative stress, increased AChE activity, TNF-α and pro-apoptotic proteins (like Bax, caspase-3, and 8) levels. JM-20 also protected against neuronal damage in the hippocampus and prefrontal cortex. Our findings expanded our understanding of the ability of JM-20 to preserve memory in rats under neurotoxic conditions and confirm its potential capacity to counteract cognitive impairment and etiological factors of AD by breaking the progression of key steps associated with neurodegeneration.
据估计，到2018年全球痴呆症患者人数达5000万，且仍在持续上升，主要原因是老龄化加剧和人口增长。目前干预措施的临床效果仍然有限，因此所有旨在确定新治疗方法的努力都至关重要。此前，我们发现二氢吡啶 - 苯二氮䓬杂合分子JM - 20可保护记忆过程免受东莨菪碱诱导的胆碱能功能障碍影响。为了进一步深入了解JM - 20对认知衰退和阿尔茨海默病（AD）病理的治疗潜力，我们在此评估了其在给大鼠长期施用氯化铝（AlCl）后的神经保护作用，并评估了几种情景记忆类型及相关病理机制可能发生的变化。给啮齿动物口服铝可重现多种神经病理改变和认知障碍，被认为是测试痴呆症新疗法疗效的便捷工具。我们使用行为任务来测试空间记忆、情感联想记忆和新物体识别记忆，以及分子、酶学和组织学分析来评估选定的生化参数。我们的研究表明，JM - 20可预防记忆衰退，同时抑制AlCl诱导的氧化应激、增加乙酰胆碱酯酶（AChE）活性、肿瘤坏死因子 -α（TNF -α）和促凋亡蛋白（如Bax、半胱天冬酶 - 3和8）水平。JM - 20还可保护海马体和前额叶皮质免受神经元损伤。我们的研究结果扩展了我们对JM - 20在神经毒性条件下保护大鼠记忆能力的理解，并证实了其通过阻断与神经退行性变相关的关键步骤进展来对抗认知障碍和AD病因的潜在能力。
