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 (AlCl₃) 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 AlCl₃ -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.

到 2018 年，全球痴呆症患者人数估计将达到 5000 万，并且由于老龄化加剧和人口增长，该人数仍在持续增加。当前干预措施的临床影响仍然不大，因此旨在确定新治疗方法的所有努力都至关重要。此前，我们证明 JM-20（一种二氢吡啶-苯二氮杂卓杂合分子）可以保护记忆过程免受东莨菪碱诱导的胆碱能功能障碍的影响。为了进一步了解 JM-20 对认知能力下降和阿尔茨海默病 (AD) 病理学的治疗潜力，我们在此评估了其对大鼠长期服用氯化铝 (AlCl 3 ) 后的神经保护作用，并评估了几种类型的可能_变化。情景记忆和相关的病理机制。啮齿类动物口服铝会导致一些神经病理学改变和认知障碍，被认为是测试痴呆新疗法疗效的便捷工具。我们使用行为任务来测试空间、情感关联和新物体识别记忆，以及分子、酶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 可以防止记忆力下降，同时抑制 AlCl ₃诱导的氧化应激、增加 AChE 活性、TNF-α 和促凋亡蛋白（如 Bax、caspase-3 和 8）水平。JM-20 还可以防止海马体和前额皮质的神经元损伤。我们的研究结果扩展了我们对 JM-20 在神经毒性条件下保留大鼠记忆能力的理解，并证实了其通过破坏与神经退行性变相关的关键步骤的进展来抵消认知障碍和 AD 病因因素的潜在能力。